Hydrogen-Bonding Activation of Gold(I) Chloride Complexes: Enantioselective Synthesis of 3(2H)-Furanones by a Cycloisomerization-Addition Cascade.

Enantioselective synthesis of 3(2H)-furanones has been achieved using the intermolecular H-bonding activation of gold(I) chloride complexes. A DM-BINAP [(R)-(+)-2,2'-Bis[di(3,5-xylyl)phoshino]-1,1'-binaphthyl] digold(I) dichloride complex in combination with a sulfonyl squaramide (SO2Sq) has been identified as the optimal catalytic system. The process involves a 5-endo-dig oxa-cyclization followed by stereocontrolled addition of indoles. Interestingly, the soft L*Au-Cl activation by H-bonding allowed the recovery of both L*Au-Cl and the activator after chromatographic purification.

Toxicogenomics of the Freshwater Oligochaete, Tubifex tubifex (Annelida, Clitellata), in Acute Water-Only Exposure to Arsenic.

A toxicogenomic approach was used for toxicity evaluation of arsenic in the aquatic environment, and differential gene expression was investigated from 24 h and 96 h water-only acute toxicity tests with the aquatic oligochaete, Tubifex tubifex (Annelida, Clitellata). Several toxicological endpoints (survival and autotomy) of the oligochaete and tissue residues were measured, and dose-response modelling of gene expression data was studied. A reference transcriptome of the aquatic oligochaete, T. tubifex, was reconstructed for the first time, and genes related to cell stress response (Hsc70, Hsp10, Hsp60, and Hsp83), energy metabolism (COX1), oxidative stress (Cat, GSR, and MnSOD), and the genes involved in the homeostasis of organisms (CaM, RpS13, and UBE2) were identified and characterised. The potential use of the genes identified for risk assessment in freshwater ecosystems as early biomarkers of arsenic toxicity is discussed.

Efectividad de la vacuna antigripal para prevenir casos graves de gripe. Temporada 2022/2023 / Effectiveness of influenza vaccine in preventing severe cases of influenza: Season 2022/2023

Introducción: La gripe supone una importante carga en términos de morbimortalidad, siendo la vacunación una de las medidas más efectivas para su prevención. Por lo que el objetivo de este estudio es conocer la efectividad de la vacuna antigripal para prevenir casos de gripe grave en los pacientes ingresados en un hospital de tercer nivel durante la temporada 2022/23. Metodología: Estudio de casos y controles. Se incluyeron todos los pacientes hospitalizados con resultado positivo en una RT-PCR de gripe. Se consideró caso a aquellos que cumplieron criterio de caso grave (neumonía, sepsis, fallo multiorgánico, ingreso en la UCI o exitus). Quienes no los cumplían se consideraron controles. Se calculó la efectividad vacunal (EV) para prevenir los casos graves y su intervalo de confianza al 95%. Resultados: Un total de 403 pacientes ingresaron con gripe confirmada. Noventa y ocho (24,3%) de ellos desarrollaron gripe grave. Del total, el 50,6% fueron varones y el 47,1% fueron mayores de 65 años. La EV ajustada por tipo de gripe, edad y ciertas comorbilidades fue del 40,6% (−21,9-71,1). En un análisis segmentado, la vacuna de la gripe resultó efectiva para la prevención de los casos graves en todas las categorías. Resultó especialmente relevante en el grupo de 65 años o más (EVa=60,9%; −2,0-85,0) y en los pacientes con gripe A (EVa=56,7%; 1,5-80,9). Conclusiones: La vacunación antigripal redujo notablemente la aparición de casos graves de gripe en los pacientes hospitalizados, por tanto, sigue siendo la principal estrategia para reducir la morbimortalidad y los costes asociados.(AU)

