Estudios de trasplante de microbiota fecal en síndrome metabólico, obesidad y diabetes, ¿dónde nos encontramos?

Fundamento: El trasplante de microbiota fecal (FMT) consiste en la transferencia de las heces de un donante sano a otro paciente con el objetivo de cambiar o restablecer la composición y función de su microbiota. Su única aplicación clínica actualmente aceptada es el tratamiento de infección recurrente por Clostridium difficile. No obstante, se está estudiando su empleo en enfermedades como la enfermedad inflamatoria intestinal, el autismo y las enfermedades metabólicas. En este último grupo encontramos el síndrome metabólico, la obesidad y la diabetes tipo 2, tres enfermedades relacionadas entre sí y cada vez más prevalentes en nuestro tiempo. Las tres se caracterizan por cursar con una disbiosis de la microbiota intestinal y en este contexto surge la idea del empleo del FMT para su tratamiento. El objetivo de este Trabajo de Fin de Grado es conocer los estudios que se han realizado para evaluar el efecto del FMT con donantes humanos en síndrome metabólico, obesidad y diabetes. Metodología: Se ha llevado a cabo una revisión sistemática utilizando la base de datos PubMed, realizando tres búsquedas por términos MeSH relacionando “fecal microbiota transplantation” con “obesity”, “diabetes” y “metabolic syndrome” y aplicando las metodologías PRISMA y PICO para seleccionar los resultados de interés. Resultados: Se han valorado siete artículos de intervención que evalúan el efecto del FMT con donantes humanos y receptores humanos o animales. Existen pocos resultados concluyentes sobre el efecto del FMT en la microbiota del receptor, debido a que los artículos son heterogéneos y valoran parámetros diferentes. Conclusión: El FMT supone un avance en el conocimiento de la relación entre la microbiota y las enfermedades metabólicas y, conforme obtenemos más información de los estudios de intervención realizados, nos acercamos a la posibilidad de aplicar este procedimiento en el tratamiento de otras enfermedades además de la infección por Clostridium difficile.Background: The fecal microbiota transplantation (FMT) consists in the transfer of gastrointestinal microbiota from a healthy individual to another in order to change or restore the composition and function of the recipient’s microbiota. Nowadays this method is only accepted as a therapeutic option for Clostridium difficile infection. However, there are many studies evaluating its applicability in other diseases such as inflammatory bowel disease, irritable bowel syndrome, autism and metabolic disorders, like obesity, diabetes or metabolic syndrome. In this project we are focusing on these three metabolic diseases, which incidence has increased rapidly worldwide. They are characterized by a dysbiosis of the intestinal microbiota and that is the reason why the idea of fecal microbiota transplantation as a possible therapeutic option arises. The main objective of this project is to analyse the currently available studies that evaluate the effect of fecal microbiota transplantation, from humans to either humans or animals, in the physiopathology of obesity, diabetes and metabolic syndrome. Methodology: A systematic review was carried out using the PubMed database with three independent searches using MeSH terms relating “fecal microbiota transplantation” and “obesity”, “diabetes” and “metabolic syndrome”. PRISMA and PICO methodologies were applied to select the studies of interest. Results: Seven articles from intervention studies that evaluate FMT with human donors and human or animal recipients have been included in this systematic review. To date, there are few conclusive results due to the heterogeneity of the studies. Conclusion: New studies on FMT represent an advance in the knowledge of the relationship between the microbiota and metabolic disorders. As we obtain more information regarding the applicability of this technique and its effect, we approach the possibility of applying it in the treatment of other diseases a part from infection by Clostridium difficile

Novel N,N' -Disubstituted Acylselenoureas as Potential Antioxidant and Cytotoxic Agents

Selenium compounds are pivotal in medicinal chemistry for their antitumoral and antioxidant properties. Forty seven acylselenoureas have been designed and synthesized following a fragment-based approach. Different scaffolds, including carbo- and hetero-cycles, along with mono- and bi-cyclic moieties, have been linked to the selenium containing skeleton. The doseand time-dependent radical scavenging activity for all of the compounds were assessed using the in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,20 -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assays. Some of them showed a greater radical scavenging capacity at low doses and shorter times than ascorbic acid. Therefore, four compounds were evaluated to test their protective effects against H2O2-induced oxidative stress. One derivative protected cells against H2O2-induced damage, increasing cell survival by up to 3.6-fold. Additionally, in vitro cytotoxic activity of all compounds was screened against several cancer cells. Eight compounds were selected to determine their half maximal inhibitory concentration (IC50) values towards breast and lung cancer cells, along with their selectivity indexes. The breast cancer cells turned out to be much more sensitive than the lung. Two compounds (5d and 10a) stood out with IC50 values between 4.2 µM and 8.0 µM towards MCF-7 and T47D cells, with selectivity indexes greater than 22.9. In addition, compound 10b exhibited dual antioxidant and cytotoxic activities. Although further evidence is needed, the acylselenourea scaffold could be a feasible frame to develop new dual agents

