Ruiz Alcaraz, Antonio José

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Ruiz Alcaraz, Antonio José

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Ruiz Alcaraz, Antonio José

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Universidad de Murcia. Departamento de Bioquímica y Biología Molecular"B" e Inmunología

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Open Access
In vitro study of the differential anti-inflammatory activity of dietary phytochemicals upon human macrophage-like cells as a previous step for dietary intervention
(MDPI, 2024-10-05) Ruiz Alcaraz, Antonio José; Baquero, Lorena; Martínez Pérez-Munar, Paula; Oliva-Bolarín, Alba; Sánchez-Martínez, María A.; Ramos-Molina, Bruno; Núñez-Sánchez, María A.; Moreno, Diego A.; Bioquímica y Biología Molecular B e Inmunología; Facultad de Biología
Chronic inflammatory diseases pose a substantial health challenge globally, significantly contributing to morbidity and mortality. Addressing this issue requires the use of effective anti-inflammatory strategies with fewer side effects than those provoked by currently used drugs. In this study, a range of phytochemicals (phenolic di-caffeoylquinic acid (Di-CQA), flavonoid cyanidin-3,5-diglucoside (Cy3,5DiG), aromatic isothiocyanate sinalbin (SNB) and aliphatic isothiocyanate sulforaphane (SFN)) sourced from vegetables and fruits underwent assessment for their potential anti-inflammatory activity. An in vitro model of human macrophage-like cells treated with a low dose of LPS to obtain a low degree of inflammation that emulates a chronic inflammation scenario revealed promising results. Cell viability and production of the key pro-inflammatory cytokines were assessed in the presence of various phytochemicals. The compounds Di-CQA and Cy-3,5-DiG, within low physiologically relevant doses, demonstrated notable anti-inflammatory effects by significantly reducing the production of key pro-inflammatory cytokines TNF-α and IL-6 without affecting cell viability. These findings underscore the potential of plant-derived bioactive compounds as valuable contributors to the prevention or treatment of chronic inflammatory diseases. These results suggest that these compounds, whether used individually or as part of natural mixtures, hold promise for their inclusion in nutritional interventions designed to mitigate inflammation in associated pathologies.
Open Access
Therapeutic potential of pteridine derivatives: a comprehensive review
(Wiley, 2018-10-19) Carmona‐Martínez, Violeta; Vera, María; Guirado, Antonio; García-Peñarrubia, Pilar; Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Bioquímica y Biología Molecular B e Inmunología
Pteridines are aromatic compounds formed by fused pyrazine and pyrimidine rings. Many living organisms synthesize pteridines, where they act as pigments, enzymatic cofactors, or immune system activation molecules. This variety of biological functions has motivated the synthesis of a huge number of pteridine derivatives with the aim of studying their therapeutic potential. This review gathers the state‐of‐the‐art of pteridine derivatives, describing their biological activities and molecular targets. The antitumor activity of pteridine‐based compounds is one of the most studied and advanced therapeutic potentials, for which several molecular targets have been identified. Nevertheless, pteridines are also considered as very promising therapeutics for the treatment of chronic inflammation‐related diseases. On the other hand, many pteridine derivatives have been tested for antimicrobial activities but, although some of them resulted to be active in preliminary assays, a deeper research is needed in this area. Moreover, pteridines may be of use in the treatment of many other diseases, such as diabetes, osteoporosis, ischemia, or neurodegeneration, among others. Thus, the diversity of the biological activities shown by these compounds highlights the promising therapeutic use of pteridine derivatives. Indeed, methotrexate, pralatrexate, and triamterene are Food and Drug Administration approved pteridines, while many others are currently under study in clinical trials.
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Peritoneal macrophage priming in cirrhosis is related to ERK phosphorylation and IL-6 secretion.