Introduction: Influenza poses a significant burden in terms of morbidity and mortality, with vaccination being one of the most effective measures for its prevention. Therefore, the aim of this study is to determine the effectiveness of the influenza vaccine in preventing cases of severe influenza in patients admitted to a tertiary hospital during the 2022/23 season. Methods: Case-control study. All hospitalised patients with a positive result in an RT-PCR for influenza were included. Those who met the criteria for a severe case (pneumonia, sepsis, multi-organ failure, admission to ICU or exitus) were considered cases. Those who did not meet these criteria were considered controls. Vaccine effectiveness (VE) to prevent severe cases and its 95% confidence interval were calculated. Results: A total of 403 patients were admitted with confirmed influenza. Of these, 98 (24.3%) developed severe influenza. Of the total, 50.6% were men and 47.1% were over 65 years of age. VE adjusted for influenza type, age and certain comorbidities was 40.6% (−21.9 to 71.1). In a segmented analysis, influenza vaccine was effective in preventing severe cases in all categories. It was particularly relevant in the 65+ age group (VEa=60.9%; −2.0 to 85.0) and in patients with influenza A (VEa=56.7%; 1.580.9). Conclusion: Influenza vaccination markedly reduced the occurrence of severe cases of influenza in hospitalised patients, therefore, it remains the main strategy to reduce morbidity and mortality and associated costs.(AU)

Effectiveness of influenza vaccine in preventing severe cases of influenza: Season 2022/2023.

INTRODUCTION: Influenza poses a significant burden in terms of morbidity and mortality, with vaccination being one of the most effective measures for its prevention. Therefore, the aim of this study is to determine the effectiveness of the influenza vaccine in preventing cases of severe influenza in patients admitted to a tertiary hospital during the 2022/23 season. METHODS: Case-control study. All hospitalised patients with a positive result in an RT-PCR for influenza were included. Those who met the criteria for a severe case (pneumonia, sepsis, multi-organ failure, admission to ICU or exitus) were considered cases. Those who did not meet these criteria were considered controls. Vaccine effectiveness (VE) to prevent severe cases and its 95% confidence interval were calculated. RESULTS: A total of 403 patients were admitted with confirmed influenza. Of these, 98 (24.3%) developed severe influenza. Of the total, 50.6% were men and 47.1% were over 65 years of age. VE adjusted for influenza type, age and certain comorbidities was 40.6% (-21.9 to 71.1). In a segmented analysis, influenza vaccine was effective in preventing severe cases in all categories. It was particularly relevant in the 65+ age group (VEa = 60.9%; -2.0 to 85.0) and in patients with influenza A (VEa = 56.7%; 1.5-80.9). CONCLUSION: Influenza vaccination markedly reduced the occurrence of severe cases of influenza in hospitalised patients, therefore, it remains the main strategy to reduce morbidity and mortality and associated costs.

Fetal programming and lactation: modulating gene expression in response to undernutrition during intrauterine life.

BACKGROUND: Adverse environmental conditions during intrauterine life, known as fetal programming, significantly contribute to the development of diseases in adulthood. Fetal programming induced by factors like maternal undernutrition leads to low birth weight and increases the risk of cardiometabolic diseases. METHODS: We studied a rat model of maternal undernutrition during gestation (MUN) to investigate gene expression changes in cardiac tissue using RNA-sequencing of day 0-1 litters. Moreover, we analyzed the impact of lactation at day 21, in MUN model and cross-fostering experiments, on cardiac structure and function assessed by transthoracic echocardiography, and gene expression changes though qPCR. RESULTS: Our analysis identified specific genes with altered expression in MUN rats at birth. Two of them, Agt and Pparg, stand out for being associated with cardiac hypertrophy and fibrosis. At the end of the lactation period, MUN males showed increased expression of Agt and decreased expression of Pparg, correlating with cardiac hypertrophy. Cross-fostering experiments revealed that lactation with control breastmilk mitigated these expression changes reducing cardiac hypertrophy in MUN males. CONCLUSIONS: Our findings highlight the interplay between fetal programming, gene expression, and cardiac hypertrophy suggesting that lactation period is a potential intervention window to mitigate the effects of fetal programming. IMPACT: Heart remodeling involves the alteration of several groups of genes and lactation period plays a key role in establishing gene expression modification caused by fetal programming. We could identify expression changes of relevant genes in cardiac tissue induced by undernutrition during fetal life. We expose the contribution of the lactation period in modulating the expression of Agt and Pparg, relevant genes associated with cardiac hypertrophy. This evidence reveal lactation as a crucial intervention window for preventing or countering fetal programming.

