The beneficial effects of various polyphenols with plant origins on different cardiovascular-associated disorders, such as hypertension, diabetes mellitus type 2 and metabolic syndrome are well known. Recently, marine crude-drugs are emerging as potential treatments in many noncommunicable conditions, including those involving the cardiovascular system. Among the active compounds responsible for these activities, seaweed polyphenols seem to play a key role. The aim of the present review is to summarise the current knowledge about the beneficial effects reported for edible seaweed polyphenols in the amelioration of these prevalent conditions, focusing on both preclinical and clinical studies. This review will help to establish the basis for future studies in this promising field. ; This work was supported by the Junta de Andalucía (CTS 164) and by the Spanish Ministry of Economy and Competitiveness (AGL2015-67995-C3-3-R) with funds from the European Union. The CIBER-EHD is funded by the Instituto de Salud Carlos III.
Probiotics microorganisms exert their health-associated activities through some of the following general actions: competitive exclusion, enhancement of intestinal barrier function, production of bacteriocins, improvement of altered microbiota, and modulation of the immune response. Among them, Limosilactobacillus fermentum CECT5716 has become one of the most promising probiotics and it has been described to possess potential beneficial effects on inflammatory processes and immunological alterations. Different studies, preclinical and clinical trials, have evidenced its anti-inflammatory and immunomodulatory properties and elucidated the precise mechanisms of action involved in its beneficial effects. Therefore, the aim of this review is to provide an updated overview of the effect on host health, mechanisms, and future therapeutic approaches. ; This work was supported by the Junta de Andalucía (CTS 164) and Instituto de Salud Carlos III (PI19/01058) with funds from the European Union. ; Yes
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestine that compromises the patients' life quality and requires sustained pharmacological and surgical treatments. Since their etiology is not completely understood, non-fully-efficient drugs have been developed and those that have shown effectiveness are not devoid of quite important adverse effects that impair their long-term use. In this regard, a growing body of evidence confirms the health benefits of flavonoids. Flavonoids are compounds with low molecular weight that are widely distributed throughout the vegetable kingdom, including in edible plants. They may be of great utility in conditions of acute or chronic intestinal inflammation through different mechanisms including protection against oxidative stress, and preservation of epithelial barrier function and immunomodulatory properties in the gut. In this review we have revised the main flavonoid classes that have been assessed in different experimental models of colitis as well as the proposed mechanisms that support their beneficial effects. ; This work was supported by Junta de Andalucia (P10-AGR-6826 and CTS 164) and by the Spanish Ministry of Economy and Competitiveness (AGL2015-67995-C3-3-R) with funds from the European Union. ; The CIBER-EHD is funded by the Instituto de Salud Carlos III.
This work was supported by the Junta de Andalucía (CTS 164) and Instituto de Salud Carlos III (PI19/01058) with funds from the European Union. ; M.J. Rodríguez-Sojo is a predoctoral fellow from University of Granada ("Programa de Doctorado en Biomedicina"); A.J. Ruiz-Malagón is a predoctoral fellow from Formación de Profesorado Universitario Program ("Programa de Doctorado en Medicina Clínica y Salud Pública"), and A. Rodríguez-Nogales is a postdoctoral fellow of Instituto de Salud Carlos III (Miguel Servet Program). ; Probiotics microorganisms exert their health-associated activities through some of the following general actions: competitive exclusion, enhancement of intestinal barrier function, production of bacteriocins, improvement of altered microbiota, and modulation of the immune response. Among them, Limosilactobacillus fermentum CECT5716 has become one of the most promising probiotics and it has been described to possess potential beneficial effects on inflammatory processes and immunological alterations. Different studies, preclinical and clinical trials, have evidenced its anti-inflammatory and immunomodulatory properties and elucidated the precise mechanisms of action involved in its beneficial effects. Therefore, the aim of this review is to provide an updated overview of the effect on host health, mechanisms, and future therapeutic approaches. ; Junta de Andalucia CTS 164 ; Instituto de Salud Carlos III European Commission PI19/01058 ; European Commission
