Metabolic Modulators in Cardiovascular Complications of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multifactorial disorder with contributions from hormones, genetics, and the environment, predominantly affecting young women. Cardiovascular disease is the primary cause of mortality in SLE, and hypertension is more prevalent among SLE patients. The dysregulation of both innate and adaptive immune cells in SLE, along with their infiltration into kidney and vascular tissues, is a pivotal factor contributing to the cardiovascular complications associated with SLE. The activation, proliferation, and differentiation of CD4+ T cells are intricately governed by cellular metabolism. Numerous metabolic inhibitors have been identified to target critical nodes in T cell metabolism. This review explores the existing evidence and knowledge gaps concerning whether the beneficial effects of metabolic modulators on autoimmunity, hypertension, endothelial dysfunction, and renal injury in lupus result from the restoration of a balanced immune system. The inhibition of glycolysis, mitochondrial metabolism, or mTORC1 has been found to improve endothelial dysfunction and prevent the development of hypertension in mouse models of SLE. Nevertheless, limited information is available regarding the potential vasculo-protective effects of drugs that act on immunometabolism in SLE patients.Grants from the Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RB-I00 funded by MCIN/AEI/10.13039/501100011033) co-funded by the European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193, and A-CTS-318-UGR20) with funds from the European Union, and by the Instituto de Salud Carlos III (CIBER-CV and Ref. PI22/01046).The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”

Trimethylamine N-Oxide Promotes Autoimmunity and a Loss of Vascular Function in Toll-like Receptor 7-Driven Lupus Mice

This work was supported by Grants from Comision Interministerial de Ciencia y Tecnologia, Ministerio de Economia y competitividad (MINECO) (SAF2017-84894-R), Ministerio de Ciencia e Innovacion (MCIN)/Agencia Estatal de Investigacion (AEI)/10.13039/501100011033 (PID2020-116347RB-I00), Junta de Andalucia (CTS 164, P20_00193) with funds from the European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV). J.M. and C.G.C. are predoctoral fellows of MINECO and Junta de Andalucia, respectively. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, FEDER una manera de hacer Europa).Plasma levels of trimethylamine N-oxide (TMAO) are elevated in lupus patients. We analyzed the implication of TMAO in autoimmunity and vascular dysfunction of the murine model of systemic lupus erythematosus (SLE) induced by the activation of the Toll-like receptor (TLR)7 with imiquimod (IMQ). Female BALB/c mice were randomly divided into four groups: untreated control mice, control mice treated with the trimethylamine lyase inhibitor 3,3-dimethyl-1-butanol (DMB), IMQ mice, and IMQ mice treated with DMB. The DMB-treated groups were administered the substance in their drinking water for 8 weeks. Treatment with DMB reduced plasma levels of TMAO in mice with IMQ-induced lupus. DMB prevents the development of hypertension, reduces disease progression (plasma levels of anti-dsDNA autoantibodies, splenomegaly, and proteinuria), reduces polarization of T lymphocytes towards Th17/Th1 in secondary lymph organs, and improves endothelial function in mice with IMQ-induced lupus. The deleterious vascular effects caused by TMAO appear to be associated with an increase in vascular oxidative stress generated by increased NADPH oxidase activity, derived in part from the vascular infiltration of Th17/Th1 lymphocytes, and reduced nrf2-driven antioxidant defense. In conclusion, our findings identified the bacterialderived TMAO as a regulator of immune system, allowing for the development of autoimmunity and endothelial dysfunction in SLE mice.Comision Interministerial de Ciencia y Tecnologia, Ministerio de Economia y competitividad (MINECO) SAF2017-84894-RMinisterio de Ciencia e Innovacion (MCIN)/Agencia Estatal de Investigacion (AEI) PID2020-116347RB-I00Junta de Andalucia CTS 164 P20_00193European CommissionMinisterio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV)European Union (Fondo Europeo de Desarrollo Regional, FEDER, FEDER una manera de hacer Europa

Targeting the gut microbiota with dietary fibers: a novel approach to prevent the development cardiovascular complications linked to systemic lupus erythematosus in a preclinical study