First report of fatal fungemia due Fusarium oxysporum in a patient with COVID-19 in Ecuador.

Filamentous fungal infections are an important cause of systemic infections in immunocompromised patients. Fusarium genus members potentially cause disseminated infections, especially in patients with catheters, due to the ability to adhere to these devices. We describe a case of fatal fungemia due to Fusarium oxysporum in a patient with COVID-19 in Ecuador. The genus identification was carried out with conventional techniques and species identification by molecular and phylogenetic techniques through sequencing of the ITS region.

Tailoring modifications in labrenzin synthesis: a-la-carte production of pathway intermediates.

Pederin-family polyketides today constitute a group of more than 30 molecules being produced as natural products by different microorganisms across multitude of ecological niches. They are mostly known for their extreme cytotoxic activity and the decades of long exploration as potential antitumor drugs. The difference in their potency and biological activity lies in the tailoring modifications of the core molecule. Despite the isolation of many pederin-like molecules until the date, only marine bacterium Labrenzia sp. PHM005 was reported as a cultivable producer and able to be genetically modified. Here, we study the role of tailoring enzymes from the lab gene cluster responsible for methylation and hydroxylation of labrenzin core molecule. We managed to produce a spectrum of differently tailored labrenzin analogs for the development of future drugs. This work constitutes one-step forward in understanding the biosynthesis of pederin-family polyketides and provides the tools to modify and overproduce these anticancer drugs in a-la-carte manner in Labrenzia sp. PHM005, but also in other producers in the future.

Alteraciones del bulbo olfatorio identificadas por resonancia magnética en una cohorte de pacientes con anosmia tras COVID-19 / Olfactory bulb abnormalities identified using magnetic resonance in a cohort of patients with anosmia after COVID-19

Resumen Dentro de los síntomas que presentaron los pacientes que cursaron COVID-19 se documentó una importante incidencia de anosmia, asociada muchas veces a alteraciones en el gusto, sin una base fisiopatológica concluyente. La resonancia magnética proporciona datos estructurales morfológicos sobre el nervio olfatorio, el bulbo olfatorio y las cortezas primarias y secundarias. En esta serie de pacientes con anosmia posterior a COVID-19 se identificaron alteraciones estructurales de los bulbos olfatorios principalmente con elevación de la señal en secuencias T2, y en menor medida aumento de su volumen. Dichas características fueron interpretadas en probable relación con edema e inflamación posterior a la infección viral, observando en ciertos casos, además, asimetría de los bulbos olfatorios.

Abstract Anosmia, a frequent symptom among patients affected by COVID-19 and often associated with alterations in taste, does not have a clear pathophysiological basis in this context. Magnetic resonance imaging enables the structural assessment of the olfactory nerve, olfactory bulb, and primary and secondary cortices. In this group of patients with post-COVID anosmia, were identified structural abnormalities at the level of the olfactory bulb mainly depicted as elevation of the signal in T2-weighted sequences, and to a lesser extent as an increase in their volume. These characteristics were interpreted in probable relation to edema and inflammation after the viral infection, showing in certain cases asymmetry of the olfactory bulbs.

Evaluation of Parameters Which Influence Voluntary Ingestion of Supplements in Rats.