(Wiley, 2010-08-19) Ruiz Alcaraz, Antonio José; Martínez-Esparza Alvargonzález, María Concepción; Caño, Rocío; Hernández Caselles, Trinidad; Ricarti, Chiara; Llanos, Lucía; Zapater, Pedro; Martín-Orozco Santiago, María Elena; Pérez Mateo, Miguel; Such, José; García Peñarrubia, María del Pilar; Francés, Rubén; Tapia Abellán, Ana; Bioquímica y Biología Molecular B e Inmunología
Background: Bacterial infections are common complications arising in patients with cirrhosis and ascites. Translocation of bacterial DNA is a dynamic process that is associated with an increased inflammatory response and a poor prognosis in this setting. The aim of this study was to study whether peritoneal macrophages remain in a chronic primed status to allow a rapid response to subsequent events of bacterial translocation. Patients and methods: Peritoneal monocyte-derived macrophages were isolated from 25 patients with cirrhosis and non-infected ascites and compared with donor's blood monocytes. Activation cell-surface markers were screened using flow-cytometry, and the phosphorylation state of ERK 1/2, p38 MAP Kinase, PKB/Akt and transcription factors c-Jun and p65 NFκB were evaluated using Western blot. Synthesis of tumour necrosis factor alpha, interleukin 6 (IL-6) and interleukin-10 (IL-10) at baseline and in response to bacterial stimuli was evaluated using ELISA. Results: A high expression of CD54, CD86 and HLA-DR at baseline was displayed by peritoneal macrophages. Increased phosphorylated levels of ERK1/2, protein kinase B (PKB) and c-Jun, together with IL-6 production, were observed in peritoneal macrophages at baseline compared with donors' blood monocytes. A positive correlation was established between basal IL-6 levels and extracellular signal-regulated kinase (ERK) phosphorylation in peritoneal macrophages from patients with cirrhosis (r=0·9; P=0·005). Addition of lipopolysaccharide induced higher phosphorylation levels of all studied signalling intermediates than synthetic-oligodeoxydinucleotides, but similar end-stage p65 NFκB. Conclusions: A sustained immune response is present in ascitic fluid of cirrhotic patients, even in the temporal absence of bacterial antigens. This would facilitate a fast response, probably controlled by IL-6, against repeated bacterial-DNA translocation or in liver chronic inflammation.
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Quinoxalines Potential to Target Pathologies
(Bentham Science Publishers, 2015) Tristán-Manzano, María; Guirado, Antonio; Gálvez, Jesús; García-Peñarrubia, Pilar; Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Bioquímica y Biología Molecular B e Inmunología
The study of quinoxalines has increased immeasurably during the last two decades, due firstly to their relatively simple chemical synthesis, which has generated a vast variety of compounds with diverse structural modifications, and secondly, to the wide therapeutic potential and biological activities exhibited by this family of compounds. Quinoxalines constitute a rising biomedical class of low-molecular weight heterocyclic compounds with potential functions as antitumour, anti-inflammatory, antibacterial, antiviral, antifungal, antiparasitic and antidiabetic agents, as well as being of interest for the potential treatment of glaucoma, insomnia, cardiovascular and neurological diseases, among others. However, a deeper knowledge of the molecular targets of quinoxalines that fulfil a key role in certain pathologies is required for the development of new and more specific drugs through a rational design strategy to avoid undesirable side effects. In the present review, we summarize the most important molecular targets of the quinoxaline derivatives discovered to date, thus providing a first reference index for researchers to identify the potential targets of their quinoxalines derived collections, which could facilitate the development of new quinoxaline- based therapies.
Open Access
Anti-leukemia activity of 4-amino-2-aryl-6,9-dichlorobenzo[g]pteridines
(Springer, 2019-02) Carmona-Martínez, Violeta; Guirado, Antonio; Gálvez, Jesús; García-Peñarrubia, Pilar; Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Bioquímica y Biología Molecular B e Inmunología
Open Access
Inflammatory status in human hepatic cirrhosis
(Baishideng publishing Group, 2015-11-07) Tristán-Manzano, María; García-Peñarrubia, Pilar; Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Bioquímica y Biología Molecular B e Inmunología
This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus (HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcohol-induced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis (HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared with HCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gut-mesenteric lymph nodes-peritoneal-systemic axis.