Association between an oxidative balance score and mortality: a prospective analysis in the SUN cohort

We aimed to prospectively investigate the association of an overall oxidative balance score (OBS) with all-cause death and cause-specifc mortality among participants in the Seguimiento Universidad de Navarra (SUN) Study, a Mediterranean cohort of Spanish graduates. Methods Using baseline information on 12 a priori selected dietary and non-dietary lifestyle pro- and antioxidants exposures—vitamins C and E, β-carotenes, selenium, zinc, heme iron, polyphenols, total antioxidant capacity, body mass index, alcohol, smoking, and physical activity—we constructed an equally weighted OBS categorized into quartiles, with higher scores representing greater antioxidant balance. Cox proportional hazards models were ftted to evaluate the association between the OBS and mortality. Results A total of 18,561 participants (mean [SD] age, 38.5 [12.4] years; 40.8% males) were included in the analysis. During a median follow-up of 12.2 years (interquartile range 8.3–14.9), 421 deaths were identifed, including 80 deaths from cardiovascular disease (CVD), 215 from cancer, and 126 from other causes. After adjustment for potential confounders, the hazard ratios and 95% confdence interval (CIs) between the highest quartile (predominance of antioxidants) vs. the lowest quartile (reference category) were 0.35 (95% CI 0.22–0.54, P-trend<0.001) for all-cause mortality, 0.18 (95% CI 0.06–0.51, P-trend=0.001) for CVD mortality, 0.35 (95% CI 0.19–0.65, P-trend=0.002) for cancer mortality, and 0.45 (95% CI 0.20–1.02, P-trend=0.054) for other-cause mortality. Conclusion Our fndings suggest a strong inverse association between the OBS and all-cause, CVD, and cancer mortality. Individuals exposed to both antioxidant dietary and lifestyle factors may potentially experience the lowest mortality riskOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. The SUN Project has received funding from the Spanish Government-Instituto de Salud Carlos III, and the European Regional Development Fund (FEDER) (RD 06/0045, CIBER-OBN, Grants PI10/02658, PI10/02293, PI13/00615, PI14/01668, PI14/01798, PI14/01764, PI17/01795, and G03/140), the Navarra Regional Government (27/2011, 45/2011, 122/2014), the Government Delegation for the National Drug Plan (2020/ 021) and the University of Navarra. Maria Soledad Hershey receives ERC traininggrant support (T42 OH008416

Synaptic vulnerability to amyloid-β and tau pathologies differentially disrupts emotional and memory neural circuits

Altres ajuts: Junta de Andalucía (P20-0881); BrightFocus Foundation (A2022047S); Juan de la Cierva-Incorporación (IJC2019-042468-I); Ramón y Cajal Programs (RYC2022-037843-I)Alzheimer's disease (AD) is characterized by memory loss and neuropsychiatric symptoms associated with cerebral amyloid-β (Aβ) and tau pathologies, but whether and how these factors differentially disrupt neural circuits remains unclear. Here, we investigated the vulnerability of memory and emotional circuits to Aβ and tau pathologies in mice expressing mutant human amyloid precursor protein (APP), Tau or both APP/Tau in excitatory neurons. APP/Tau mice develop age- and sex-dependent Aβ and phosphorylated tau pathologies, the latter exacerbated at early stages, in vulnerable brain regions. Early memory deficits were associated with hippocampal tau pathology in Tau and APP/Tau mice, whereas anxiety and fear appeared linked to intracellular Aβ in the basolateral amygdala (BLA) of APP and APP/Tau mice. Transcriptome hippocampal profiling revealed gene changes affecting myelination and RNA processing in Tau mice, and inflammation and synaptic-related pathways in APP/Tau mice at 6 months. At 9 months, we detected common and region-specific changes in astrocytic, microglia and 63 AD-associated genes in the hippocampus and BLA of APP/Tau mice. Spatial learning deficits were associated with synaptic tau accumulation and synapse disruption in the hippocampus of Tau and APP/Tau mice, whereas emotional disturbances were linked to Aβ pathology but not synaptic tau in the BLA. Interestingly, Aβ and tau exhibited synergistic detrimental effects in long-term potentiation (LTP) in the hippocampus but they counteract with each other to mitigate LTP impairments in the amygdala. These findings indicate that Aβ and tau pathologies cause region-specific effects and synergize to induce synaptic dysfunction and immune responses, contributing to the differing vulnerability of memory and emotional neural circuits in AD