Drug safety and efficacy studies frequently use oral gavage, but repetitive usage may cause problems. Administration through voluntary ingestion represents an opportunity for refinement. We aimed to develop a protocol for voluntary ingestion of gelatin-based supplements in rats, assessing the influence of age, sex, fasting (4 h), and additives (vanilla, VF; sucralose, S), and to test it in lactating dams. Three-week-old and 5-month-old Sprague-Dawley rats were placed individually in an empty cage containing a gelatin cube and trained daily (5 days/week), recording the day the whole cube was consumed (latency). Rats trained prior to gestation were offered a gelatin containing 250 mg/kg cocoa shell extract (CSE) during lactation. Rats that did not eat the cube after 8 training days were considered non-habituated, with a proportion similar in young males (7.1%), young females (11.1%), and adult females (10.3%), but significantly higher in adult males (39.3%). Excluding non-habituated rats, latency was 2-3 days, without differences between young and adult rats (p = 0.657) or between males and females (p = 0.189). VF or VF + S in the gelatin did not modify latency, while fasting significantly reduced it in females (p = 0.007) but not in males (p = 0.501). During lactation, trained females ate the CSE-gelatin within 1-5 min without litter problems. Conclusions: Acceptance of a gelatin-based supplement is negatively influenced by male sex, facilitated by fasting, and not modified by additives. Training is remembered after 2 months and does not interfere with lactation. Gelatin-based voluntary ingestion is suitable to administer drugs that need to pass through the digestive system, ensuring adequate dosage, and is important to detect non-habituated rats prior to the study. The current protocol may be implemented by training the rats in their own cage.

Cocoa Shell Extract Reduces Blood Pressure in Aged Hypertensive Rats via the Cardiovascular Upregulation of Endothelial Nitric Oxide Synthase and Nuclear Factor (Erythroid-Derived 2)-like 2 Protein Expression.

Cocoa shell is a by-product of cocoa manufacturing. We obtained an aqueous extract (CSE) rich in polyphenols and methylxanthines with antioxidant and vasodilatory properties. We aimed to evaluate the effects of CSE supplementation in aged hypertensive rats on blood pressure and the mechanism implicated. Eighteen-month-old male and female rats exposed to undernutrition during the fetal period who developed hypertension, with a milder form in females, were used (MUN rats). Systolic blood pressure (SBP; tail-cuff plethysmography) and a blood sample were obtained before (basal) and after CSE supplementation (250 mg/kg; 2 weeks, 5 days/week). Plasma SOD, catalase activity, GSH, carbonyls, and lipid peroxidation were assessed (spectrophotometry). In hearts and aortas from supplemented and non-supplemented age-matched rats, we evaluated the protein expression of SOD-2, catalase, HO-1, UCP-2, total and phosphorylated Nrf2 and e-NOS (Western blot), and aorta media thickness (confocal microscopy). MUN males had higher SBP compared with females, which was reduced via CSE supplementation with a significant difference for group, sex, and interaction effect. After supplementation with plasma, GSH, but not catalase or SOD, was elevated in males and females. Compared with non-supplemented rats, CSE-supplemented males and females exhibited increased aorta e-NOS and Nrf2 protein expression and cardiac phosphorylated-Nrf2, without changes in SOD-2, catalase, HO-1, or UCP-2 in cardiovascular tissues or aorta remodeling. In conclusion, CSE supplementation induces antihypertensive actions related to the upregulation of e-NOS and Nrf2 expression and GSH elevation and a possible direct antioxidant effect of CSE bioactive components. Two weeks of supplementation may be insufficient to increase antioxidant enzyme expression.

Clinical Characteristics and Prognostic Impact of Short Physical Performance Battery in Hospitalized Patients with Acute Heart Failure-Results of the PROFUND-IC Registry.