Open Access
Inherited epigenetic hallmarks of childhood obesity derived from prenatal exposure to obesogens
(MDPI, 2023-03-07) Núñez-Sánchez, María Á.; Jiménez-Méndez, Almudena; Suárez Cortés, María; Martínez-Sánchez, María A.; Sánchez-Solís de Querol, Manuel; Blanco Carnero, José Eliseo; Ruiz Alcaraz, Antonio José; Ramos-Molina, Bruno; Bioquímica y Biología Molecular B e Inmunología; Facultad de Biología
Childhood obesity has reached epidemic levels in developed countries and is becoming a major cause for concern in the developing world. The causes of childhood obesity are complex and multifactorial, involving the interaction between individual genetics and environmental and developmental factors. Among the environmental factors, there is a growing interest in understanding the possible relationship between the so-called environmental obesogens and the development of obesity in children. Exposure to these obesogens such as phthalates, bisphenol A, or parabens, has been identified as a promoter of obesity through different mechanisms such as the alteration of adipocyte development from mesenchymal progenitors, the interference with hormone receptors, and induced inflammation. However, less attention has been paid to the inheritance of epigenetic modifications due to maternal exposure to these compounds during pregnancy. Thus, the aim of this review is to summarize the current knowledge of epigenetic modifications due to maternal exposure to those obesogens during pregnancy as well as their potential implication on long-term obesity development in the offspring and transgenerational inheritance of epiphenotypes.
Open Access
The peritoneal macrophage inflammatory profile in cirrhosis depends on the alcoholic or hepatitis C viral etiology and is related to ERK phosphorylation.
(BMC, 2012-08-06) Martínez-Pascual, Cristina; Miras-López, Manuel; Such, José; Francés, Rubén; García-Peñarrubia, Pilar; Hernández Caselles, Trinidad; Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Tapia Abellán, Ana; Bioquímica y Biología Molecular B e Inmunología
Background: The development of ascites in cirrhotic patients generally heralds a deterioration in their clinical status. A differential gene expression profile between alcohol- and hepatitis C virus (HCV)-related cirrhosis has been described from liver biopsies, especially those associated with innate immune responses. The aim of this work was to identify functional differences in the inflammatory profile of monocyte-derived macrophages from ascites in cirrhotic patients of different etiologies in an attempt to extrapolate studies from liver biopsies to immune cells in ascites. To this end 45 patients with cirrhosis and non-infected ascites, distributed according to disease etiology, HCV (n=15) or alcohol (n=30) were studied. Cytokines and the cell content in ascites were assessed by ELISA and flow cytometry, respectively. Cytokines and ERK phosphorylation in peritoneal monocyte-derived macrophages isolated and stimulated in vitro were also determined. Results: A different pattern of leukocyte migration to the peritoneal cavity and differences in the primed status of macrophages in cirrhosis were observed depending on the viral or alcoholic etiology. Whereas no differences in peripheral blood cell subpopulations could be observed, T lymphocyte, monocyte and polymorphonuclear cell populations in ascites were more abundant in the HCV than the alcohol etiology. HCV-related cirrhosis etiology was associated with a decreased inflammatory profile in ascites compared with the alcoholic etiology. Higher levels of IL-10 and lower levels of IL-6 and IL-12 were observed in ascitic fluid from the HCV group. Isolated peritoneal monocyte-derived macrophages maintained their primed status in vitro throughout the 24 h culture period. The level of ERK1/2 phosphorylation was higher in ALC peritoneal macrophages at baseline than in HCV patients, although the addition of LPS induced a greater increase in ERK1/2 phosphorylation in HCV than in ALC patients. Conclusions: The macrophage inflammatory status is higher in ascites of alcohol-related cirrhotic patients than in HCV-related patients, which could be related with differences in bacterial translocation episodes or regulatory T cell populations. These findings should contribute to identifying potential prognostic and/or therapeutic targets for chronic liver diseases of different etiology.
