Repositorio Institucional Académico. Universidad Andrés Bello. Chile :: Examinando por Autor "Cabello-Verrugio, C."

Examinando por Autor "Cabello-Verrugio, C."

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Andrographolide Ameliorates Inflammation and Fibrogenesis and Attenuates Inflammasome Activation in Experimental Non-Alcoholic Steatohepatitis
(Nature Publishing Group, 2017-06) Cabrera, D.; Wree, A.; Povero, D.; Solís, N.; Hernandez, A.; Pizarro, M.; Moshage, H.; Torres, J.; Feldstein, A.E.; Cabello-Verrugio, C.; Brandan, E.; Barrera, F.; Arab, J.P.; Arrese, M.
Therapy for nonalcoholic steatohepatitis (NASH) is limited. Andrographolide (ANDRO), a botanical compound, has a potent anti-inflammatory activity due to its ability to inhibit NF-κB. ANDRO has been also shown to inhibit the NLRP3 inflammasome, a relevant pathway in NASH. Our aim was to evaluate the effects of ANDRO in NASH and its influence on inflammasome activation in this setting. Thus, mice were fed a choline-deficient-Amino-Acid-defined (CDAA) diet with/without concomitant ANDRO administration (1 mg/kg, 3-Times/week). Also, we assessed serum levels of alanine-Aminotransferase (ALT), liver histology, hepatic triglyceride content (HTC) and hepatic expression of pro-inflammatory, pro-fibrotic and inflammasome genes. Inflammasome activation was also evaluated in fat-laden HepG2 cells. Our results showed that ANDRO administration decreased HTC and attenuated hepatic inflammation and fibrosis in CDAA-fed mice. ANDRO treatment determined a strong reduction in hepatic macrophage infiltration and reduced hepatic mRNA levels of both pro-inflammatory and pro-fibrotic genes. In addition, mice treated with ANDRO showed reduced expression of inflammasome genes. Finally, ANDRO inhibited LPS-induced interleukin-1β expression through NF-κB inhibition in fat-laden HepG2 cells and inflammasome disassembly. In conclusion, ANDRO administration reduces inflammation and fibrosis in experimental NASH. Inflammasome modulation by a NF-κB-dependent mechanism may be involved in the therapeutic effects of ANDRO.
Angiotensin-(1-7) attenuates disuse skeletal muscle atrophy in mice via its receptor, Mas
(Universidad Andrés Bello, 2016-04) Morales, M.G.; Abrigo, J.; Acuna, M.J.; Santos, R.A.; Bader, M.; Brandan, E.; Simon, F.; Olguin, H.; Cabrera, D.; Cabello-Verrugio, C.
Immobilization is a form of disuse characterized by a loss of strength and muscle mass. Among the main features are decreased IGF-1/Akt signalling and increased ubiquitin-proteasome pathway signalling, which induce greater myosin heavy chain degradation. Activation of the classical renin-angiotensin system (RAS) causes deleterious effects in skeletal muscle, including muscle wasting. In contrast, angiotensin-(1-7) [Ang-(1-7)], a peptide of the non-classical RAS, produces beneficial effects in skeletal muscle. However, the role of Ang-(1-7) in skeletal muscle disuse atrophy and independent of classical RAS activation has not been evaluated. Therefore, we assessed the functions of Ang-(1-7) and the Mas receptor in disuse muscle atrophy in vivo using unilateral cast immobilization of the hind limb in male, 12-week-old wild-type (WT) and Mas-knockout (Mas KO) mice for 1 and 14 days. Additionally, we evaluated the participation of IGF-1/IGFR-1/Akt signalling and ubiquitin-proteasome pathway expression on the effects of Ang-(1-7) immobilization-induced muscle atrophy. Our results found that Ang-(1-7) prevented decreased muscle strength and reduced myofiber diameter, myosin heavy chain levels, and the induction of atrogin-1 and MuRF-1 expressions, all of which normally occur during immobilization. Analyses indicated that Ang-(1-7) increases IGF-1/IGFR-1/Akt pathway signalling through IGFR-1 and Akt phosphorylation, and the concomitant activation of two downstream targets of Akt, p70S6K and FoxO3. These anti-atrophic effects of Ang-(1-7) were not observed in Mas KO mice, indicating crucial participation of the Mas receptor. This report is the first to propose anti-atrophic effects of Ang-(1-7) via the Mas receptor and the participation of the IGF-1/IGFR-1/Akt/p70S6K/FoxO3 mechanism in disuse skeletal muscle atrophy.
