Papers by Javier González-Gallego
Free Radical Biology and Medicine, 2017
Gut microbiota is involved in obesity, metabolic syndrome and the progression of nonalcoholic fat... more Gut microbiota is involved in obesity, metabolic syndrome and the progression of nonalcoholic fatty liver disease (NAFLD). It has been recently suggested that the flavonoid quercetin may have the ability to modulate the intestinal microbiota composition, suggesting a prebiotic capacity which highlights a great therapeutic potential in NAFLD. The present study aims to investigate benefits of experimental treatment with quercetin on gut microbial balance and related gut-liver axis activation in a nutritional animal model of NAFLD associated to obesity. C57BL/6J mice were challenged with high fat diet (HFD) supplemented or not with quercetin for 16 weeks. HFD induced obesity, metabolic syndrome and the development of hepatic steatosis as main hepatic histological finding. Increased accumulation of intrahepatic lipids was associated with altered gene expression related to lipid metabolism, as a result of deregulation of their major modulators. Quercetin supplementation decreased insulin resistance and NAFLD activity score, by reducing the intrahepatic lipid accumulation through its ability to modulate lipid metabolism gene expression, cytochrome P450 2E1 (CYP2E1)-dependent lipoperoxidation and related lipotoxicity. Microbiota composition was determined via 16S ribosomal RNA Illumina next-generation sequencing. Metagenomic studies revealed HFD-dependent differences at phylum, class and genus levels leading to dysbiosis, characterized by an increase in Firmicutes/Bacteroidetes ratio and in Gram-negative bacteria, and a dramatically increased detection of Helicobacter genus. Dysbiosis was accompanied by endotoxemia, intestinal barrier dysfunction and gut-liver axis alteration and subsequent inflammatory gene overexpression. Dysbiosis-mediated toll-like receptor 4 (TLR-4)-NF-B signaling pathway activation was associated with inflammasome initiation response and reticulum stress pathway induction. Quercetin reverted gut microbiota imbalance and related endotoxemia-mediated TLR-4 pathway induction, with subsequent inhibition of inflammasome response and reticulum stress pathway activation, leading to the blockage of lipid metabolism gene expression deregulation. Our results support the suitability of quercetin as a therapeutic approach for obesity-associated NAFLD via its anti-inflammatory, antioxidant and prebiotic integrative response.
Journal of Hepatology, 2019
Using random forest method, we further constructed a prediction model based on the gut microbial ... more Using random forest method, we further constructed a prediction model based on the gut microbial signature, with the area under curve being 0.81 for the test set. Based on our results, HBeAg seroconversion was found to be associated positively with AST, and several genera belonging to TM7-3, and Actinomycetaceae families. Conclusion: By analyzing the fecal microbiota from the patients with and without HBeAg seroconversion, we identified intestinal microbiota signatures that is associated with HBeAg seroconversion after oral antiviral therapy. FRI-274 Exercise modulates gut microbiota and intestinal barrier functionality counteracting early obesity and NAFLD in an in vivo model
Medicine & Science in Sports & Exercise, 1995
Advances in Clinical Chemistry, 2015
Oxidative stress is characterized by imbalanced reactive oxygen species (ROS) production and anti... more Oxidative stress is characterized by imbalanced reactive oxygen species (ROS) production and antioxidant defenses. Two main antioxidant systems exist. The nonenzymatic system relies on molecules to directly quench ROS and the enzymatic system is composed of specific enzymes that detoxify ROS. Among the latter, the superoxide dismutase (SOD) family is important in oxidative stress modulation. Of these, manganese-dependent SOD (MnSOD) plays a major role due to its mitochondrial location, i.e., the main site of superoxide ( [Formula: see text] ) production. As such, extensive research has focused on its capacity to modulate oxidative stress. Early data demonstrated the relevance of MnSOD as an [Formula: see text] scavenger. More recent research has, however, identified a prominent role for MnSOD in carcinogenesis. In addition, SOD downregulation appears associated with health risk in heart and brain. A single nucleotide polymorphism which alters the mitochondria signaling sequence for the cytosolic MnSOD form has been identified. Transport into the mitochondria was differentially affected by allelic presence and a new chapter in MnSOD research thus begun. As a result, an ever-increasing number of diseases appear associated with this allelic variation including metabolic and cardiovascular disease. Although diet and exercise upregulate MnSOD, the relationship between environmental and genetic factors remains unclear.