This work was supported by Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RB- I00 funded by MCIN/AEI/10.13039/501100011033, PID2021- 122490NB-I00 funded by MCIN/AEI/10.13039/ 501100011033) co-funded by the European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193) with funds from the European Union, and by the Instituto de Salud Carlos III (CIBER-CV). IR-V is postdoctoral funded by MINECO (FJC2021-048099-I). JM is a predoctoral fellow of MINECO (FPU18/02561), and CG-C and SM are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).This study is to investigate whether dietary fiber intake prevents vascular and renal damage in a genetic mouse model of systemic lupus erythematosus (SLE), and the contribution of gut microbiota in the protective effects. Female NZBWF1 (SLE) mice were treated with resistantstarch (RS) or inulin-type fructans (ITF). In addition, inoculation of fecal microbiota from these experimental groups to recipient normotensive female C57Bl/6J germ-free (GF) mice was performed. Both fiber treatments, especially RS, prevented the development of hypertension, renal injury, improved the aortic relaxation induced by acetylcholine, and the vascular oxidative stress. RS and ITF treatments increased the proportion of acetate- and butyrate-producing bacteria, respectively, improved colonic inflammation and integrity, endotoxemia, and decreased helper T (Th)17 proportion in mesenteric lymph nodes (MLNs), blood, and aorta in SLE mice. However, disease activity (splenomegaly and anti-ds-DNA) was unaffected by both fibers. T cell priming and Th17 differentiation in MLNs and increased Th17 infiltration was linked to aortic endothelial dysfunction and hypertension after inoculation of fecal microbiota from SLE mice to GF mice, without changes in proteinuria and autoimmunity. All these effects were lower in GF mice after fecal inoculation from fiber-treated SLE mice. In conclusion, these findings support that fiber consumption prevented the development of hypertension by rebalancing of dysfunctional gutimmune system-vascular wall axis in SLE.Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RB- I00 funded by MCIN/AEI/10.13039/501100011033, PID2021- 122490NB-I00 funded by MCIN/AEI/10.13039/ 501100011033)European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193) with funds from the European Union, and by the Instituto de Salud Carlos III (CIBER-CV)MINECO (FJC2021-048099-I)MINECO (FPU18/02561)Junta de AndalucíaEuropean Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”

Cancer incidence estimation from mortality data: a validation study within a population-based cancer registry

Background: Population-based cancer registries are required to calculate cancer incidence in a geographical area, and several methods have been developed to obtain estimations of cancer incidence in areas not covered by a cancer registry. However, an extended analysis of those methods in order to confirm their validity is still needed. Methods: We assessed the validity of one of the most frequently used methods to estimate cancer incidence, on the basis of cancer mortality data and the incidence-to-mortality ratio (IMR), the IMR method. Using the previous 15-year cancer mortality time series, we derived the expected yearly number of cancer cases in the period 2004– 2013 for six cancer sites for each sex. Generalized linear mixed models, including a polynomial function for the year of death and smoothing splines for age, were adjusted. Models were fitted under a Bayesian framework based on Markov chain Monte Carlo methods. The IMR method was applied to five scenarios reflecting different assumptions regarding the behavior of the IMR. We compared incident cases estimated with the IMR method to observed cases diagnosed in 2004–2013 in Granada. A goodness-of-fit (GOF) indicator was formulated to determine the best estimation scenario. Results: A total of 39,848 cancer incidence cases and 43,884 deaths due to cancer were included. The relative differences between the observed and predicted numbers of cancer cases were less than 10% for most cancer sites. The constant assumption for the IMR trend provided the best GOF for colon, rectal, lung, bladder, and stomach cancers in men and colon, rectum, breast, and corpus uteri in women. The linear assumption was better for lung and ovarian cancers in women and prostate cancer in men. In the best scenario, the mean absolute percentage error was 6% in men and 4% in women for overall cancer. Female breast cancer and prostate cancer obtained the worst GOF results in all scenarios. Conclusion: A comparison with a historical time series of real data in a population-based cancer registry indicated that the IMR method is a valid tool for the estimation of cancer incidence. The goodness-of-fit indicator proposed can help select the best assumption for the IMR based on a statistical argument.Subprogram "Cancer surveillance" of the CIBER of Epidemiology and Public Health (CIBERESP)MINECO/FEDER PGC2018-098860-B-I00Andalusian Department of Health Research, Development and Innovation PI-0152/201

