RESUMEN
Purinergic signaling has emerged as an important paracrine-autocrine intercellular system that regulates physiological and pathological processes in practically all organs of the body. Although this system has been thoroughly defined since the nineties, recent research has made substantial advances regarding its role in aspects of liver physiology. However, most studies have mainly targeted the entire organ, 70% of which is made up of parenchymal cells or hepatocytes. Because of its physiological role, the liver is exposed to toxic metabolites, such as xenobiotics, drugs, and fatty acids, as well as to pathogens such as viruses and bacteria. Under injury conditions, all cell types within the liver undergo adaptive changes. In this context, the concentration of extracellular ATP has the potential to increase dramatically. Indeed, this purinergic response has not been studied in sufficient detail in non-parenchymal liver cells. In the present review, we systematize the physiopathological adaptations related to the purinergic system in chronic liver diseases of non-parenchymal liver cells, such as hepatic stellate cells, Kupffer cells, sinusoidal endothelial cells, and cholangiocytes. The role played by non-parenchymal liver cells in these circumstances will undoubtedly be strategic in understanding the regenerative activities that support the viability of this organ under stressful conditions.
Asunto(s)
Hígado , Receptores Purinérgicos , Transducción de Señal , Humanos , Animales , Hígado/metabolismo , Receptores Purinérgicos/metabolismo , Macrófagos del Hígado/metabolismo , Células Estrelladas Hepáticas/metabolismo , Adenosina Trifosfato/metabolismo , Hepatopatías/metabolismo , Hepatopatías/patología , Hepatocitos/metabolismoRESUMEN
Background: Iron overload is frequent in patients with chronic liver disease, associated with shorter survival after liver transplantation in patients with hereditary hemochromatosis. Its effect on patients without hereditary hemochromatosis is unclear. The aim of the study was to study the clinical impact of iron overload in patients who underwent liver transplantation at an academic tertiary referral center. Methods: We performed a retrospective cohort study including all patients without hereditary hemochromatosis who underwent liver transplantation from 2015 to 2017 at an academic tertiary referral center in Mexico City. Explant liver biopsies were reprocessed to obtain the histochemical hepatic iron index, considering a score ≥ 0.15 as iron overload. Baseline characteristics were compared between patients with and without iron overload. Survival was estimated using the Kaplan-Meier method, compared with the log-rank test and the Cox proportional hazards model. Results: Of 105 patients included, 45% had iron overload. Viral and metabolic etiologies, alcohol consumption, and obesity were more frequent in patients with iron overload than in those without iron overload (43% vs. 21%, 32% vs. 22%, p = 0.011; 34% vs. 9%, p = 0.001; and 32% vs. 12%, p = 0.013, respectively). Eight patients died within 90 days after liver transplantation (one with iron overload). Complication rate was higher in patients with iron overload versus those without iron overload (223 vs. 93 events/100 personmonths; median time to any complication of 2 vs. 3 days, p = 0.043), without differences in complication type. Fatality rate was lower in patients with iron overload versus those without iron overload (0.7 vs. 4.5 deaths/100 person-months, p = 0.055). Conclusion: Detecting iron overload might identify patients at risk of early complications after liver transplantation. Further studies are required to understand the role of iron overload in survival.
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Hemocromatosis , Sobrecarga de Hierro , Hepatopatías , Trasplante de Hígado , Humanos , Trasplante de Hígado/efectos adversos , Hemocromatosis/complicaciones , Hemocromatosis/epidemiología , Hemocromatosis/patología , Estudios Retrospectivos , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/complicaciones , Hepatopatías/complicaciones , Hepatopatías/metabolismo , Hepatopatías/patología , Hígado/metabolismoRESUMEN
Redox imbalance leads to oxidative stress that causes irreversible cellular damage. The incorporation of the antioxidant element selenium (Se) in the structure of pyridinium salts has been used as a strategy in chemical synthesis and can be useful in drug development. We investigated the antioxidant activity of Se-containing pyridinium salts (named Compounds 3A, 3B, and 3C) through in vitro tests. We focused our study on liver protein carbonylation, liver lipoperoxidation, free radical scavenging activity (1,1-diphenyl-2-picryl-hydrazil [DPPH]; 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid [ABTS]), and enzyme-mimetic activity assays (glutathione S-transferase [GST]-like; superoxide dismutase [SOD]-like). In addition, 2-(4-chlorophenyl)-2-oxoethyl)-2-((phenylselanyl)methyl)pyridin-1-ium bromide (3C) was selected to evaluate the acute oral toxicity in mice due to the best antioxidant profile. The three compounds were effective in reducing the levels of protein carbonylation and lipoperoxidation in the liver in a µM concentration range. All compounds demonstrated scavenger activity of DPPH and ABTS radicals, and GST-like action. No significant effects were detected in the SOD-like assay. Experimental data also showed that the acute oral treatment of mice with Compound 3C (50 and 300 mg/kg) did not cause mortality or change markers of liver and kidney functions. In summary, our findings reveal the antioxidant potential of Se-containing pyridinium salts in liver tissue, which could be related to their radical scavenging ability and mimetic action on the GST enzyme. They also demonstrate a low toxicity potential for Compound 3C. Together, the promising results open space for future studies on the therapeutic application of these molecules.
