Introduction Hypertension contributes to cardiovascular disease, with growing evidence of sex-specific differences in its underlying mechanisms. T-type voltage-gated calcium channels (VGCCs) have emerged as key regulators of vascular tone, particularly under conditions of nitric oxide (NO) deficiency. However, their role in mediating vascular dysfunction across sexes remains poorly understood.Methods This study examined the role of T-type VGCCs and their modulation by NO in the renal artery of male and female spontaneously hypertensive rats (SHR). Vascular reactivity was assessed through phenylephrine-induced contractions in the presence or absence of nickel chloride (NiCl2), a T-type VGCC blocker, and L-NAME, an inhibitor of nitric oxide synthase (NOS). Gene expression of T-type VGCCs (CaV3.1 and CaV3.2) and eNOS was quantified by RT-PCR. Oxidative stress parameters in leukocytes were assessed by flow cytometry to explore the systemic redox.Results Hypertension induced a rightward shift of the acetylcholine-mediated vasorelaxation curve. In male rats, hypertension did not significantly alter the phenylephrine concentration-response curve. A single data point showed a significant difference following incubation with L-NAME. The contribution of T-type VGCCs to vascular reactivity remained unchanged. Male SHRs displayed increased mRNA expression of CaV3.1, CaV3.2, and eNOS, yet showed no corresponding increase in T-type VGCC activity or NO availability. Conversely, in female SHR, phenylephrine concentration-response curve showed a leftward shift, reduced NO release, and increased participation of T-type VGCCs in response to phenylephrine. Furthermore, pharmacological inhibition of NO synthesis in female WKY rats, used to simulate hypertensive conditions, enhanced the involvement of T-type VGCCs in phenylephrine-induced vasoconstriction. mRNA expression of eNOS was not modified by hypertension in females. Despite the heightened T-type VGCCs activity, female SHRs had reduced mRNA expression of CaV3.1 and CaV3.2, suggesting a potential compensatory downregulation. Finally, leukocytes of male SHR exhibited significantly increased production of H2O2 and ONOO- compared to the other studied groups, suggesting that hypertension contributes to a greater oxidative stress in male.Discussion These findings reveal sex-specific differences in the role of T-type VGCCs during hypertension and underscore the therapeutic potential of targeting T-type VGCCs, particularly in females, as a sex-specific strategy for more effective and personalized hypertension management.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in xenobiotic sensing and multiple physiological functions, including intestinal homeostasis. Aging is associated with reduced colonic motility and constipation, but the contribution of AhR to intestinal motor function across sex and age remains incompletely defined. We performed a phenotypic characterization of AhR-deficient (AhR−/−) and wild-type (WT) C57BL/6J mice in both sexes at two ages (young: 4–6 months; adult: 12–13 months). Lifespan, body weight, food and water intake were monitored longitudinally. Body composition (DXA), hematological parameters, fecal output features (number, length, moisture and stool color analysis), ex vivo colonic function in organ bath (spontaneous peristalsis with or without L-NAME and responses to acetylcholine and norepinephrine), histological muscle thickness, and molecular markers (PGP9.5 and NOS1 protein; Nos1, Nos2, Aqp1/3/4/8, Il6, Il10 gene expression) were assessed. AhR−/− mice exhibited reduced survival and attenuated body weight gain, particularly in females, without differences in food consumption but with increased water intake. Fecal length and moisture were unchanged; however, AhR−/− females displayed fewer stools at both ages. Ex vivo, spontaneous peristaltic amplitude was selectively reduced in AhR−/− females at both ages, whereas males were unaffected. L-NAME increased spontaneous peristalsis in WT males but not in AhR−/− males, suggesting impaired nitrergic modulation in the absence of AhR. Acetylcholine-induced contraction was reduced in young AhR−/− females but not in adults. Histology revealed reduced colonic muscle thickness in young AhR−/− females only, accompanied by decreased PGP9.5 protein expression. Gene expression showed sex- and age-dependent changes in Nos1/Nos2, aquaporins, and inflammatory markers. AhR deficiency leads to a sex-dependent colonic motor phenotype predominantly affecting females, integrating functional impairment with early neuromuscular remodeling and altered neural markers. These findings support AhR as a regulator of intestinal motor function with potential relevance to age-related dysmotility.