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Novel N,N' -Disubstituted Acylselenoureas as Potential Antioxidant and Cytotoxic Agents

Selenium compounds are pivotal in medicinal chemistry for their antitumoral and antioxidant properties. Forty seven acylselenoureas have been designed and synthesized following a fragment-based approach. Different scaffolds, including carbo- and hetero-cycles, along with mono- and bi-cyclic moieties, have been linked to the selenium containing skeleton. The doseand time-dependent radical scavenging activity for all of the compounds were assessed using the in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,20 -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assays. Some of them showed a greater radical scavenging capacity at low doses and shorter times than ascorbic acid. Therefore, four compounds were evaluated to test their protective effects against H2O2-induced oxidative stress. One derivative protected cells against H2O2-induced damage, increasing cell survival by up to 3.6-fold. Additionally, in vitro cytotoxic activity of all compounds was screened against several cancer cells. Eight compounds were selected to determine their half maximal inhibitory concentration (IC50) values towards breast and lung cancer cells, along with their selectivity indexes. The breast cancer cells turned out to be much more sensitive than the lung. Two compounds (5d and 10a) stood out with IC50 values between 4.2 µM and 8.0 µM towards MCF-7 and T47D cells, with selectivity indexes greater than 22.9. In addition, compound 10b exhibited dual antioxidant and cytotoxic activities. Although further evidence is needed, the acylselenourea scaffold could be a feasible frame to develop new dual agents

Mediterranean lifestyle index and 24-h systolic blood pressure and heart rate in community-dwelling older adults

Specific foods, nutrients, dietary patterns, and physical activity are associated with lower blood pressure (BP) and heart rate (HR), but little is known about the joint effect of lifestyle factors captured in a multidimensional score. We assessed the association of a validated Mediterranean-lifestyle (MEDLIFE) index with 24-h-ambulatory BP and HR in everyday life among community-living older adults. Data were taken from 2,184 individuals (51% females, mean age: 71.4 years) from the Seniors-ENRICA-2 cohort. The MEDLIFE index consisted of 29 items arranged in three blocks: 1) Food consumption; 2) Dietary habits; and 3) Physical activity, rest, and conviviality. A higher MEDLIFE score (0-29 points) represented a better Mediterranean lifestyle adherence. 24-h-ambulatory BP and HR were obtained with validated oscillometric devices. Analyses were performed with linear regression adjusted for the main confounders. The MEDLIFE-highest quintile (vs Q1) was associated with lower nighttime systolic BP (SBP) (-3.17 mmHg [95% CI: -5.25, -1.08]; p-trend = 0.011), greater nocturnal-SBP fall (1.67% [0.51, 2.83]; p-trend = 0.052), and lower HR (-2.04 bpm [daytime], -2.33 bpm [nighttime], and -1.93 bpm [24-h]; all p-trend < 0.001). Results were similar for each of the three blocks of MEDLIFE and by hypertension status (yes/no). Among older adults, higher adherence to MEDLIFE was associated with lower nighttime SBP, greater nocturnal-SBP fall, and lower HR in their everyday life. These results suggest a synergistic BP-related protection from the components of the Mediterranean lifestyle. Future studies should determine whether these results replicate in older adults from other Mediterranean and non-Mediterranean countries

Association between an oxidative balance score and mortality: a prospective analysis in the SUN cohort