Combined therapies for Duchenne muscular dystrophy to optimize treatment efficacy
(Frontiers Media, 2018-04) Cordova, G.; Negroni, E.; Cabello-Verrugio, C.; Mouly, V.; Trollet, C.
Duchene Muscular Dystrophy (DMD) is the most frequent muscular dystrophy and one of the most severe due to the absence of the dystrophin protein. Typical pathological features include muscle weakness, muscle wasting, degeneration, and inflammation. At advanced stages DMD muscles present exacerbated extracellular matrix and fat accumulation. Recent progress in therapeutic approaches has allowed new strategies to be investigated, including pharmacological, gene-based and cell-based therapies. Gene and cell-based therapies are still limited by poor targeting and low efficiency in fibrotic dystrophic muscle, therefore it is increasingly evident that future treatments will have to include "combined therapies" to reach maximal efficiency. The scope of this mini-review is to provide an overview of the current literature on such combined therapies for DMD. By "combined therapies" we mean those that include both a therapy to correct the genetic defect and an additional one to address one of the secondary pathological features of the disease. In this mini-review, we will not provide a comprehensive view of the literature on therapies for DMD, since many such reviews already exist, but we will focus on the characteristics, efficiency, and potential of such combined therapeutic strategies that have been described so far for DMD. © 2018 Cordova, Negroni, Cabello-Verrugio, Mouly and Trollet.
Gestational hypothyroxinemia affects its offspring with a reduced suppressive capacity impairing the outcome of the experimental autoimmune encephalomyelitis
(Frontiers Media, 2018-06) Haensgen, H.; Albornoz, E.; Opazo, M.C.; Bugueño, K.; Jara Fernández, E.L.; Binzberger, R.; Rivero-Castillo, T.; Venegas Salas, L.F.; Simon, F.; Cabello-Verrugio, C.; Elorza, A.A.; Kalergis, A.M.; Bueno, S.M.; Riedel, C.A.
Hypothyroxinemia (Hpx) is a thyroid hormone deficiency (THD) condition highly frequent during pregnancy, which although asymptomatic for the mother, it can impair the cognitive function of the offspring. Previous studies have shown that maternal hypothyroidism increases the severity of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model for multiple sclerosis (MS). Here, we analyzed the immune response after EAE induction in the adult offspring gestated in Hpx. Mice gestated in Hpx showed an early appearance of EAE symptoms and the increase of all parameters of the disease such as: the pathological score, spinal cord demyelination, and immune cell infiltration in comparison to the adult offspring gestated in euthyroidism. Isolated CD4+CD25+ T cells from spleen of the offspring gestated in Hpx that suffer EAE showed reduced capacity to suppress proliferation of effector T cells (TEff) after being stimulated with anti-CD3 and anti-CD28 antibodies. Moreover, adoptive transfer experiments of CD4+CD25+ T cells from the offspring gestated in Hpx suffering EAE to mice that were induced with EAE showed that the receptor mice suffer more intense EAE pathological score. Even though, no significant differences were detected in the frequency of Treg cells and IL-10 content in the blood, spleen, and brain between mice gestated in Hpx or euthyroidism, T cells CD4+CD25+ from spleen have reduced capacity to differentiate in vitro to Treg and to produce IL-10. Thus, our data support the notion that maternal Hpx can imprint the immune response of the offspring suffering EAE probably due to a reduced capacity to trigger suppression. Such "imprints" on the immune system could contribute to explaining as to why adult offspring gestated in Hpx suffer earlier and more intense EAE. © 2018 Haensgen, Albornoz, Opazo, Bugueño, Jara Fernández, Binzberger, Rivero-Castillo, Venegas Salas, Simon, Cabello-Verrugio, Elorza, Kalergis, Bueno and Riedel.
Impact of exercise training on the sarcopenia criteria in non-alcoholic fatty liver disease: A systematic review and meta-analysis
(Page Press Publications, 2021-03) Gonzalez, A.; Valero-Breton, M.; Huerta-Salgado, C.; Achiardi, O.; Simon, F.; Cabello-Verrugio, C.