BACKGROUND: Most patients diagnosed with heart failure (HF) are older adults with multiple comorbidities. Multipathological patients constitute a population with common characteristics: greater clinical complexity and vulnerability, frailty, mortality, functional deterioration, polypharmacy, and poorer health-related quality of life with more dependency. OBJECTIVES: To evaluate the clinical characteristics of hospitalized patients with acute heart failure and to determine the prognosis of patients with acute heart failure according to the Short Physical Performance Battery (SPPB) scale. METHODS: Observational, prospective, and multicenter cohort study conducted from September 2020 to May 2022 in patients with acute heart failure as the main diagnosis and NT-ProBNP > 300 pg. The cohort included patients admitted to internal medicine departments in 18 hospitals in Spain. Epidemiological variables, comorbidities, cardiovascular risk factors, cardiovascular history, analytical parameters, and treatment during admission and discharge of the patients were collected. Level of frailty was assessed by the SPPB scale, and dependence, through the Barthel index. A descriptive analysis of all the variables was carried out, expressed as frequencies and percentages. A bivariate analysis of the SPPB was performed based on the score obtained (SPPB ≤ 5 and SPPB > 5). For the overall analysis of mortality, HF mortality, and readmission of patients at 30 days, 6 months, and 1 year, Kaplan-Meier survival curves were used, in which the survival experience among patients with an SPPB > 5 and SPPB ≤ 5 was compared. RESULTS: A total of 482 patients were divided into two groups according to the SPPB with a cut-off point of an SPPB < 5. In the sample, 349 patients (77.7%) had an SPPB ≤ 5 and 100 patients (22.30%) had an SPPB > 5. Females (61%) predominated in the group with an SPPB ≤ 5 and males (61%) in those with an SPPB > 5. The mean age was higher in patients with an SPPB ≤ 5 (85.63 years). Anemia was more frequent in patients with an SPPB ≤ 5 (39.5%) than in patients with an SPPB ≥ 5 (29%). This was also seen with osteoarthritis (32.7%, p = 0.000), diabetes (49.6%, p = 0.001), and dyslipidemia (69.6%, p = 0.011). Patients with an SPPB score > 5 had a Barthel index < 60 in only 4% (n = 4) of cases; the remainder of the patients (96%, n = 96) had a Barthel index > 60. Patients with an SPPB > 5 showed a higher probability of survival at 30 days (p = 0.029), 6 months (p = 0.031), and 1 year (p = 0.007) with (OR = 7.07; 95%CI (1.60-29.80); OR: 3.9; 95%CI (1.30-11.60); OR: 6.01; 95%CI (1.90-18.30)), respectively. No statistically significant differences were obtained in the probability of readmission at 30 days, 6 months, and 1 year (p > 0.05). CONCLUSIONS: Patients admitted with acute heart failure showed a high frequency of frailty as assessed by the SPPB. Patients with an SPPB ≤ 5 had greater comorbidities and greater functional limitations than patients with an SPPB > 5. Patients with heart failure and a Barthel index > 60 frequently presented an SPPB < 5. In daily clinical practice, priority should be given to performing the SPPB in patients with a Barthel index > 60 to assess frailty. Patients with an SPPB ≤ 5 had a higher risk of mortality at 30 days, 6 months, and 1 year than patients with an SPPB ≤ 5. The SPPB is a valid tool for identifying frailty in acute heart failure patients and predicting 30-day, 6-month, and 1-year mortality.

Vascular nitrosative stress in hypertension induced by fetal undernutrition in rats

Fetal undernutrition predisposes to hypertension development. Since nitric oxide (NO) is a key factor in blood pressure control, we aimed to investigate the role of NO alterations in hypertension induced by fetal undernutrition in rats. Male and female offspring from dams exposed to undernutrition during the second half of gestation (MUN) were studied at 21 days (normotensive) and 6 months of age (hypertension developed only in males). In aorta, we analyzed total and phosphorylated endothelial NO synthase (eNOS, p-eNOS), 3-nitrotyrosine (3-NT), and Nrf2 (Western blot). In plasma we assessed L-arginine, asymmetric and symmetric dimethylarginine (ADMA, SDMA; LC–MS/MS), nitrates (NOx, Griess reaction), carbonyl groups, and lipid peroxidation (spectrophotometry). In iliac arteries, we studied superoxide anion production (DHE staining, confocal microscopy) and vasodilatation to acetylcholine (isometric tension). Twenty-one-day-old MUN offspring did not show alterations in vascular e-NOS or 3NT expression, plasma L-Arg/ADMA ratio, or NOx. Compared to control group, 6-month-old MUN rats showed increased aortic expression of p-eNOS/eNOS and 3-NT, being Nrf2 expression lower, elevated plasma L-arginine/ADMA, NOx and carbonyl levels, increased iliac artery DHE staining and reduced acetylcholine-mediated relaxations. These alterations in MUN rats were sex-dependent, affecting males. However, females showed some signs of endothelial dysfunction. We conclude that increased NO production in the context of a pro-oxidative environment, leads to vascular nitrosative damage and dysfunction, which can participate in hypertension development in MUN males. Females show a better adaptation, but signs of endothelial dysfunction, which can explain hypertension in ageing. (AU)

Effect of Supplementation with Coffee and Cocoa By-Products to Ameliorate Metabolic Syndrome Alterations Induced by High-Fat Diet in Female Mice.