Pyruvate is a normal constituent of the body that participates in carbohydrate metabolism and functions as a scavenger of free radicals. Calcium pyruvate monohydrate (CPM) is a more stable derivative that has proved its anti-inflammatory effect in experimental colitis, among other disorders, and that could also be considered a source of calcium. Thus, it would be useful for the treatment of diseases with an inflammatory component and a high prevalence of osteoporosis like the irritable bowel syndrome (IBS). The aim of the present study is to evaluate the effects of CPM in a rat model of chronic post-inflammatory visceral pain induced by deoxycholic acid (DCA) that resembles IBS. Rats were administered DCA for three days intracolonically and then treated daily with CPM (40 and 100 mg/kg) or gabapentin (70 mg/kg) (positive control) by oral gavage for 17 days. The treatments reduced the visceral hypersensitivity measured by response to colorectal distension and referred pain. DCA induced changes in the colonic immune response characterized by increased expression of the cytokine Il-1b and the inducible enzyme Cox-2, which was reduced by the treatments. DCA also decreased the gut expression of the mucins Muc-2 and Muc-3, which was normalized by CPM, whereas gabapentin only increased significantly Muc-3. Moreover, DCA increased the expression of Tlr3, which was decreased to basal levels by all the treatments. However, the serotonin receptor Htr-4, which was also elevated, was not affected by any of the treatments, indicating no effect through this signalling pathway. In conclusion, CPM ameliorated the visceral hypersensitivity and the referred pain caused by DCA, being as effective as the control drug. Furthermore, it improved the immune status of the animals, which could contribute to the visceral analgesia and the regeneration of the intestinal epithelial barrier integrity. ; This work was supported by the Junta de Andalucía (CTS 164) and by the Spanish Ministry of Economy and Competitiveness (AGL2015-67995-C3-3-R) with funds from the European Union. The CIBER-EHD is funded by the Instituto de Salud Carlos III.
Nitric-oxide synthase, the enzyme responsible for mammalian nitric oxide generation, and cytochrome P450, the major enzymes involved in drug metabolism, share striking similarities. Therefore, it makes sense that cytochrome P450 drug mediated biotransformations might play an important role in the pharmacological modulation of nitric oxide synthase. In this work, we have undertaken an integrated in vitro assessment of the hepatic metabolism and nitric oxide modulation of previously described dual inhibitors (imidazoles and macrolides) of these enzymes in order assess the implication of CYP450 activities over production of nitric oxide. In vitro systems based in human liver microsomes and activated mouse macrophages were developed for these purposes. Additionally in vitro production the hepatic metabolites of dual inhibitor, roxithromycin, was investigated achieving the identification and isolation of main hepatic biotransformation products. Our results suggested that for some macrolide compounds, the cytochrome P450 3A4 derived drug metabolites have an important effect on nitric oxide production and might critically contribute to the pharmacological immunomodulatory activity observed. ; This work was supported by the Spanish Ministry of Economy and Competitivity (SAF2011-29648) and Junta de Andalucía (AGR-6826 and CTS 164) with funds from the European Union; FA is a predoctoral fellow of Junta de Andalucia; MR is a postdoctoral fellow of CIBER-EHD. The CIBEREHD is funded by the Instituto de Salud Carlos III. The MEDINA authors disclosed the receipt of financial support from Fundación MEDINA, a public-private partnership of Merck Sharp and Dohme de España S.A./Universidad de Granada/Junta de Andalucía. In the case of Noemi Vergara Segura, she was a CEIBioTic fellow from the program at the Granada University. The results presented in this work will be compiled in the doctoral thesis (knowledge area code 32089 and subject code 320903) entitled "Evaluación de la actividad de los metabolitos hepáticos derivados de compuestos inmunomodulares e inhibidores de GSK3," carried out currently by JP at FUNDACIÓN MEDINA in collaboration with the department of Pharmacology at the University of Granada, being the thesis directors, FV (FUNDACIÓN MEDINA) and JG (Universidad de Granada).