Sarcopenia is a highly prevalent complication of non-alcoholic fatty liver disease (NAFLD). We aimed to conduct a systematic review and meta-analyses to elucidate the exercise training (ET)'s efficacy on NAFLD adult patients' sarcopenia criteria. We identified relevant randomized controlled trials (RCT) in electronic databases PubMed, CINAHL, and Scopus. We selected seven RCT from 66 screened studies. The ET programs included endurance or combined (endurance and resistance) training. No study performed resistance training alone. The physical function improved with endurance or combined training (mean differences [MD] 8.26 mL/Kg*min [95% CI 5.27 to 11.24 mL/Kg*min], p < 0.0001); Muscle mass showed no evidence of the beneficial effects of endurance or combined training (MD 1.01 Kg [95% CI -1.78 to 3.80 Kg], p = 0.48). None of the selected studies evaluated muscle strength. Endurance and combined training increase physical function criteria but do not improve muscle mass criteria on sarcopenia in NAFLD patients. These results must be interpreted with caution for the small number of patients included in the RCTs analyzed, the different characteristics of the ET carried out, the non-use of resistance training, which prevents assess its effect on sarcopenia despite the evidence that recommends it and does not assessment muscle strength criteria in RCT include. Future research should include muscle strength assessments and resistance training to evaluate the effects in this condition. Exercise training is beneficial for sarcopenia in NAFLD but is necessary more experimental evidence to define the best type of training that positively affects the three criteria of sarcopenia. PROSPERO reference number CRD42020191471. © 2021 PAGEPress Publications. All rights reserved.
Lipopolysaccharide induces a fibrotic-like phenotype in endothelial cells
(Wiley Open Access, 2013-06) Echeverría, C.; Montorfano, I.; Sarmiento, D.; Becerra, A.; Nuñez-Villena, F.; Figueroa, X.; Cabello-Verrugio, C.; Elorza, A.; Riedel, C.; Simon, F.
Endothelial dysfunction is crucial in endotoxaemia-derived sepsis syndrome pathogenesis. It is well accepted that lipopolysaccharide (LPS) induces endothelial dysfunction through immune system activation. However, LPS can also directly generate actions in endothelial cells (ECs) in the absence of participation by immune cells. Although interactions between LPS and ECs evoke endothelial death, a significant portion of ECs are resistant to LPS challenge. However, the mechanism that confers endothelial resistance to LPS is not known. LPS-resistant ECs exhibit a fibroblast-like morphology, suggesting that these ECs enter a fibrotic programme in response to LPS. Thus, our aim was to investigate whether LPS is able to induce endothelial fibrosis in the absence of immune cells and explore the underlying mechanism. Using primary cultures of ECs and culturing intact blood vessels, we demonstrated that LPS is a crucial factor to induce endothelial fibrosis. We demonstrated that LPS was able and sufficient to promote endothelial fibrosis, in the absence of immune cells through an activin receptor-like kinase 5 (ALK5) activity-dependent mechanism. LPS-challenged ECs showed an up-regulation of both fibroblast-specific protein expression and extracellular matrix proteins secretion, as well as a down-regulation of endothelial markers. These results demonstrate that LPS is a crucial factor in inducing endothelial fibrosis in the absence of immune cells through an ALK5-dependent mechanism. It is noteworthy that LPS-induced endothelial fibrosis perpetuates endothelial dysfunction as a maladaptive process rather than a survival mechanism for protection against LPS. These findings are useful in improving current treatment against endotoxaemia-derived sepsis syndrome and other inflammatory diseases.
Oxidative stress in disease and aging: Mechanisms and therapies 2018
(Hindawi Limited, 2018) Cabello-Verrugio, C.; Vilos, C.; Rodrigues-Diez, R.; Estrada, L.
Procoagulant phenotype induced by oxidized high-density lipoprotein associates with acute kidney injury and death
(Elsevier, 2023-03) Prado, Y.; Pérez, L.; Eltit, F.; Echeverría, C.; Llancalahuen, F.; Tapia, P.; González, P.; Kalergis, A.; Cabello-Verrugio, C.