Pharmacology & Toxicology, 2002
Epomediol is a synthetic terpenoid compound that has been reported to reduce ethinyloestradiol-in... more Epomediol is a synthetic terpenoid compound that has been reported to reduce ethinyloestradiol-induced cholestasis. The choleretic action of epomediol is related to an increase in both the bile acid-dependent and independent fractions of bile flow, but the role of glutathione metabolism and transport is still unknown. This study was aimed to evaluate if changes in glutathione homeostasis could contribute to the beneficial effects of epomediol in rats with ethinyloestradiol-induced cholestasis. When compared to control animals, ethinyloestradiol treatment resulted in a significant decrease in the liver concentration of reduced (GSH) and oxidized glutathione. Both GSH and oxidized glutathione concentrations returned to normal in animals receiving ethinyloestradiol plus epomediol. Ethinyloestradiol administration induced a significant decrease in plasma and renal GSH and the tripeptide was almost absent from bile. Combined treatment with epomediol plus ethinyloestradiol normalised renal GSH and both biliary and liver cysteine were significantly increased. Liver and kidney g-glutamyltranspeptidase activities were higher in rats receiving ethinyloestradiol and still remained elevated in animals with the combined treatment. Liver g-glutamylcysteine synthetase activity rose significantly by administration of ethinyloestradiol plus epomediol but the corresponding mRNA levels were not modified. Changes in glutathione homeostasis and higher biliary levels of GSH amino acid constituents could contribute to the beneficial effects of epomediol in rats with ethinyloestradiol-induced cholestasis.
altered fecal microbiota profile in patients with non-alcoholic fatty liver disease (NA-FLD) asso... more altered fecal microbiota profile in patients with non-alcoholic fatty liver disease (NA-FLD) associated with obesity. Rev Esp Enferm Dig 2019;111(4):275-282.
Sorafenib, a multikinase inhibitor with antiproliferative, antiangiogenic, and proapoptotic prope... more Sorafenib, a multikinase inhibitor with antiproliferative, antiangiogenic, and proapoptotic properties, constitutes the only effective first-line drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Despite its capacity to increase survival in HCC patients, its success is quite low in the long term owing to the development of resistant cells through several mechanisms. Among these mechanisms, the antiangiogenic effects of sustained sorafenib treatment induce a reduction of microvessel density, promoting intratumoral hypoxia and hypoxia-inducible factors (HIFs)-mediated cellular responses that favor the selection of resistant cells adapted to the hypoxic microenvironment. Clinical data have demonstrated that overexpressed HIF-1α and HIF-2α in HCC patients are reliable markers of a poor prognosis. Thus, the combination of current sorafenib treatment with gene therapy or inhibitors against HIFs have been documented as promising approaches to overcome sorafenib resistance both in vitro and in vivo. Because the depletion of one HIF-α subunit elevates the expression of the other HIF-α isoform through a compensatory loop, targeting both HIF-1α and HIF-2α would be a more interesting strategy than therapies that discriminate among HIF-α isoforms. In conclusion, there is a marked correlation between the hypoxic microenvironment and sorafenib resistance, suggesting that targeting HIFs is a promising way to increase the efficiency of treatment.
Studies using the European rabbit Oryctolagus cuniculus contributed to elucidating numerous funda... more Studies using the European rabbit Oryctolagus cuniculus contributed to elucidating numerous fundamental aspects of antibody structure and diversification mechanisms and continue to be valuable for the development and testing of therapeutic humanized polyclonal and monoclonal antibodies. Additionally, during the last two decades, the use of the European rabbit as an animal model has been increasingly extended to many human diseases. This review documents the continuing wide utility of the rabbit as a reliable disease model for development of therapeutics and vaccines and studies of the cellular and molecular mechanisms underlying many human diseases. Examples include syphilis, tuberculosis, HIV-AIDS, acute hepatic failure and diseases caused by noroviruses, ocular herpes, and papillomaviruses. The use of rabbits for vaccine development studies, which began with Louis Pasteur's rabies vaccine in 1881, continues today with targets that include the potentially blinding HSV-1 virus infection and HIV-AIDS. Additionally, two highly fatal viral diseases, rabbit hemorrhagic disease and myxomatosis, affect the European rabbit and provide unique models to understand co-evolution between a vertebrate host and viral pathogens.