[Background]: Amoxicillin (AX) is nowadays the β-lactam that more frequently induces immediate allergic reactions. Nevertheless, diagnosis of AX allergy is occasionally challenging due to risky in vivo tests and non-optimal sensitivity of in vitro tests. AX requires protein haptenation to form multivalent conjugates with increased size to be immunogenic. Knowing adduct structural features for promoting effector cell activation would help to improve in vitro tests. We aimed to identify the optimal structural requirement in specific cellular degranulation to AX using well-precised nanoarchitectures of different lengths. ; [Method]: We constructed eight Bidendron Antigens (BiAns) based on polyethylene glycol (PEG) linkers of different lengths (600–12,000 Da), end-coupled with polyamidoamine dendrons that were terminally multi-functionalized with amoxicilloyl (AXO). In vitro IgE recognition was studied by competitive radioallergosorbent test (RAST) and antibody–nanoarchitecture complexes by transmission electron microscopy (TEM). Their allergenic activity was evaluated using bone marrow-derived mast cells (MCs) passively sensitized with mouse monoclonal IgE against AX and humanized RBL-2H3 cells sensitized with polyclonal antibodies from sera of AX-allergic patients. ; [Results]: All BiAns were recognized by AX-sIgE. Dose-dependent activation responses were observed in both cellular assays, only with longer structures, containing spacers in the range of PEG 6000–12,000 Da. Consistently, greater proportion of immunocomplexes and number of antibodies per complex for longer BiAns were visualized by TEM. ; [Conclusions]: BiAns are valuable platforms to study the mechanism of effector cell activation. These nanomolecular tools have demonstrated the importance of the adduct size to promote effector cell activation in AX allergy, which will impact for improving in vitro diagnostics. ; The present study was supported by the Institute of Health "Carlos III" (ISCIII) of MINECO (grants cofunded by ERDF: "Una manera de hacer Europa" (grant numbers PI12/02529, PI15/01206, CP15/00103, PI17/01237, PI18/00095, PI20/01734, PI20/01447, RETICS ARADYAL RD16/0006/0001, Euronanomed Program AC19/00082); Andalusian Regional Ministry of Economy and Knowledge (grants cofunded by ERDF: "Andalucía se mueve con Europa": grant no. CTS-06603); Andalusian Regional Ministry of Health (grant nos PI-0699-2011, PI-0179-2014); and "Premio UNICAJA a la innovación en biomedicina y salud." AT has received funding from the European Union's H2020 research and innovation program under the Marie Skłodowska-Curie (grant no. 713721). S.B. acknowledges financial support of Ministerio de Ciencia, Innovación y Universidades from Spain through a Juan de la Cierva Incorporación contract. C.M. holds "Nicolas Monardes" research contract by Andalusian Regional Ministry Health (grant no. RC-0004-2021). G.B. holds a "Juan Rodes" grant (JR18/00054), J.L.P holds a "Sara Borrell" grant (CD19/00250), A.R.N. and M.I.M. hold a "Miguel Servet I" grant (CP19/00191 and CP15/00103), both grants cofunded by European Social Fund ("El FSE invierte en futuro"). Tesfaye reports grants from Marie Skłodowska-Curie [grant No 713721], during the conduct of the study; in addition, Tesfaye has a patent PCT/ES2021/070103 pending. Dr. RODRIGUEZ NOGALES reports grants from ISCIII, during the conduct of the study; in addition, Dr. RODRIGUEZ NOGALES has a patent PCT/ES2021/070103 pending. Dr. Benede reports grants from Ministerio de Ciencia, Innovación y Universidades, during the conduct of the study. Dr. Fernandez reports grants from ISCIII, during the conduct of the study; In addition, Dr. Fernandez has a patent PCT/ES2021/070103 pending. Dr. Paris reports a Sara Borrell fellowship from ISCIII (CD19/00250), cofunded by European Social Fund. Dr. Rodriguez reports grants from ISCIII, during the conduct of the study. JIMÉNEZ-SÁNCHEZ reports grants from MICIN (PEJ2018-002865-A), during the conduct of the study; Dr. BOGAS HERRERA reports grants from ISCIII, during the conduct of the study. Dr. Mayorga reports grants from ISCIII, from Andalusian Regional Ministry Health, during the conduct of the study; in addition, Dr. Mayorga has a patent PCT/ES2021/070103 pending. Dr. Torres reports grants from ISCIII, during the conduct of the study; in addition, Dr. Torres has a patent PCT/ES2021/070103 pending. Dr. Montañez reports grants from ISCIII, during the conduct of the study; in addition, Dr. Montañez has a patent PCT/ES2021/070103 pending. ; Peer reviewed