Background Oxidative stress derived from severe systemic inflammation promotes conversion from high-density lipoprotein HDL to oxidized HDL (oxHDL), which interacts with vascular endothelial cells (ECs). OxHDL acquires procoagulant features playing a role in modulating coagulation, which has been linked with organ failure in ICU patients. However, whether oxHDL elicits a ECs-mediated procoagulant phenotype generating organ failure and death, and the underlying molecular mechanism is not known. Therefore, we studied whether oxHDL-treated rats and high-oxHDL ICU patients exhibit a procoagulant phenotype and its association with kidney injury and mortality and the endothelial underlying molecular mechanism. Methods Human ECs, oxHDL-treated rats and ICU patients were subjected to several cellular and molecular studies, coagulation analyses, kidney injury assessment and mortality determination. Results OxHDL-treated ECs showed a procoagulant protein expression reprograming characterized by increased E-/P-selectin and vWF mRNA expression through specific signaling pathways. OxHDL-treated rats exhibited a procoagulant phenotype and modified E-/P-selectin, vWF, TF and t-PA mRNA expression correlating with plasma TF, t-PA and D-dimer. Also, showed increased death events and the relative risk of death, and increased creatinine, urea, BUN/creatinine ratio, KIM-1, NGAL, β2M, and decreased eGFR, all concordant with kidney injury, correlated with plasma TF, t-PA and D-dimer. ICU patients showed correlation between plasma oxHDL and increased creatinine, cystatin, BUN, BUN/creatinine ratio, KIM-1, NGAL, β2M, and decreased GFR. Notably, ICU high-oxHDL patients showed decreased survival. Interestingly, altered coagulation factors TF, t-PA and D-dimer correlated with both increased oxHDL levels and kidney injury markers, indicating a connection between these factors. Conclusion Increased circulating oxHDL generates an endothelial-dependent procoagulant phenotype that associates with acute kidney injury and increased risk of death.
Protective effect of angiotensin 1–7 on sarcopenia induced by chronic liver disease in mice
(MDPI AG, 2020-04) Aguirre, F.; Abrigo, J.; Gonzalez, F.; Gonzalez, A.; Simon, F.; Cabello-Verrugio, C.
Sarcopenia associated with chronic liver disease (CLD) is one of the more common extrahepatic features in patients with these pathologies. Among the cellular alterations observed in the muscle tissue under CLD is the decline in the muscle strength and function, as well as the increased fatigue. Morphological changes, such as a decrease in the fiber diameter and transition in the fiber type, are also reported. At the molecular level, sarcopenia for CLD is characterized by: (i) a decrease in the sarcomeric protein, such as myosin heavy chain (MHC); (ii) an increase in the ubiquitin–proteasome system markers, such as atrogin-1/MAFbx1 and MuRF-1/TRIM63; (iii) an increase in autophagy markers, such as LC3II/LC3I ratio. Among the regulators of muscle mass is the renin-angiotensin system (RAS). The non-classical axis of RAS includes the Angiotensin 1–7 [Ang-(1-7)] peptide and its receptor Mas, which in skeletal muscle has anti-atrophic effect in models of muscle wasting induced by immobilization, lipopolysaccharide, myostatin or angiotensin II. In this paper, we evaluated the effect of Ang-(1-7) on the sarcopenia by CLD in a murine model induced by the 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) hepatotoxin administered through diet. Our results show that Ang-(1-7) administration prevented the decline of the function and strength of muscle and increased the fatigue detected in the DDC-fed mice. Besides, we observed that the decreased fiber diameter and MHC levels, as well as the transition of fiber types, were all abolished by Ang-(1-7) in mice fed with DDC. Finally, Ang-(1-7) can decrease the atrogin-1 and MuRF-1 expression as well as the autophagy marker in mice treated with DDC. Together, our data support the protective role of Ang-(1-7) on the sarcopenia by CLD in mice. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Role of Oxidative Stress in Hepatic and Extrahepatic Dysfunctions during Nonalcoholic Fatty Liver Disease (NAFLD)
(Hindawi, 2020) Gonzalez, A.; Huerta-Salgado, C.; Orozco-Aguilar, J.; Aguirre, F.; Tacchi, F.; Simon, F.; Cabello-Verrugio, C.
Nonalcoholic fatty liver disease (NAFLD) is a pathology that contains a broad liver dysfunctions spectrum. These alterations span from noninflammatory isolated steatosis until nonalcoholic steatohepatitis (NASH), a more aggressive form of the disease characterized by steatosis, inflammatory status, and varying liver degrees fibrosis. NAFLD is the most prevalent chronic liver disease worldwide. The causes of NAFLD are diverse and include genetic and environmental factors. The presence of NASH is strongly associated with cirrhosis development and hepatocellular carcinoma, two conditions that require liver transplantation. The liver alterations during NAFLD are well described. Interestingly, this pathological condition also affects other critical tissues and organs, such as skeletal muscle and even the cardiovascular, renal, and nervous systems. Oxidative stress (OS) is a harmful state present in several chronic diseases, such as NAFLD. The purpose of this review is to describe hepatic and extrahepatic dysfunctions in NAFLD. We will also review the influence of OS on the physiopathological events that affect the critical function of the liver and peripheral tissues.