Obesity as a Risk Factor for Prostate Cancer Mortality: A Systematic Review and Dose-Response Meta-Analysis of 280,199 Patients

Khalid Saeed Khan is a Distinguished Investigator funded by the Beatriz Galindo (senior modality) Program grant given to the University of Granada by the Ministry of Science, Innovation, and Universities of the Spanish Government.Simple Summary Results from individual studies on the association between obesity and prostate cancer mortality remain inconclusive; additionally, several large cohort studies have recently been conducted. We aimed to systematically review all available evidence and synthetize it using meta-analytic techniques. The results of our study showed that obesity was associated with prostate cancer specific mortality and all-cause mortality. The temporal association was consistent with a dose-response relationship. Our results demonstrated that obesity, a potentially modifiable prognostic factor, was associated with higher prostate cancer mortality. This study improved the evidence regarding the potential impact of lifestyle on improving prostate cancer prognosis. Strategies aimed at maintaining normal, or reducing abnormal, body mass index in diagnosed prostate cancer patients might improve survival. These results should guide urologists, oncologists, patients, policy-makers and primary care providers with respect to evidence-based practice and counselling concerning lifestyle changes after prostate cancer diagnosis.The aim of this study was to systematically review all evidence evaluating obesity as a prognostic factor for PC mortality. Cohort and case-control studies reporting mortality among PC patients stratified by body mass index (BMI) were included. The risk of mortality among obese patients (BMI >= 30) was compared with the risk for normal weight (BMI = 8), obesity was associated with increased PC-specific mortality (HR: 1.24, 95% CI: 1.14-1.35, I-2: 0.0%) and maintained the dose-response relationship (HR: 1.11 per 5 kg/m(2) increase in BMI, 95% CI: 1.07-1.15, I-2: 26.6%). Obesity had a moderate, consistent, temporal, and dose-response association with PC mortality. Weight control programs may have a role in improving PC survival.Ministry of Science, Innovation, and Universities of the Spanish Governmen

From local monitoring to a broad-scale viability assessment: a case study for the Bonelli’s Eagle in western Europe

Population viability analysis (PVA) has become a basic tool of current conservation practice. However, if not accounted for properly, the uncertainties inherent to PVA predictions can decrease the reliability of this type of analysis. In the present study, we performed a PVA of the whole western European population (France, Portugal, and Spain) of the endangered Bonelli's Eagle (Aquila fasciata), in which we thoroughly explored the consequences of uncertainty in population processes and parameters on PVA predictions. First, we estimated key vital rates (survival, fertility, recruitment, and dispersal rates) using monitoring, ringing, and bibliographic data from the period 1990-2009 from 12 populations found throughout the studied geographic range. Second, we evaluated the uncertainty about model structure (i.e., the assumed processes that govern individual fates and population dynamics) by comparing the observed growth rates of the studied populations with model predictions for the same period. Third, using the model structures suggested in the previous step, we assessed the viability of both the local populations and the overall population. Finally, we analyzed the effects of model and parameter uncertainty on PVA predictions. Our results strongly support the idea that all local populations in western Europe belong to a single, spatially structured population operating as a source-sink system, whereby the populations in the south of the Iberian Peninsula act as sources and, thanks to dispersal, sustain all other local populations, which would otherwise decline. Predictions regarding population dynamics varied considerably, and models assuming more constrained dispersal predicted more pessimistic population trends than models assuming greater dispersal. Model predictions accounting for parameter uncertainty revealed a marked increase in the risk of population declines over the next 50 years. Sensitivity analyses indicated that adult and pre-adult survival are the chief vital rates regulating these populations, and thus, the conservation efforts aimed at improving these survival rates should be strengthened in order to guarantee the long-term viability of the European populations of this endangered species. Overall, the study provides a framework for the implementation of multi-site PVAs and highlights the importance of dispersal processes in shaping the population dynamics of long-lived birds distributed across heterogeneous landscapes.Ministerio de Educación y Ciencia CGL200-64805/BOS CGL2010-17056 SAB-2006-0014/Roge

Mineralocorticoid receptor blockade improved gut microbiota dysbiosis by reducing gut sympathetic tone in spontaneously hypertensive rats.