The beneficial effects of probiotics on immune-based pathologies such as inflammatory bowel disease (IBD) have been well reported. However, their exact mechanisms have not been fully elucidated. Few studies have focused on the impact of probiotics on the composition of the colonic microbiota. The aim of the present study was to correlate the intestinal anti-inflammatory activity of the probiotic Escherichia coli Nissle 1917 (EcN) in the dextran sodium sulfate (DSS) model of mouse colitis with the changes induced in colonic microbiota populations. EcN prevented the DSSinduced colonic damage, as evidenced by lower disease activity index (DAI) values and colonic weight/length ratio, when compared with untreated control mice. The beneficial effects were confirmed biochemically, since the probiotic treatment improved the colonic expression of different cytokines and proteins involved in epithelial integrity. In addition, it restored the expression of different micro-RNAs (miR-143, miR-150, miR-155, miR- 223, and miR-375) involved in the inflammatory response that occurs in colitic mice. Finally, the characterization of the colonic microbiota by pyrosequencing showed that the probiotic administration was able to counteract the dysbiosis associated with the intestinal inflammatory process. This effect was evidenced by an increase in bacterial diversity in comparison with untreated colitic mice. The intestinal anti-inflammatory effects of the probiotic EcN were associated with an amelioration of the altered gut microbiome in mouse experimental colitis, especially when considering bacterial diversity, which is reduced in these intestinal conditions. Moreover, this probiotic has shown an ability to modulate expression levels of miRNAs and different mediators of the immune response involved in gut inflammation. This modulation could also be of great interest to understand the mechanism of action of this probiotic in the treatment of IBD. ; This work was supported by the Junta de Andalucía (CTS 164) and by the Spanish Ministry of Economy and Competitiveness (SAF2011-29648 and AGL2015-67995-C3-3-R) with funds from the European Union. The funders had no role in the study design, data collection, and analysis.
Nowadays, there is an increasing interest in alternative therapies in the treatment of metabolic syndrome that combine efficacy and safety profiles. Therefore, this study aimed to evaluate the effect of an extract of Thymus serpyllum, containing rosmarinic acid, on high-fat diet (HFD)- induced obesity mice, highlighting the impact of its antioxidant activity on the inflammatory status and gut dysbiosis. The extract was administered daily (50, 100 and 150 mg/kg) in HFD-fed mice. The treatment reduced body weight gain, glucose and lipid metabolic profiles. Moreover, the extract ameliorated the inflammatory status, with the c-Jun N-terminal kinases (JUNK) pathway being involved, and showed a significant antioxidant effect by the reduction of radical scavenging activity and the mitigation of lipid peroxidation. Moreover, the extract was able to modulate the altered gut microbiota, restoring microbial richness and diversity, and augmenting the counts of short-chain fatty acid producing bacteria, which have been associated with the maintenance of gut permeability and weight regulation. In conclusion, the antioxidant activity of Thymus serpyllum extract displayed a positive impact on obesity and its metabolic alterations, also reducing systemic inflammation. These effects may be mediated by modulation of the gut microbiota. ; Junta de Andalucia CTS 164 ; Instituto de Salud Carlos III European Commission PI19.01058 ; Spanish Government AGL201567995-C3-3-R ; European Commission ; Instituto de Salud Carlos III