Coffee and cocoa manufacturing produces large amounts of waste. Generated by-products contain bioactive compounds with antioxidant and anti-inflammatory properties, suitable for treating metabolic syndrome (MetS). We aimed to compare the efficacy of aqueous extracts and flours from coffee pulp (CfPulp-E, CfPulp-F) and cocoa shell (CcShell-E, CcShell-F) to ameliorate MetS alterations induced by a high-fat diet (HFD). Bioactive component content was assessed by HPLC/MS. C57BL/6 female mice were fed for 6 weeks with HFD followed by 6 weeks with HFD plus supplementation with one of the ingredients (500 mg/kg/day, 5 days/week), and compared to non-supplemented HFD and Control group fed with regular chow. Body weight, adipocyte size and browning (Mitotracker, confocal microscopy), plasma glycemia (basal, glucose tolerance test-area under the curve, GTT-AUC), lipid profile, and leptin were compared between groups. Cocoa shell ingredients had mainly caffeine, theobromine, protocatechuic acid, and flavan-3-ols. Coffee pulp showed a high content in caffeine, protocatechuic, and chlorogenic acids. Compared to Control mice, HFD group showed alterations in all parameters. Compared to HFD, CcShell-F significantly reduced adipocyte size, increased browning and high-density lipoprotein cholesterol (HDL), and normalized basal glycemia, while CcShell-E only increased HDL. Both coffee pulp ingredients normalized adipocyte size, basal glycemia, and GTT-AUC. Additionally, CfPulp-E improved hyperleptinemia, reduced triglycerides, and slowed weight gain, and CfPulp-F increased HDL. In conclusion, coffee pulp ingredients showed a better efficacy against MetS, likely due to the synergic effect of caffeine, protocatechuic, and chlorogenic acids. Since coffee pulp is already approved as a food ingredient, this by-product could be used in humans to treat obesity-related MetS alterations.

New genus of Lumbriculidae (Annelida, Clitellata) from a karst spring in the Cantabrian Mountains, northern Spain.

The groundwater worms of the family Lumbriculidae exhibit high diversity and endemism in southern Europe. All stygobiont lumbriculid species known so far in this region belong to six genera. In the present study, a new stygobiont lumbriculid Fendia cantabrica n. gen. n. sp. is described, mainly based on distinct characteristics of the male duct structure. The male duct is semiprosoporous and the spermathecae (two pairs) are postatrial, starting in the ovarian segment. These characteristics are shared with only two lumbriculid genera: the Nearctic Eremidrilus and Holarctic Trichodrilus. The new genus is clearly distinguished from the former by the absence of proboscis, and from both genera by a remarkably complex structure of the atrium: a very strong musculature organized in several crossed layers, a protrusible penis with a singular hydrostatic skeleton, and two prostate glands, which join separately to the atrial ampulla by short stalks.

Maternal and Neonatal Factors Modulating Breast Milk Cytokines in the First Month of Lactation.