Asunto(s)
Benzotiazoles , Compuestos de Bifenilo , Hepatopatías , Selenio , Ácidos Sulfónicos , Ratones , Animales , Antioxidantes/metabolismo , Selenio/farmacología , Sales (Química)/farmacología , Sales (Química)/metabolismo , Estrés Oxidativo , Hepatopatías/metabolismo , Superóxido Dismutasa/metabolismo , Hígado/metabolismo , Preparaciones Farmacéuticas/metabolismoRESUMEN
The complex interplay between dietary factors, inflammation, and macrophage polarization is pivotal in the pathogenesis and progression of chronic liver diseases (CLDs). Omega-3 fatty acids (FAs) have brought in attention due to their potential to modulate inflammation and exert protective effects in various pathological conditions. Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown promise in mitigating inflammation and enhancing the resolution of inflammatory responses. They influence the M1/M2 macrophage phenotype balance, promoting a shift towards the M2 anti-inflammatory phenotype. Specialized pro-resolving mediators (SPMs), such as resolvins (Rvs), protectins (PDs), and maresins (MaRs), have emerged as potent regulators of inflammation and macrophage polarization. They show anti-inflammatory and pro-resolving properties, by modulating the expression of cytokines, facilitate the phagocytosis of apoptotic cells, and promote tissue repair. MaR1, in particular, has demonstrated significant hepatoprotective effects by promoting M2 macrophage polarization, reducing oxidative stress, and inhibiting key inflammatory pathways such as NF-κB. In the context of CLDs, such as nonalcoholic fatty liver disease (NAFLD) and cirrhosis, omega-3s and their SPMs have shown promise in attenuating liver injury, promoting tissue regeneration, and modulating macrophage phenotypes. The aim of this article was to analyze the emerging role of omega-3 FAs and their SPMs in the context of macrophage polarization, with special interest in the mechanisms underlying their effects and their interactions with other cell types within the liver microenvironment, focused on CLDs and the development of novel therapeutic strategies.
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Ácidos Grasos Omega-3 , Hepatopatías , Humanos , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-3/metabolismo , Macrófagos/metabolismo , Inflamación/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Antiinflamatorios/uso terapéutico , Hepatopatías/metabolismo , Fenotipo , Mediadores de Inflamación/metabolismoRESUMEN
Chronic liver diseases are a group of pathologies affecting the liver with high prevalence worldwide. Among them, cholestatic chronic liver diseases (CCLD) are characterized by alterations in liver function and increased plasma bile acids. Secondary to liver disease, under cholestasis, is developed sarcopenia, a skeletal muscle dysfunction with decreased muscle mass, strength, and physical function. CCL5/RANTES is a chemokine involved in the immune and inflammatory response. Indeed, CCL5 is a myokine because it is produced by skeletal muscle. Several studies show that bile acids induce CCL5/RANTES expression in liver cells. However, it is unknown if the expression of CCL5/RANTES is changed in the skeletal muscle of mice with cholestatic liver disease. We used a murine model of cholestasis-induced sarcopenia by intake of hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC diet), in which we detected the mRNA levels for ccl5. We determined that mice fed the DDC diet presented high levels of serum bile acids and developed typical features of sarcopenia. Under these conditions, we detected the ccl5 gene expression in diaphragm muscle showing elevated mRNA levels compared to mice fed with a standard diet (chow diet). Our results collectively suggest an increased ccl5 gene expression in the diaphragm muscle concomitantly with elevated serum bile acids and the development of sarcopenia.