Somatotropic axis dysfunction in non-alcoholic fatty liver disease: Beneficial hepatic and systemic effects of hormone supplementation
(MDPI AG, 2018-05) Cabrera, D.; Cabello-Verrugio, C.; Solís, N.; Martín, D.S.; Cofré, C.; Pizarro, M.; Arab, J.P.; Abrigo, J.; Campos, F.; Irigoyen, B.; Carrasco-Avino, G.; Bezares, K.; Riquelme, V.; Riquelme, A.; Arrese, M.; Barrera, F.
Background: Somatotropic axis dysfunction associated with non-alcoholic fatty liver disease (NAFLD) has potential multisystemic detrimental effects. Here, we analysed the effects of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) supplementation on liver histology, adipokine profile and muscle function in an NAFLD model. Methods: C57BL/6 mice were fed with a high fat diet (HFD) for 12 weeks and were separated into three groups treated for 4 weeks with: (1) High fat diet (HFD) (n = 10); (2) HFD + GH 9 μg/g/d (n = 10); (3) HFD + IGF-1 0.02 μg/g/d (n = 9). A control group fed a chow diet was included (n = 6). Liver histology, liver triglycerides content, serum alanine aminotransferase (ALT) activity, adiponectin and leptin serum levels, in vivo muscle strength, tetanic force and muscle fibre cross-sectional area (CSA) were measured. Results: HFD + GH and HFD + IGF-1 groups showed significantly lower ALT activity compared to HFD (p < 0.01). Liver triglyceride content in HFD + GH was decreased compared to HFD (p < 0.01). Histologic steatosis score was increased in HFD and HFD + GH group (p < 0.01), whereas HFD + IGF-1 presented no difference compared to the chow group (p = 0.3). HFD + GH group presented lower serum leptin and adiponectin levels compared to HFD. GH and IGF-1 supplementation therapy reverted HFD-induced reduction in muscle strength and CSA (sarcopenia). Conclusions: GH and IGF-1 supplementation induced significant improvement in liver steatosis, aminotransferases and sarcopenia in a diet-induced NAFLD model. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.
The complex of PAMAM-OH dendrimer with Angiotensin (1–7) prevented the disuse-induced skeletal muscle atrophy in mice
(Dove Medical Press Ltd., 2017-03) Márquez-Miranda, V.; Abrigo, J.; Rivera, J.C.; Araya-Durán, I.; Aravena, J.; Simon, F.; Pacheco, N.; González-Nilo, F.D.; Cabello-Verrugio, C.
Angiotensin (1–7) (Ang-(1–7)) is a bioactive heptapeptide with a short half-life and has beneficial effects in several tissues – among them, skeletal muscle – by preventing muscle atrophy. Dendrimers are promising vehicles for the protection and transport of numerous bioactive molecules. This work explored the use of a neutral, non-cytotoxic hydroxyl-terminated poly(amidoamine) (PAMAM-OH) dendrimer as an Ang-(1–7) carrier. Bioinformatics analysis showed that the Ang-(1–7)-binding capacity of the dendrimer presented a 2:1 molar ratio. Molecular dynamics simulation analysis revealed the capacity of neutral PAMAM-OH to protect Ang-(1–7) and form stable complexes. The peptide coverage ability of the dendrimer was between ~50% and 65%. Furthermore, an electrophoretic mobility shift assay demonstrated that neutral PAMAM-OH effectively bonded peptides. Experimental results showed that the Ang-(1–7)/PAMAM-OH complex, but not Ang-(1–7) alone, had an anti-atrophic effect when administered intraperitoneally, as evaluated by muscle strength, fiber diameter, myofibrillar protein levels, and atrogin-1 and MuRF-1 expressions. The results of the Ang-(1–7)/PAMAM-OH complex being intraperitoneally injected were similar to the results obtained when Ang-(1–7) was systemically administered through mini-osmotic pumps. Together, the results suggest that Ang-(1–7) can be protected for PAMAM-OH when this complex is intraperitoneally injected. Therefore, the Ang-(1–7)/PAMAM-OH complex is an efficient delivery method for Ang-(1–7), since it improves the anti-atrophic activity of this peptide in skeletal muscle.

Examinando por Autor "Cabello-Verrugio, C."

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