Microbiota has a crucial role in the host blood pressure (BP) regulation. The present study analyzes whether the mineralocorticoid receptor antagonist spironolactone ameliorates the dysbiosic state in a genetic model of neurogenic hypertension. Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were randomly allocated into three groups: untreated WKY, untreated SHR, and SHR treated with spironolactone for 5 weeks. Spironolactone restored the Firmicutes/Bacteroidetes proportion, and acetate-producing bacteria populations to WKY levels. Spironolactone reduced the percentage of intestinal aerobic bacteria. The amelioration of gut dysbiosis was linked to a reduction in the gut pathology, an enhanced colonic integrity, a reduced gut permeability and an attenuated sympathetic drive in the gut. Spironolactone was unable to reduce neuroinflammation and oxidative stress in the paraventricular nuclei in the hypothalamus. Spironolactone reduced the higher Th17 cells proportion in mesenteric lymph nodes and Th17 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that spironolactone reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity and pathology due to reduced sympathetic drive in the gut.This work was supported by Grants from Comision ´ Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (PID2020-116347RB-I00), and Junta de Andalucía (CTS 164, P20_00193, A-CTS-318-UGR20) with funds from the European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain. M.T. and I.R.-V. are postdoctoral fellow of Instituto de Salud Carlos III (Juan de la Cierva Incorporacion ´ Program, and Juan de la Cierva Formacion ´ Program, respectively). J.M. is a predoctoral fellow of MINECO, and C.G.-C. and S.M. are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).S

Hydroxychloroquine and Tocilizumab in the Treatment of COVID-19: A Longitudinal Observational Study

Objetivos El objetivo del trabajo fue evaluar el empleo de la hidroxicloroquina y el tocilizumab al comienzo de la pandemia, así como describir el perfil de los pacientes que recibieron estos tratamientos. Métodos Se analizaron las historias clínicas de 403 pacientes que ingresaron por COVID-19 desde el 1 de marzo hasta el 15 de abril de 2020 en el Hospital Universitario San Cecilio (Granada, España). Los datos recogidos incluían sexo, edad, días hospitalizados, patologías y/o tratamientos previos, posibles desenlaces y fármacos administrados en el centro. Para estimar las posibles asociaciones entre las variables definidas se utilizaron los parámetros estadísticos T de Student y χ² de Pearson. Resultados Los pacientes, con una edad media de 66 años (desviación estándar = 15,38), estuvieron hospitalizados un promedio de 15 días (desviación estándar = 12,89). La tasa de ingreso en UCI fue del 9,93 % y la de fallecimientos ascendió al 17,37 % del total de individuos. Durante la primera onda epidémica se administró la hidroxicloroquina a la mayoría de pacientes ingresados, mientras que el tocilizumab se restringió a los cuadros clínicos más graves. Conclusiones Los resultados obtenidos en este trabajo mostraron dos tendencias distintas en el uso de los fármacos estudiados. El tocilizumab se administró a un número muy reducido de pacientes, principalmente aquellos de mayor estancia o con complicaciones. La hidroxicloroquina se empleó independientemente de las características iniciales de los pacientes, con especial relevancia en aquellos que presentaban comorbilidades o estaban polimedicados.Objectives The objective of this study is to evaluate the use of hydroxychloroquine and tocilizumab at the beginning of the COVID-19 pandemic and to describe the profile of patients who received these treatments. Method The medical records of 403 patients admitted for COVID-19 from March 1 to April 15, 2020 at the San Cecilio University Hospital (Granada, Spain) were analyzed. The data collected included sex, age, days hospitalized, previous pathologies and/or treatments, possible outcomes and drugs administered at the hospital. Student’s t-test and Pearson’s chi-square tests were used as statistical parameters to estimate the possible associations between the defined variables. Results Patients with a mean age of 66 years (standard deviation = 15.38), were hospitalized for an average of 15 days (standard deviation = 12.89). The ICU admission rate was 9.93 %, and the death rate added up to 17.37 % of the total number of patients. During the first wave of the pandemic, hydroxychloroquine was administered to the majority of hospitalized patients, while tocilizumab was restricted to the more severe cases. Conclusions The results showed two distinct trends in the use of the drugs studied. Tocilizumab was administered to a small number of patients, mainly those with longer length of stay or with complications. Hydroxychloroquine was administered independently of the initial characteristics of patients, especially those who presented comorbidities or took multiple medications