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Colestasis , Hepatopatías , Sarcopenia , Ratones , Animales , Sarcopenia/patología , Diafragma/metabolismo , Diafragma/patología , Regulación hacia Arriba , Quimiocina CCL5/metabolismo , Colestasis/complicaciones , Colestasis/metabolismo , Colestasis/patología , Hígado/metabolismo , Ácidos y Sales Biliares , Hepatopatías/metabolismo , Expresión Génica , Ratones Endogámicos C57BLRESUMEN
Microcystins (MC) are hepatotoxic for organisms. Liver MC accumulation and structural change are intensely studied, but the functional hepatic enzymes and energy metabolism have received little attention. This study investigated the liver and hepatocyte structures and the activity of key hepatic functional enzymes with emphasis on energetic metabolism changes after subchronic fish exposure to cyanobacterial crude extract (CE) containing MC. The Neotropical erythrinid fish, Hoplias malabaricus, were exposed intraperitoneally to CE containing 100 µg MC-LR eq kg-1 for 30 days and, thereafter, the plasma, liver, and white muscle was sampled for analyses. Liver tissue lost cellular structure organization showing round hepatocytes, hyperemia, and biliary duct obstruction. At the ultrastructural level, the mitochondria and the endoplasmic reticulum exhibited disorganization. Direct and total bilirubin increased in plasma. In the liver, the activity of acid phosphatase (ACP) increased, and the aspartate aminotransferase (AST) decreased; AST increased in plasma. Alkaline phosphatase (ALP) and alanine aminotransferase (ALT) were unchanged in the liver, muscle, and plasma. Glycogen stores and the energetic metabolites as glucose, lactate, and pyruvate decrease in the liver; pyruvate decreased in plasma and lactate decreased in muscle. Ammonia levels increased and protein concentration decreased in plasma. CE alters liver morphology by causing hepatocyte intracellular disorder, obstructive cholestasis, and dysfunction in the activity of key liver enzymes. The increasing energy demand implies glucose mobilization and metabolic adjustments maintaining protein preservation and lipid recruitment to supply the needs for detoxification allowing fish survival.
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Characiformes , Cianobacterias , Hepatopatías , Fosfatasa Ácida/metabolismo , Alanina Transaminasa/metabolismo , Fosfatasa Alcalina/metabolismo , Amoníaco , Animales , Aspartato Aminotransferasas/metabolismo , Bilirrubina/metabolismo , Mezclas Complejas/metabolismo , Mezclas Complejas/toxicidad , Cianobacterias/metabolismo , Glucosa/metabolismo , Glucógeno/metabolismo , Lactatos , Lípidos , Hígado/metabolismo , Hepatopatías/metabolismo , Microcistinas/metabolismo , Microcistinas/toxicidad , Piruvatos/metabolismoRESUMEN
During liver fibrogenesis, there is an imbalance between regeneration and wound healing. The current treatment is the withdrawal of the causing agent; thus, investigation of new and effective treatments is important. Studies have highlighted the action of chondroitin sulfate (CS) in different cells; thus, our aim was to analyze its effect on an experimental model of bile duct ligation (BDL). Adult Wistar rats were subjected to BDL and treated with CS for 7, 14, 21, or 28 days intraperitoneally. We performed histomorphometric analyses on Picrosirius-stained liver sections. Cell death was analyzed according to caspase-3 and cathepsin B activity and using a TUNEL assay. Regeneration was evaluated using PCNA immunohistochemistry. BDL led to increased collagen content with corresponding decreased liver parenchyma. CS treatment reduced total collagen and increased parenchyma content after 21 and 28 days. The treatment also promoted changes in the hepatic collagen type III/I ratio. Furthermore, it was observed that CS treatment reduced caspase-3 activity and the percentage of TUNEL-positive cells after 14 days and cathepsin B activity only after 28 days. The regeneration increased after 14, 21, and 28 days of CS treatment. In conclusion, our study showed a promising hepatoprotective action of CS in fibrogenesis induced by BDL.