Open Access
Brassica bioactives could ameliorate the chronic inflammatory condition of endometriosis
(MDPI, 2020-12-10) García-Ibañez, Paula; Yepes-Molina, Lucía; Ruiz Alcaraz, Antonio José; Martínez-Esparza Alvargonzález, María Concepción; Moreno, Diego A.; Carvajal, Micaela; García Peñarrubia, María del Pilar; Bioquímica y Biología Molecular B e Inmunología; Facultad de Biología
Endometriosis is a chronic, inflammatory, hormone-dependent disease characterized by histological lesions produced by the presence of endometrial tissue outside the uterine cavity. Despite the fact that an estimated 176 million women are affected worldwide by this gynecological disorder, risk factors that cause endometriosis have not been properly defined and current treatments are not efficient. Although the interaction between diet and human health has been the focus of many studies, little information about the correlation of foods and their bioactive derivates with endometriosis is available. In this framework, Brassica crops have emerged as potential candidates for ameliorating the chronic inflammatory condition of endometriosis, due to their abundant content of health-promoting compounds such as glucosinolates and their hydrolysis products, isothiocyanates. Several inflammation-related signaling pathways have been included among the known targets of isothiocyanates, but those involving aquaporin water channels have an important role in endometriosis. Therefore, the aim of this review is to highlight the promising effects of the phytochemicals present in Brassica spp. as major candidates for inclusion in a dietary approach aiming to improve the inflammatory condition of women affected with endometriosis. This review points out the potential roles of glucosinolates and sothiocyanates from Brassicas as anti-inflammatory compounds, which might contribute to a reduction in endometriosis symptoms. In view of these promising results, further investigation of the effect of glucosinolates on chronic inflammatory diseases, either as diet coadjuvants or as therapeutic molecules, should be performed. In addition, we highlight the involvement of aquaporins in the maintenance of immune homeostasis. In brief, glucosinolates and the modulation of cellular water by aquaporins could shed light on new approaches to improve the quality of life for women with endometriosis.
Open Access
Isolation of functional mature peritoneal macrophages from healthy humans.
(Wiley, 2019-11-06) Martínez Banaclocha, Helios; Marín Sánchez, Pilar; Carmona Martínez, Violeta; Iniesta Albadalejo, Miguel Ángel; Tristán Manzano, María; García Peñarrubia, Pilar; Martínez-Esparza Alvargonzález, María Concepción; Pelegrín Vivancos, Pablo; Ruiz Alcaraz, Antonio José; Tapia Abellán, Ana; Machado Linde, Francisco; Bioquímica y Biología Molecular B e Inmunología
Macrophages play an important role in the inflammatory response. Their various biological functions are induced by different membrane receptors, including Toll-like receptors, which trigger several intracellular signaling cascades and activate the inflammasomes, which in turn elicit the release of inflammatory mediators such as cytokines. In this study, we present a novel method for the isolation of human mature peritoneal macrophages. This method can be easily implemented by gynecologists who routinely perform laparoscopy for sterilization by tubal ligation or surgically intervene in benign gynecological pathologies. Our method confirms that macrophages are the main peritoneal leukocyte subpopulation isolated from the human peritoneum in homeostasis. We showed that primary human peritoneal macrophages present phagocytic and oxidative activities, and respond to activation of the main proinflammatory pathways such as Toll-like receptors and inflammasomes, resulting in the secretion of different proinflammatory cytokines. Therefore, this method provides a useful tool for characterizing primary human macrophages as control cells for studies of molecular inflammatory pathways in steady-state conditions and for comparing them with those obtained from pathologies involving the peritoneal cavity. Furthermore, it will facilitate advances in the screening of anti-inflammatory compounds in the human system.