Gut Microbiota Has a Crucial Role in the Development of Hypertension and Vascular Dysfunction in Toll-like Receptor 7-Driven Lupus Autoimmunity

Our group has investigated the involvement of gut microbiota in hypertension in a murine model of systemic lupus erythematosus induced by Toll-like receptor (TLR)-7 activation. Female BALB/c mice were randomly assigned to four experimental groups: an untreated control (CTR), a group treated with the TLR7 agonist imiquimod (IMQ), IMQ-treated with vancomycin, and IMQtreated with a cocktail of broad-spectrum antibiotics. We carried out faecal microbiota transplant (FMT) from donor CTR or IMQ mice to recipient IMQ or CTR animals, respectively. Vancomycin inhibited the increase in blood pressure; improved kidney injury, endothelial function, and oxidative stress; and reduced T helper (Th)17 infiltration in aortas from IMQ-treated mice. The rise in blood pressure and vascular complications present in IMQ mice were also observed in the CTR mice recipients of IMQ microbiota. Reduced relative populations of Sutterella and Anaerovibrio were associated with high blood pressure in our animals, which were increased after stool transplantation of healthy microbiota to IMQ mice. The reduced endothelium-dependent vasodilator responses to acetylcholine induced by IMQ microbiota were normalized after interleukin-17 neutralization. In conclusion, gut microbiota plays a role in the TLR7-driven increase in Th17 cell, endothelial dysfunction, vascular inflammation, and hypertension. The vascular changes induced by IMQ microbiota were initiated by Th17 infiltrating the vasculature.Comisión Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (MINECO) (SAF2017-84894-R, PID2020-116347RBI00)Junta de Andalucía (CTS 164, P20_00193) with funds from the European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV)Instituto de Salud Carlos III (Sara Borrell Program)MINECOEuropean Union (Fondo Europeo de Desarrollo Regional, FEDER

Targeting the gut microbiota with dietary fibers: a novel approach to prevent the development cardiovascular complications linked to systemic lupus erythematosus in a preclinical study.

This study is to investigate whether dietary fiber intake prevents vascular and renal damage in a genetic mouse model of systemic lupus erythematosus (SLE), and the contribution of gut microbiota in the protective effects. Female NZBWF1 (SLE) mice were treated with resistant-starch (RS) or inulin-type fructans (ITF). In addition, inoculation of fecal microbiota from these experimental groups to recipient normotensive female C57Bl/6J germ-free (GF) mice was performed. Both fiber treatments, especially RS, prevented the development of hypertension, renal injury, improved the aortic relaxation induced by acetylcholine, and the vascular oxidative stress. RS and ITF treatments increased the proportion of acetate- and butyrate-producing bacteria, respectively, improved colonic inflammation and integrity, endotoxemia, and decreased helper T (Th)17 proportion in mesenteric lymph nodes (MLNs), blood, and aorta in SLE mice. However, disease activity (splenomegaly and anti-ds-DNA) was unaffected by both fibers. T cell priming and Th17 differentiation in MLNs and increased Th17 infiltration was linked to aortic endothelial dysfunction and hypertension after inoculation of fecal microbiota from SLE mice to GF mice, without changes in proteinuria and autoimmunity. All these effects were lower in GF mice after fecal inoculation from fiber-treated SLE mice. In conclusion, these findings support that fiber consumption prevented the development of hypertension by rebalancing of dysfunctional gut-immune system-vascular wall axis in SLE.This work was supported by Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RBI00 funded by MCIN/AEI/10.13039/501100011033, PID2021- 122490NB-I00 funded by MCIN/AEI/10.13039/ 501100011033) co-funded by the European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193) with funds from the European Union, and by the Instituto de Salud Carlos III (CIBER-CV). IR-V is postdoctoral funded by MINECO (FJC2021-048099-I). JM is a predoctoral fellow of MINECO (FPU18/02561), and CG-C and SM are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).S