Purpose: We aimed to evaluate the intestinal anti-inflammatory properties of silk fibroin nanoparticles, around 100 nm in size, when loaded with the stilbene compound resveratrol, in an experimental model of rat colitis. Methods: Nanoparticles were loaded with resveratrol by adsorption. The biological effects of the resveratrol-loaded nanoparticles were tested both in vitro, in a cell culture of RAW 264.7 cells (mouse macrophages), and in vivo, in the trinitrobenzenesulfonic acid model of rat colitis, when administered intracolonically. Results: The resveratrol liberation in 1× phosphate-buffered saline (PBS; pH 7.4) was characterized by fast liberation, reaching the solubility limit in 3 hours, which was maintained over a period of 80 hours. The in vitro assays revealed immunomodulatory properties exerted by these resveratrol-loaded nanoparticles since they promoted macrophage activity in basal conditions and inhibited this activity when stimulated with lipopolysaccharide. The in vivo experiments showed that after evaluation of the macroscopic symptoms, inflammatory markers, and intestinal barrier function, the fibroin nanoparticles loaded with resveratrol had a better effect than the single treatments, being similar to that produced by the glucocorticoid dexamethasone. Conclusion: Silk fibroin nanoparticles constitute an attractive strategy for the controlled release of resveratrol, showing immunomodulatory properties and intestinal anti-inflammatory effects. ; This work was supported by the Spanish Ministry of Science and Innovation (grant number SAF2011-29648) with funds from the European Union, and by the Junta de Andalucia (grant numbers AGR-6826 and CTS 164). Parts of the experiments were financed by funds of the European Regional Development Fund (ERDF) Operative Program of the Region of Murcia 2007–2013. The research contract of Dr A Abel Lozano-Pérez was partially supported (at 80%) by the FEDER Operative Program of the Region of Murcia 2007–2013. F Algieri is a predoctoral fellow of the Junta de Andalucia; J Garrido-Mesa is a predoctoral fellow of the Spanish Ministry of Education, Culture and Sport; N Garrido-Mesa is a postdoctoral fellow of the Ramon Areces Foundation; ME Rodríguez-Cabezas is a postdoctoral fellow of Centro de Investigaciones Biomédicas en Red – Enfermedades Hepáticas y Digest (CIBER-EHD), which is funded by the Instituto de Salud Carlos III.
This research was funded by the FEDER-INNTERCONECTA-CDTI program (CDTI, Centre for the Development of Industrial Technology; NATURPICK Project ITC-20181038), by the Junta de Andalucia (CTS 164) and by Instituto de Salud Carlos III (PI19/01058) with funds from the European Union. T.V. is a postdoctoral fellow from Instituto de Investigacion Biosanitaria de Granada; A.J.R.-M. and L.H.-G. are predoctoral fellows from University of Granada ("Programa de Doctorado: Medicina Clinica y Salud Publica"); P.D.-E. is a postdoctoral fellow from University of Granada. The CIBER-EHD and CIBERCV are funded by the Instituto de Salud Carlos III. ; Background: Propyl propane thiosulfonate (PTSO) is an organosulfur compound from Allium spp. that has shown interesting antimicrobial properties and immunomodulatory effects in different experimental models. In this sense, our aim was to evaluate its effect on an experimental model of obesity, focusing on inflammatory and metabolic markers and the gut microbiota. Methods and results: Mice were fed a high-fat diet and orally treated with different doses of PTSO (0.1, 0.5 and 1 mg/kg/day) for 5 weeks. PTSO lessened the weight gain and improved the plasma markers associated with glucose and lipid metabolisms. PTSO also attenuated obesityassociated systemic inflammation, reducing the immune cell infiltration and, thus, the expression of pro-inflammatory cytokines in adipose and hepatic tissues (Il-1ß, Il-6, Tnf-a, Mcp-1, Jnk-1, Jnk-2, Leptin, Leptin R, Adiponectin, Ampk, Ppar-a, Ppar-g, Glut-4 and Tlr-4) and improving the expression of different key elements for gut barrier integrity (Muc-2, Muc-3, Occludin, Zo-1 and Tff-3). Additionally, these effects were connected to a regulation of the gut microbiome, which was altered by the high-fat diet. Conclusion: Allium-derived PTSO can be considered a potential new tool for the treatment of metabolic syndrome. ; FEDER-INNTERCONECTA-CDTI program (CDTI, Centre for the Development of Industrial Technology) ITC-20181038 ; Junta de Andalucia CTS 164 ; Instituto de Salud Carlos III European Commission PI19/01058 European Commission Instituto de Salud Carlos III ; European Commission