Breast milk (BM) cytokines support and modulate infant immunity, being particularly relevant in premature neonates with adverse outcomes (NAO). This study aimed to examine, in a cohort of Spanish breastfeeding women, changes in BM cytokines in the first month of lactation, their modulation by neonatal factors (sex, gestational age, and NAO), maternal factors (obstetric complications, C-section, and diet), and their relationship with oxidative status. Sixty-three mother-neonate dyads were studied at days 7 and 28 of lactation. Dietary habits were assessed by a 72-h dietary recall, and the maternal dietary inflammatory index (mDII) was calculated. BM cytokines (IL-10, IL-13, IL-8, MCP-1, and TNFα) were assessed by ultra-sensitive chemiluminescence. Total antioxidant capacity was assessed by the ABTS method and lipid peroxidation by the MDA+HNE kit. From days 7 to 28 of lactation, the levels of IL-10 and TNFα remained stable, while IL-13 increased (ß = 0.85 ± 0.12, p < 0.001) and IL-8 and MCP-1 levels decreased (ß = -0.64 ± 0.27, p = 0.019; ß = -0.98 ± 0.22, p < 0.001; respectively). Antioxidant capacity and lipid peroxidation also decrease during lactation. Neonatal sex did not influence any of the cytokines, but BM from mothers with male infants had a higher antioxidant capacity. Gestational age was associated with male sex and NAO, being inversely correlated with the BM proinflammatory cytokines IL-8, MCP-1, and TNFα. From days 7 to 28 of lactation, BM from women with NAO infants increased MCP-1 levels and had a larger drop in antioxidant capacity, with the opposite trend in lipid peroxidation. MCP-1 was also significantly higher in women undergoing C-section; this cytokine declined in women who decreased mDII during lactation, while IL-10 increased. Linear mixed regression models evidenced that the most important factors modulating BM cytokines were lactation period and gestational age. In conclusion, during the first month of lactation, BM cytokines shift towards an anti-inflammatory profile, influenced mainly by prematurity. BM MCP-1 is associated with maternal and neonatal inflammatory processes.

Radical Scavenging and Cellular Antioxidant Activity of the Cocoa Shell Phenolic Compounds after Simulated Digestion.

The cocoa industry generates a considerable quantity of cocoa shell, a by-product with high levels of methylxanthines and phenolic compounds. Nevertheless, the digestion process can extensively modify these compounds' bioaccessibility, bioavailability, and bioactivity as a consequence of their transformation. Hence, this work's objective was to assess the influence of simulated gastrointestinal digestion on the concentration of phenolic compounds found in the cocoa shell flour (CSF) and the cocoa shell extract (CSE), as well as to investigate their radical scavenging capacity and antioxidant activity in both intestinal epithelial (IEC-6) and hepatic (HepG2) cells. The CSF and the CSE exhibited a high amount of methylxanthines (theobromine and caffeine) and phenolic compounds, mainly gallic acid and (+)-catechin, which persisted through the course of the simulated digestion. Gastrointestinal digestion increased the antioxidant capacity of the CSF and the CSE, which also displayed free radical scavenging capacity during the simulated digestion. Neither the CSF nor the CSE exhibited cytotoxicity in intestinal epithelial (IEC-6) or hepatic (HepG2) cells. Moreover, they effectively counteracted oxidative stress triggered by tert-butyl hydroperoxide (t-BHP) while preventing the decline of glutathione, thiol groups, superoxide dismutase, and catalase activities in both cell lines. Our study suggests that the cocoa shell may serve as a functional food ingredient for promoting health, owing to its rich concentration of antioxidant compounds that could support combating the cellular oxidative stress associated with chronic disease development.

Vascular nitrosative stress in hypertension induced by fetal undernutrition in rats.

Fetal undernutrition predisposes to hypertension development. Since nitric oxide (NO) is a key factor in blood pressure control, we aimed to investigate the role of NO alterations in hypertension induced by fetal undernutrition in rats. Male and female offspring from dams exposed to undernutrition during the second half of gestation (MUN) were studied at 21 days (normotensive) and 6 months of age (hypertension developed only in males). In aorta, we analyzed total and phosphorylated endothelial NO synthase (eNOS, p-eNOS), 3-nitrotyrosine (3-NT), and Nrf2 (Western blot). In plasma we assessed L-arginine, asymmetric and symmetric dimethylarginine (ADMA, SDMA; LC-MS/MS), nitrates (NOx, Griess reaction), carbonyl groups, and lipid peroxidation (spectrophotometry). In iliac arteries, we studied superoxide anion production (DHE staining, confocal microscopy) and vasodilatation to acetylcholine (isometric tension). Twenty-one-day-old MUN offspring did not show alterations in vascular e-NOS or 3NT expression, plasma L-Arg/ADMA ratio, or NOx. Compared to control group, 6-month-old MUN rats showed increased aortic expression of p-eNOS/eNOS and 3-NT, being Nrf2 expression lower, elevated plasma L-arginine/ADMA, NOx and carbonyl levels, increased iliac artery DHE staining and reduced acetylcholine-mediated relaxations. These alterations in MUN rats were sex-dependent, affecting males. However, females showed some signs of endothelial dysfunction. We conclude that increased NO production in the context of a pro-oxidative environment, leads to vascular nitrosative damage and dysfunction, which can participate in hypertension development in MUN males. Females show a better adaptation, but signs of endothelial dysfunction, which can explain hypertension in ageing.