Asunto(s)
Colestasis/complicaciones , Sulfatos de Condroitina/farmacología , Conducto Colédoco/cirugía , Hepatopatías/tratamiento farmacológico , Animales , Hepatopatías/etiología , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , Sustancias Protectoras/farmacología , Ratas , Ratas WistarRESUMEN
In addition to the kidneys and lungs, the liver also plays an important role in the regulation of the Acid-Base Equilibrium (ABE). The involvement of the liver in the regulation of ABE is crucial because of its role in lactic acid metabolism, urea production and in protein homeostasis. The main acid-base imbalance that occurs in patients with liver cirrhosis is Respiratory Alkalosis (RAlk). Due to the fact that in these patients additional pathophysiological mechanisms that affect the ABE are present, other disorders may appear which compensate or enhance the primary disorder. Conventional ABE reading models fail to identify and assess the underlying disorders in patients with liver cirrhosis. This weakness of the classical models led to the creation of new physicochemical mathematical models that take into account all the known parameters that develop and affect the ABE. In addition to the RAlk, in patients with liver cirrhosis, metabolic alkalosis (due to hypoalbuminemia), hyponatremic metabolic acidosis, hyperchloremic metabolic acidosis, lactic acidosis and metabolic alkalosis due to urea metabolism are some of the pathophysiological mechanisms that affect the ABE.
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Acidosis , Alcalosis , Hepatopatías , Acidosis/etiología , Acidosis/metabolismo , Alcalosis/complicaciones , Alcalosis/metabolismo , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Hepatopatías/metabolismo , UreaRESUMEN
In recent years, the beneficial effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) intake on human health has been widely accepted in the field of immunonutrition. Today, we find a diversity of supplements based on n-3 PUFAs and/or minerals, vitamins and other substances. The main objective of this review is to discuss the importance of n-3 PUFAs and their derivatives on immunity and inflammatory status related to liver disease and other non-communicable illnesses. Based on the burden of liver diseases in 2019, more than two million people die from liver pathologies per year worldwide, because it is the organ most exposed to agents such as viruses, toxins and medications. Consequently, research conducted on n-3 PUFAs for liver disease has been gaining prominence with encouraging results, given that these fatty acids have anti-inflammatory and cytoprotective effects. In addition, it has been described that n-3 PUFAs are converted into a novel species of lipid intermediaries, specialized pro-resolving mediators (SPMs). At specific levels, SPMs improve the termination of inflammation as well as the repairing and regeneration of tissues, but they are deregulated in liver disease. Since evidence is still insufficient to carry out pharmacological trials to benefit the resolution of acute inflammation in non-communicable diseases, there remains a call for continuing preclinical and clinical research to better understand SPM actions and outcomes.
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Ácidos Grasos Omega-3/metabolismo , Sistema Inmunológico/metabolismo , Hepatopatías/metabolismo , Hepatopatías/patología , Enfermedades no Transmisibles , Fenómenos Fisiológicos de la Nutrición , Animales , Humanos , Estado NutricionalRESUMEN
Glycine betaine (N, N, N-trimethyl amine) is an osmolyte accumulated in cells that is key for cell volume and turgor regulation, is the principal methyl donor in the methionine cycle and is a DNA and proteins stabilizer. In humans, glycine betaine is synthesized from choline and can be obtained from some foods. Glycine betaine (GB) roles are illustrated in chemical, metabolic, agriculture, and clinical medical studies due to its chemical and physiological properties. Several studies have extensively described GB role and accumulation related to specific pathologies, focusing mainly on analyzing its positive and negative role in these pathologies. However, it is necessary to explain the relationship between glycine betaine and different pathologies concerning its role as an antioxidant, ability to methylate DNA, interact with transcription factors and cell receptors, and participate in the control of homocysteine concentration in liver, kidney and brain. This review summarizes the most important findings and integrates GB role in neurodegenerative, cardiovascular, hepatic, and renal diseases. Furthermore, we discuss GB impact on other dysfunctions as inflammation, oxidative stress, and glucose metabolism, to understand their cross-talks and provide reliable data to establish a base for further investigations.