Obesity and associated comorbidities, including non-alcoholic fatty liver disease (NAFLD), are a ... more Obesity and associated comorbidities, including non-alcoholic fatty liver disease (NAFLD), are a major concern to public well-being worldwide due to their high prevalence among the population, and its tendency on the rise point to as important threats in the future. Therapeutic approaches for obesity-associated disorders have been circumscribed to lifestyle modifications and pharmacological therapies have demonstrated limited efficacy. Over the last few years, different studies have shown a significant role of intestinal microbiota (IM) on obesity establishment and NAFLD development. Therefore, modulation of IM emerges as a promising therapeutic strategy for obesity-associated diseases. Administration of prebiotic and probiotic compounds, fecal microbiota transplantation (FMT) and exercise protocols have shown a modulatory action over the IM. In this review we provide an overview of current approaches targeting IM which have shown their capacity to counteract NAFLD and metabolic syndrome features in human patients and animal models.
Integrative Physiology, a section of the journal Frontiers in Physiology The endoplasmic reticulu... more Integrative Physiology, a section of the journal Frontiers in Physiology The endoplasmic reticulum (ER) is a dynamic and multifunctional organelle responsible for protein biosynthesis, folding, assembly and modifications. Loss of protein folding regulation, which leads to unfolded or misfolded proteins accumulation inside the ER lumen, drives ER stress (ERS) and unfolded protein response (UPR) activation. During aging, there is a decline in the ability of the cell to handle protein folding, accumulation and aggregation, and the function of UPR is compromised. There is a progressive failure of the chaperoning systems and a decline in many of its components, so that the UPR activation cannot rescue the ERS. Physical activity has been proposed as a powerful tool against aged-related diseases, which are linked to ERS. Interventional studies have demonstrated that regular exercise is able to decrease oxidative stress and inflammation and reverse mitochondrial and ER dysfunctions. Exercise-induced metabolic stress could activate the UPR since muscle contraction is directly involved in its activation, mediating exercise-induced adaptation responses. In fact, regular moderate-intensity exercise-induced ERS acts as a protective mechanism against current and future stressors. However, biological responses vary according to exercise intensity and therefore induce different degrees of ERS and UPR activation. This article reviews the effects of aging and exercise on ERS and UPR, also analyzing possible changes induced by different types of exercise in elderly subjects.
In the hepatopulmonary syndrome (HPS), a common complication of liver cirrhosis, pulmonary endoth... more In the hepatopulmonary syndrome (HPS), a common complication of liver cirrhosis, pulmonary endothelial endothelin B (ETB) receptor overexpression, enhanced endothelial nitric oxide (NO) synthase (eNOS)-derived NO production, and increases in pulmonary inducible NO synthase (iNOS) and heme oxygenase (HO-1) are important factors in the development of vasodilatation. These changes may be influenced by redox-sensitive signaling pathways, including nuclear factor-kB (NF-kB). In this study, our aim was to evaluate the effects of the flavonoid antioxidant quercetin on the development of HPS in rats with common bile duct ligation (CBDL). Rats were divided into the following 4 groups: rats subjected to CBDL, Sham (rats subjected to simulated CBDL), quercetin-treated sham, and quercetin-treated CBDL. Quercetin (50 mg/kg) was administered for 2 wk starting on d 14 after surgery. Increased NO production, overexpression of iNOS, eNOS, HO-1, and ETB-receptor and activation of NF-kB were observed in lung of CBDL rats. Quercetin inhibited oxidative stress, NF-kB activation, and the expression of different pulmonary mediators involved in HPS. Quercetin also ameliorated liver injury and reduced the expression of hepatic endothelin-1 and HO-1 in untreated cirrhotic rats. Our findings suggest that quercetin administered after the onset of hepatic injury significantly ameliorates pulmonary complications in CBDL rats and that limitation of cirrhotic evolution contributes to this effect.