Nucleophagy contributes to genome stability through degradation of type II topoisomerases A and B and nucleolar components.

The nuclear architecture of mammalian cells can be altered as a consequence of anomalous accumulation of nuclear proteins or genomic alterations. Most of the knowledge about nuclear dynamics comes from studies on cancerous cells. How normal healthy cells maintain genome stability, avoiding accumulation of nuclear damaged material, is less understood. Here, we describe that primary mouse embryonic fibroblasts develop a basal level of nuclear buds and micronuclei, which increase after etoposide-induced DNA double-stranded breaks. Both basal and induced nuclear buds and micronuclei colocalize with the autophagic proteins BECN1 and LC3B (also known as MAP1LC3B) and with acidic vesicles, suggesting their clearance by nucleophagy. Some of the nuclear alterations also contain autophagic proteins and type II DNA topoisomerases (TOP2A and TOP2B), or the nucleolar protein fibrillarin, implying they are also targets of nucleophagy. We propose that basal nucleophagy contributes to genome and nuclear stability, as well as in response to DNA damage.

Silver-Free Gold-Catalyzed Heterocyclizations through Intermolecular H-Bonding Activation.

Modulable monosulfonyl squaramides have been shown to exert activation of gold(I) chloride complexes through H-bonding in an intermolecular way. Combinations of (PPh3)AuCl or IPrAuCl complexes and an optimal sulfonyl squaramide cocatalyst bearing two 3,5-bis(trifluoromethyl)phenyl groups efficiently catalyzed diverse heterocyclizations and a cyclopropanation reaction, avoiding in all cases undesired side reactions. Computational studies indicate that the Au-Cl bond breaks by transligation to the triple bond in a ternary complex formed by the actual AuCl···HBD catalyst and the substrate.

Renal profile of patients treated with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate and dolutegravir/abacavir/lamivudine: 120-week results from a real-world cohort.

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (EVG/c/FTC/TAF) and dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) are currently available for HIV patients. OBJECTIVES: This study evaluated modifications in the renal safety profile in a large real-world cohort of patients who had received EVG/c/FTC/TAF or DTG/ABC/3TC. METHODS: A retrospective observational study of HIV-infected patients who received EVG/c/FTC/TAF or DTG/ABC/3TC between March 2015 and June 2019 at a reference hospital in north-western Spain was conducted. Epidemiological, clinical, immunovirological data and information regarding antiretroviral therapy were recorded. The statistical differences between treatments were calculated. RESULTS: A total of 457 patients were evaluated, 266 using EVG/c/FTC/TAF and 191 using DTG/ABC/3TC. Up to week 120, serum creatinine improved in both study groups among experienced patients (EVG/c/FTC/TAF 1.01±0.24 vs 0.91±0.19, p<0.001; DTG/ABC/3TC 1.08±0.24 vs 1.02±0.31, p<0.001), while in naïve patients serum creatinine remained stable compared with baseline. Statistically significant differences were found in serum creatinine when comparing both treatments at week 48 in experienced (0.94±0.21 vs 1.09±0.28, p<0.001) and naïve patients (0.89±0.16 vs 1.06±0.20, p=0.001), and among experienced patients at week 120 (0.91±0.19 vs 1.02±0.31, p=0.015) for the EVG/c/FTC/TAF and DTG/ABC/3TC groups, respectively. During the follow-up, 39 patients in EVG/c/FTC/TAF and 33 in DTG/ABC/3TC (p=0.449) discontinued treatment. The main reason for stopping treatment was adverse events, which were similar in both groups. CONCLUSIONS: During the follow-up, patients experienced changes that were not clinically relevant in both treatment groups. Differences in renal events were not found.