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Betaína/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Renales/metabolismo , Hepatopatías/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Tamaño de la Célula , Humanos , Hiperhomocisteinemia/metabolismo , Concentración Osmolar , S-Adenosilmetionina/metabolismoRESUMEN
Alternative splicing produces complex and dynamic changes in the protein isoforms that are necessary for the proper biological functioning of the metabolic pathways involved in liver development and hepatocyte homeostasis. Changes in the physiological state of alternatively spliced forms are increasingly linked to liver pathologies. This may occur when the expression or function of the set of proteins controlling the alternative splicing processes are altered by external effectors such as oxidative stress and other environmental variations. Studies addressing these modifications reveal a complex interplay between the expression levels of different proteins that regulate the alternative splicing process as well as the changes in alternative splicing. This interplay results in a cascade of different protein isoforms that correlate with the progression of non-alcoholic fatty liver disease, hepatocellular carcinoma, and alcoholic liver disease. However, research on the detailed molecular mechanism underlying the production of these isoforms is needed. It is imperative to identify the physiological processes affected by the differentially spliced isoforms and confirm their role on the onset and maintenance of the pathology. This is required to design potential therapeutic approaches targeting the key splicing changes to revert the pathological condition as well as identify prognostic markers. In this review, we describe the complexity of the splicing process through an example to encourage researchers to go down this path. Subsequently, rather than a catalog of splicing events we have hand-picked and discuss a few selected studies of specific liver pathologies and suggested ways to focus research on these areas.
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Empalme Alternativo/genética , Perfilación de la Expresión Génica/métodos , Hepatopatías/genética , ARN Mensajero/genética , Humanos , Hepatopatías/metabolismoRESUMEN
Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs' critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.
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Hepatopatías/tratamiento farmacológico , Hepatopatías/patología , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Animales , Humanos , Hepatopatías/metabolismo , Terapia Molecular DirigidaRESUMEN
Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1-/- mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.
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Hepatocitos/metabolismo , Hígado/metabolismo , Enfermedad de Niemann-Pick Tipo C/metabolismo , Proteoma/metabolismo , Animales , Western Blotting , Células Cultivadas , Hígado/patología , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , RatonesRESUMEN
OBJECTIVE: To describe the metabolic and nutritional repercussions of chronic liver disease (CLD), proposing strategies that optimize nutritional therapy in the pre- and post-liver transplantation (LT) period, in order to promote favorable clinical outcomes and adequate growth and development, respectively. DATA SOURCES: Bibliographic search in the PubMed, Lilacs and SciELO databases of the last 12 years, in English and Portuguese; target population: children from early childhood to adolescence; keywords in Portuguese and their correlates in English: "Liver Transplant," "Biliary Atresia," "Nutrition Therapy," "Nutritional Status," and "Child"; in addition to Boolean logics "and" and "or," and the manual search of articles. DATA SYNTHESIS: Malnutrition in children with CLD is a very common condition and an important risk factor for morbidity and mortality. There is an increase in energy and protein demand, as well as difficulties in the absorption of carbohydrates, lipids and micronutrients such as fat-soluble vitamins and some minerals. An increase in the supply of energy, carbohydrates and proteins and micronutrients, especially fat-soluble vitamins, iron, zinc and calcium, is suggested, except in cases of hepatic encephalopathy (this restriction is indicated for a short period). CONCLUSIONS: Based on metabolic changes and anthropometric and body composition monitoring, a treatment plan should be developed, following the nutritional recommendations available, in order to minimize the negative impact of malnutrition on clinical outcomes during and after LT.
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Atresia Biliar/dietoterapia , Ingestión de Energía , Hepatopatías/dietoterapia , Atresia Biliar/metabolismo , Niño , Femenino , Humanos , Hepatopatías/metabolismo , Masculino , Desnutrición/prevención & control , Evaluación Nutricional , Estado NutricionalRESUMEN
BACKGROUND: Malnutrition induced by dietary restriction produces several metabolic changes that affect body weight, the digestive system, and annex organs, including the liver. Malnutrition generates an inflammatory state and increases oxidative stress. The liver is one of the body vital organs, becoming necessary to analyze the impact of food supplementation on the repair of possible changes that may occur in this organ due to malnutrition. AIMS: To evaluate the effects of a low-cost supplementation derived from Buriti and dairy byproducts on liver recovery in malnourished mice, focusing on the expression of oxidative stressrelated genes, as well as biochemical and histological parameters. METHODS: Swiss mice were divided into six groups and submitted to two treatment phases: food restriction, for malnutrition onset; and renutrition, with mice being fed with different diets. RESULTS: Our results indicate that dietary supplementation was successful in recovering liver damage caused by malnutrition in animal models. The new supplement has been shown to recover liver damage with similar or superior results compared to the commercial reference supplement on the market. CONCLUSION: Our work presents a new composition of low cost food supplement based on buriti and dairy by-products, proven to be effective in the malnutrition treatment of malnutrition. The improvements were proven through the recovery of body weight, reduction of inflammation and oxidative stress.