Endoplasmic reticulum (ER) stress and apoptotic cell death play an important role in the pathogen... more Endoplasmic reticulum (ER) stress and apoptotic cell death play an important role in the pathogenesis and perpetuation of inflammatory bowel disease (IBD). We aimed to explore the potential of glutamine to reduce ER stress and apoptosis in a rat model of experimental IBD. Colitis was induced in male Wistar rats by intracolonic administration of 30 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Glutamine (25 mg/dL) was given by rectal route daily for 2 d or 7 d. Both oxidative stress (TBARS concentration and oxidised/reduced glutathione ratio) and ER stress markers (CHOP, BiP, calpain-1 and caspase-12 expression) increased significantly within 48 h of TNBS instillation, and glutamine attenuated the extent of the changes. Glutamine also inhibited the significant increases of ATF6, ATF4 and spliced XBP-1 mRNA levels induced by TNBS instillation. TNBS-colitis resulted in a significant increase in p53 and cytochrome c expression, and a reduced Bcl-xL expression and Bax/Bcl-2 ratio. These effects were significantly inhibited by glutamine. Treatment with the amino acid also resulted in significant decreases of caspase-9, caspase-8 and caspase-3 activities. Double immunofluorescence staining showed co-localization of CHOP and cleaved caspase-3 in colon sections. Phospho-JNK and PARP-1 expression was also significantly higher in TNBS-treated rats, and treatment with glutamine significantly decreased JNK phosphorylation and PARP-1 proteolysis. To directly address the effect of glutamine on ER stress and apoptosis in epithelial cells, the ER stress inducers brefeldin A and tunicamycin were added to Caco-2 cells that were treated with glutamine (5 mM and 10 mM). The significant enhancement in PERK, ATF6 phosphorylated IRE1, BiP and cleaved caspase-3 expression induced by brefeldin A and tunicamycin was partly prevented by glutamine. Data obtained indicated that modulation of ER stress signalling and anti-apoptotic effects contribute to protection by glutamine against damage in TNBS-induced colitis. Citation: Crespo I, San-Miguel B, Prause C, Marroni N, Cuevas MJ, et al. (2012) Glutamine Treatment Attenuates Endoplasmic Reticulum Stress and Apoptosis in TNBS-Induced Colitis. PLoS ONE 7(11): e50407.
The antiangiogenic effects of sustained sorafenib treatment in hepatocellular carcinoma (HCC) lea... more The antiangiogenic effects of sustained sorafenib treatment in hepatocellular carcinoma (HCC) lead to the occurrence of hypoxia-mediated drug resistance resulting in low therapy efficiency and negative outcomes. Combined treatments with coadjuvant compounds to target the hypoxia-inducible factor-1α (HIF-1α) represent a promising therapeutic approach through which sorafenib efficiency may be improved. Melatonin is a well-documented oncostatic agent against different cancer types. Here, we evaluated whether melatonin could enhance sorafenib cytotoxicity and overcome the hypoxia-mediated resistance mechanisms in HCC. The pharmacological melatonin concentration (2 mM) potentiated the oncostatic effects of sorafenib (5 μM) on Hep3B cells even under hypoxia. Melatonin downregulated the HIF-1α protein synthesis through the inhibition of the mammalian target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase beta-1 (p70S6K)/ribosomal protein S6 (RP-S6) pathway, although the indole enhanced Akt phosphorylation by the mTORC1/C2 negative feedback. Furthermore, melatonin and sorafenib coadministration reduced the HIF-1α-mitophagy targets expression, impaired autophagosome formation and subsequent mitochondria and lysosomes colocalization. Together, our results indicate that melatonin improves the Hep3B sensitivity to sorafenib, preventing HIF-1α synthesis to block the cytoprotective mitophagy induced by the hypoxic microenvironment, an important element of the multifactorial mechanisms responsible for the chemotherapy failure.
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Aging is associated with a decline in autophagy and a state of low-grade inflammation which furth... more Aging is associated with a decline in autophagy and a state of low-grade inflammation which further affects apoptosis and autophagy. Importantly, these alterations could reverse with regular physical activity. This study assessed the effects of a resistance exercise training program on autophagy, NLRP3 inflammasome, and apoptosis in peripheral blood mononuclear cells (PBMCs) from old subjects. Twenty-six healthy women and men (age, 69.6±1.5 yr) were randomized to a training (TG) or a control (CG) group. TG performed an 8-week resistance training program, while CG followed their daily routines. Protein expression of beclin-1, Atg12, Atg16 and LAMP-2 increased following the training program, while expression of p62/SQSTM1 and phosphorylation of ULK-1 at Ser757 were significantly lower. Resistance exercise also induced a decrease in NLRP3 expression and in the caspase-1/procaspase-1 ratio. Expression of Bcl-2 and Bcl-xL, as well as the Bad/BcL-2 ratio were reduced, and there was a significant decrease in the protein content of caspase-3. The results obtained seem to indicate that 8-week resistance training stimulates autophagy, prevents NLRP3 inflammasome activation, and reduces apoptosis in PBMCs from elderly subjects. These data could have a significant impact in prevention and rehabilitation programs currently employed in elderly population.
The sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) system is involved in different path... more The sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) system is involved in different pathological processes, including fibrogenesis. Melatonin abrogates activation of hepatic stellate cells (HSCs) and attenuates different profibrogenic pathways in animal models of fibrosis, but it is unknown if protection associates with its inhibitory effect on the SphK1/S1P axis. Mice in treatment groups received carbon tetrachloride (CCl4 ) 5 μL g-1 body wt i.p. twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg kg-1 day-1 i.p, beginning 2 weeks after the start of CCl4 administration. At both 4 and 6 weeks following CCl4 treatment, liver mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production, and expression of S1P receptor (S1PR)1, S1PR3 and acid sphingomyelinase (ASMase) were significantly elevated. However, there was a decreased expression of S1PR2 and S1P lyase (S1PL). Melatonin attenuated liver fibrosis, as shown by a significant inhibition of the expression of α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β and collagen (Col) Ι. Furthermore, melatonin inhibited S1P production, lowered expression of SphK1, S1PR1, SP1R3, and ASMase, and increased expression of S1PL. Melatonin induced a reversal of activated human HSCs cell line LX2, as evidenced by a reduction in α-SMA, TGF-β, and Col I expression. Melatonin-treated cells also exhibited an inhibition of the SphK1/S1P axis. Antifibrogenic effect of SphK1 inhibition was confirmed by treatment of LX2 cells with PF543. Abrogation of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in liver fibrogenesis.
Liver fibrosis is an excess production of extracellular matrix proteins as a result of chronic li... more Liver fibrosis is an excess production of extracellular matrix proteins as a result of chronic liver disease which leads to cell death and organ dysfunction. The key cells involved in fibrogenesis are resident hepatic stellate cells (HSCs) which are termed myofibroblasts after activation, acquiring contractile, proliferative, migratory and secretory capability. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with well-established effects on angiogenesis, carcinogenesis and immunity. Accumulating evidence demonstrates that this metabolite is involved in the profibrotic inflammatory process through the regulation of pleiotropic cell responses, such as vascular permeability, leukocyte infiltration, cell survival, migration, proliferation and HSCs differentiation to myofibroblasts. S1P is synthesized by sphingosine kinases (SphKs) and many of its actions are mediated by S1P specific cell surface receptors (S1P1-5), although different intracellular targets of S1P have been identified. Modulation of SphKs/S1P/S1P receptors signaling is known to result in beneficial effects on various in vivo and in vitro models of liver fibrosis. Thus, a better knowledge of the molecular mechanisms involved in the modulation of the S1P pathway could help to improve liver fibrosis therapy. In this review, we analyze the effects of the S1P axis on the fibrogenic process, and the involvement of a range of inhibitors or approaches targeting enzymes related to S1P in the abrogation of pathological fibrogenesis. All in all, targeting this pathway offers therapeutic potential in the treatment of hepatic fibrosis.
Aging is a natural, multifactorial and multiorganic phenomenon wherein there are gradual physiolo... more Aging is a natural, multifactorial and multiorganic phenomenon wherein there are gradual physiological and pathological changes over time. Aging has been associated with a decrease of autophagy capacity and mitochondrial functions, such as biogenesis, dynamics, and mitophagy. These processes are essential for the maintenance of mitochondrial structural integrity and, therefore, for cell life, since mitochondrial dysfunction leads to an impairment of energy metabolism and increased production of reactive oxygen species, which consequently trigger mechanisms of cellular senescence and apoptotic cell death. Moreover, reduced mitochondrial function can contribute to age-associated disease phenotypes in model organisms and humans. Literature data show beneficial effects of exercise on the impairment of mitochondrial biogenesis and dynamics and on the decrease in the mitophagic capacity associated to aging. Thus, exercise could have effects on the major cell signaling pathways that are involved in the mitochondria quality and quantity control in the elderly. Although it is known that several exercise protocols are able to modify the activity and turnover of mitochondria, further studies are necessary in order to better identify the mechanisms of interaction between mitochondrial functions, aging, and physical activity, as well as to analyze possible factors influencing these processes.
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Papers by Javier González-Gallego
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