Purpose We aimed to prospectively investigate the association of an overall oxidative balance score (OBS) with all-cause death and cause-specifc mortality among participants in the Seguimiento Universidad de Navarra (SUN) Study, a Mediterranean cohort of Spanish graduates. Methods Using baseline information on 12 a priori selected dietary and non-dietary lifestyle pro- and antioxidants exposures—vitamins C and E, β-carotenes, selenium, zinc, heme iron, polyphenols, total antioxidant capacity, body mass index, alcohol, smoking, and physical activity—we constructed an equally weighted OBS categorized into quartiles, with higher scores representing greater antioxidant balance. Cox proportional hazards models were ftted to evaluate the association between the OBS and mortality. Results A total of 18,561 participants (mean [SD] age, 38.5 [12.4] years; 40.8% males) were included in the analysis. During a median follow-up of 12.2 years (interquartile range 8.3–14.9), 421 deaths were identifed, including 80 deaths from cardiovascular disease (CVD), 215 from cancer, and 126 from other causes. After adjustment for potential confounders, the hazard ratios and 95% confdence interval (CIs) between the highest quartile (predominance of antioxidants) vs. the lowest quartile (reference category) were 0.35 (95% CI 0.22–0.54, P-trend<0.001) for all-cause mortality, 0.18 (95% CI 0.06–0.51, P-trend=0.001) for CVD mortality, 0.35 (95% CI 0.19–0.65, P-trend=0.002) for cancer mortality, and 0.45 (95% CI 0.20–1.02, P-trend=0.054) for other-cause mortality. Conclusion Our fndings suggest a strong inverse association between the OBS and all-cause, CVD, and cancer mortality. Individuals exposed to both antioxidant dietary and lifestyle factors may potentially experience the lowest mortality risk

Association between an oxidative balance score and mortality: a prospective analysis in the SUN cohort

Purpose We aimed to prospectively investigate the association of an overall oxidative balance score (OBS) with all-cause death and cause-specifc mortality among participants in the Seguimiento Universidad de Navarra (SUN) Study, a Mediterranean cohort of Spanish graduates. Methods Using baseline information on 12 a priori selected dietary and non-dietary lifestyle pro- and antioxidants exposures—vitamins C and E, β-carotenes, selenium, zinc, heme iron, polyphenols, total antioxidant capacity, body mass index, alcohol, smoking, and physical activity—we constructed an equally weighted OBS categorized into quartiles, with higher scores representing greater antioxidant balance. Cox proportional hazards models were ftted to evaluate the association between the OBS and mortality. Results A total of 18,561 participants (mean [SD] age, 38.5 [12.4] years; 40.8% males) were included in the analysis. During a median follow-up of 12.2 years (interquartile range 8.3–14.9), 421 deaths were identifed, including 80 deaths from cardiovascular disease (CVD), 215 from cancer, and 126 from other causes. After adjustment for potential confounders, the hazard ratios and 95% confdence interval (CIs) between the highest quartile (predominance of antioxidants) vs. the lowest quartile (reference category) were 0.35 (95% CI 0.22–0.54, P-trend<0.001) for all-cause mortality, 0.18 (95% CI 0.06–0.51, P-trend=0.001) for CVD mortality, 0.35 (95% CI 0.19–0.65, P-trend=0.002) for cancer mortality, and 0.45 (95% CI 0.20–1.02, P-trend=0.054) for other-cause mortality. Conclusion Our fndings suggest a strong inverse association between the OBS and all-cause, CVD, and cancer mortality. Individuals exposed to both antioxidant dietary and lifestyle factors may potentially experience the lowest mortality risk

Chronic coronary syndromes without standard modifiable cardiovascular risk factors and outcomes: the CLARIFY registry

Background and Aims: It has been reported that patients without standard modifiable cardiovascular (CV) risk factors (SMuRFs—diabetes, dyslipidaemia, hypertension, and smoking) presenting with first myocardial infarction (MI), especially women, have a higher in-hospital mortality than patients with risk factors, and possibly a lower long-term risk provided they survive the post-infarct period. This study aims to explore the long-term outcomes of SMuRF-less patients with stable coronary artery disease (CAD). Methods: CLARIFY is an observational cohort of 32 703 outpatients with stable CAD enrolled between 2009 and 2010 in 45 countries. The baseline characteristics and clinical outcomes of patients with and without SMuRFs were compared. The primary outcome was a composite of 5-year CV death or non-fatal MI. Secondary outcomes were 5-year all-cause mortality and major adverse cardiovascular events (MACE—CV death, non-fatal MI, or non-fatal stroke). Results: Among 22 132 patients with complete risk factor and outcome information, 977 (4.4%) were SMuRF-less. Age, sex, and time since CAD diagnosis were similar across groups. SMuRF-less patients had a lower 5-year rate of CV death or non-fatal MI (5.43% [95% CI 4.08–7.19] vs. 7.68% [95% CI 7.30–8.08], P = 0.012), all-cause mortality, and MACE. Similar results were found after adjustments. Clinical event rates increased steadily with the number of SMuRFs. The benefit of SMuRF-less status was particularly pronounced in women. Conclusions: SMuRF-less patients with stable CAD have a substantial but significantly lower 5-year rate of CV death or non-fatal MI than patients with risk factors. The risk of CV outcomes increases steadily with the number of risk factors