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Arecaceae/metabolismo , Productos Lácteos/análisis , Hepatopatías/dietoterapia , Hígado/lesiones , Desnutrición/complicaciones , Animales , Arecaceae/química , Peso Corporal , Suplementos Dietéticos/análisis , Frutas/química , Frutas/metabolismo , Humanos , Hepatopatías/etiología , Hepatopatías/metabolismo , Hepatopatías/fisiopatología , Masculino , Ratones , Estrés OxidativoRESUMEN
Sepsis is a severe disease characterized by an uncontrolled systemic inflammation and consequent organ dysfunction generated in response to an infection. Extracellular ATP acting through the P2X7 receptor induces the maturation and release of pro-inflammatory cytokines (i.e., IL-1ß) and the production of reactive nitrogen and oxygen species that lead to oxidative tissue damage. Here, we investigated the role of the P2X7 receptor in inflammation, oxidative stress, and liver injury in sepsis. Sepsis was induced by cecal ligation and puncture (CLP) in wild-type (WT) and P2X7 knockout (P2X7-/-) mice. The oxidative stress in the liver of septic mice was assessed by 2',7'-dichlorofluorescein oxidation reaction (DCF), thiobarbituric acid-reactive substances (TBARS), and nitrite levels dosage. The status of the endogenous defense system was evaluated through catalase (CAT) and superoxide dismutase (SOD) activities. The inflammation was assessed histologically and by determining the expression of inflammatory cytokines and chemokines by RT-qPCR. We observed an increase in the reactive species and lipid peroxidation in the liver of septic WT mice, but not in the liver from P2X7-/- animals. We found an imbalance SOD/CAT ratio, also only WT septic animals. The number of inflammatory cells and the gene expression of IL-1 ß, IL-6, TNF-α, IL-10, CXCL1, and CXCL2 were higher in the liver of WT septic mice in comparison to P2X7-/- septic animals. In summary, our results suggest that the P2X7 receptor might be a therapeutic target to limit oxidative stress damage and liver injury during sepsis.
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Hepatopatías/metabolismo , Estrés Oxidativo/fisiología , Receptores Purinérgicos P2X7/metabolismo , Sepsis/metabolismo , Sepsis/patología , Animales , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
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.
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Angiotensina I/farmacología , Hepatopatías/complicaciones , Fragmentos de Péptidos/farmacología , Sarcopenia/terapia , Animales , Autofagia , Biomarcadores , Enfermedad Crónica , Fibrosis/patología , Hepatopatías/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/patología , Proteínas Musculares/metabolismo , Fuerza Muscular , Músculo Esquelético/metabolismo , Atrofia Muscular/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Ligasas SKP Cullina F-box/metabolismo , Sarcopenia/etiología , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Schistosomiasis is a debilitating parasitic disease that affects more than 200 million people worldwide and causes approximately 280,000 deaths per year. Inside the definitive host, eggs released by Schistosoma mansoni lodge in the intestine and especially in the liver where they induce a granulomatous inflammatory process, which can lead to fibrosis. The molecular mechanisms initiating or promoting hepatic granuloma formation remain poorly understood. Inflammasome activation has been described as an important pathway to induce pathology mediated by NLRP3 receptor. Recently, other components of the inflammasome pathway, such as NLRP6, have been related to liver diseases and fibrotic processes. Nevertheless, the contribution of these components in schistosomiasis-associated pathology is still unknown. In the present study, using dendritic cells, we demonstrated that NLRP6 sensor is important for IL-1ß production and caspase-1 activation in response to soluble egg antigens (SEA). Furthermore, the lack of NLRP6 has been shown to significantly reduce periovular inflammation, collagen deposition in hepatic granulomas and mRNA levels of α-SMA and IL-13. Livers of Nlrp6-/- mice showed reduced levels of CXCL1/KC, CCL2, CCL3, IL-5, and IL-10 as well as Myeloperoxidase (MPO) and Eosinophilic Peroxidase (EPO) enzymatic activity. Consistently, the frequency of macrophage and neutrophil populations were lower in the liver of NLRP6 knockout mice, after 6 weeks of infection. Finally, it was further demonstrated that the onset of hepatic granuloma and collagen deposition were also compromised in Caspase-1-/- , IL-1R-/- and Gsdmd-/- mice. Our findings suggest that the NLRP6 inflammasome is an important component for schistosomiasis-associated pathology.
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Hígado/inmunología , Hígado/patología , Receptores de Superficie Celular/metabolismo , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Animales , Antígenos Helmínticos/metabolismo , Antígenos Helmínticos/farmacología , Caspasa 1/genética , Caspasa 1/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Fibrosis , Técnicas de Inactivación de Genes , Granuloma/inmunología , Granuloma/metabolismo , Inflamasomas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Hepatopatías/inmunología , Hepatopatías/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas de Unión a Fosfato/genética , Proteínas de Unión a Fosfato/metabolismo , Receptores de Superficie Celular/genética , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Esquistosomiasis mansoni/parasitologíaRESUMEN
O objetivo deste artigo foi abordar as controvérsias científicas acerca dos distúrbios ácido-base nas doenças hepáticas. Nos estágios avançados da doença hepática, os distúrbios ácido-base atuam de forma complexa, comprometendo a qualidade de vida do paciente e desafiando o manejo clínico. A literatura apresenta a alcalose respiratória como uma das principais alterações, porém há uma longa discussão sobre o mecanismo fisiopatológico; em especial, citam-se a hipóxia, a hipocapnia e o nível de progesterona. Nas desordens metabólicas, com destaque para a acidose, os estudos apontam principalmente o lactato, os unmeasured ions ou íons não medidos e as alterações hidroeletrolíticas, mas cada componente desse sobressai-se dependendo da fase da doença estudada, compensada ou descompensada. As controvérsias dos distúrbios ácido-base nas doenças hepáticas devem-se ora à complexidade da fisiopatologia da própria doença, ora à necessidade de mais estudos esclarecedores.
The aim of this study is to address the scientific controversy about acid-base disorders in liver diseases. In the end stage of liver diseases, the acid-base disorder has a complex performance, impairing the patient's quality of life and challenging the clinic management. Although the literature shows respiratory alkalosis as one of the main alterations, there is a long discussion about the pathophysiological mechanism, specially regarding hypoxia, hypocapnia, and progesterone level. In metabolic disorders, especially acidosis, the studies mainly indicate the lactate, unmeasured ions, and hydroelectrolytic alterations, but, depending on the disease phase, either compensated or decompensated, each element has a particular action. The controversy about acid-base disorders in liver diseases is associated with the complexity of this condition, as well as with the necessity of more specialized research.
Asunto(s)
Humanos , Desequilibrio Ácido-Base/etiología , Hepatopatías/complicaciones , Desequilibrio Hidroelectrolítico/fisiopatología , Acidosis Láctica/fisiopatología , Alcalosis Respiratoria/fisiopatología , Hepatopatías/fisiopatología , Hepatopatías/metabolismoRESUMEN
Cirrhosis is a primary cause of liver-related mortality and morbidity. The basic process driving chronic liver disease to cirrhosis is accelerated fibrogenesis. Although the pathogenesis of liver cirrhosis is a multifactorial process, the essential step in the evolution of liver fibrosis is the activation of hepatic stellate cells, which are the main source of collagen produced in the extracellular matrix. This activation process is mediated by multiple growth factors, cytokines, and chemokines. One of the hepatic stellate cell-activating signaling molecules (and also one associated with cell injury and fibrosis) is osteopontin (OPN). OPN concentration in the plasma has been found to be predictive of liver fibrosis in various liver diseases. OPN concentrations correlate significantly with the stage of fibrosis, liver insufficiency, portal hypertension, and the presence of hepatocellular cancer. However, due to its versatile signaling functions, OPN not only contributes to the development of liver cirrhosis, but is also implicated in the pathogenesis of other chronic hepatic diseases such as viral hepatitis, both alcoholic and non-alcoholic steatohepatitis, drug-induced liver injury, and hepatocellular cancer. Thus, the targeting of OPN pathways seems to be a promising approach in the treatment of chronic liver diseases.