T-type voltage-gated calcium channels (VGCCs) are comparatively understudied in large conduit artery function relative to the well-characterized L-type channel subtype. This study investigates the vascular roles of T-type VGCCs in the aorta and renal artery of healthy rabbits using functional reactivity assays and immunofluorescence and further elucidates the interaction between T-type VGCC activity and the nitric oxide (NO) signalling pathway. T-type VGCCs contributed to contractile responses induced by phenylephrine and angiotensin II in both arteries. Moreover, in the renal artery, the contribution of T-type VGCCs in response to phenylephrine increased in the absence of NO and was associated with endothelium-dependent vasodilation. Immunofluorescence analysis revealed co-localization of CaV3.1 with endothelial nitric oxide synthase in the renal artery, but not in the aorta, suggesting a vasodilatory role in renal circulation. These findings highlight vascular bed-specific functions of T-type VGCCs and their interaction with endothelial pathways in the renal artery.

Aging is associated with increased oxidative stress, which contributes to cellular dysfunction and age-related diseases. Pomegranate extract (PE), rich in antioxidant polyphenols, may help mitigate oxidative damage. This study evaluated whether PE supplementation modulates oxidative stress by reducing reactive oxygen species (ROS) levels in white blood cells of aging mice. Aged mice (18 months) were supplemented with PE for four months, and cytoplasmic and mitochondrial ROS levels were assessed in leukocytes under basal conditions and oxidative stress conditions induced by tert-butyl hydroperoxide (t-BHP) using flow cytometry. Our results indicate that aged mice exhibit increased basal ROS levels in both the mitochondrial and cytoplasmic compartments, which were mitigated by PE supplementation. Furthermore, PE reversed the increase in hydrogen peroxide levels induced by τ-BHP and protected neutrophils by reducing mitochondrial ROS levels. These findings suggest that PE supplementation modulates the oxidative stress response, potentially improving immune function in aging. Given the central role of oxidative stress in age-related decline, PE may represent a valuable nutritional strategy to promote healthy aging.

Sodium valproate (VPA), a histone deacetylase (HDAC) inhibitor, could be a promising candidate to treat acute myocardial infarction (AMI). In this study, AMI was induced in New Zealand White rabbits by occluding the left circumflex coronary artery for 1 h, followed by reperfusion. The animals were distributed into three experimental groups: the sham-operated group (SHAM), the AMI group and the AMI + VPA group (AMI treated with VPA 500 mg/kg/day). After 5 weeks, abdominal aorta was removed and used for isometric recording of tension in organ baths or protein expression by Western blot, and plasma for the determination of nitrate/nitrite (NOx) levels by colorimetric assay. Our results indicated that AMI induced a reduction of the endothelium-dependent response to acetylcholine without modifying the endothelium-independent response to sodium nitroprusside, leading to endothelial dysfunction. VPA treatment reversed AMI-induced endothelial dysfunction and even increased NO sensitivity in vascular smooth muscle. This response was consistent with an antioxidant effect of VPA, as it was able to reverse the superoxide dismutase 1 (SOD 1) down-regulation induced by AMI. Our experiments also ruled out that the VPA mechanism was related to eNOS, iNOS, sGC and arginase expression or changes in NOx plasma levels. Therefore, we conclude that VPA improves vasodilation by increasing NO bioavailability, likely due to its antioxidant effect. Since endothelial dysfunction was closely related to AMI, VPA treatment could increase aortic blood flow, making it a potential agent in reperfusion therapy that can prevent the vascular damage.

Probiotics are living microorganisms recognized for conferring health benefits on the host by modulating the gut microbiota. They interact with various signaling pathways, including the aryl hydrocarbon receptor (AhR), which plays a crucial role in maintaining intestinal homeostasis and immune function. The activation of AhR by probiotics has been associated with benefits such as improved intestinal barrier function, reduced inflammation, and modulation of immune responses. This systematic review aims to summarize current knowledge on the signaling of AhR, mediated by probiotics in physiological conditions and gastrointestinal pathologies. We conducted a comprehensive search across databases, including PubMed and Embase, up until July 2024. Out of 163 studies screened, 18 met the inclusion criteria. Our findings revealed in healthy populations that probiotic consumption increases the production of AhR ligands promoting intestinal immune tolerance. Furthermore, in populations with gastrointestinal pathologies, probiotics ameliorated symptoms through AhR activation by Trp metabolites, leading to the upregulation of the anti-inflammatory response.

Background/Objectives: Acute myocardial infarction (AMI) is a critical medical condition that requires immediate attention to minimise heart damage and improve survival rates. Early identification and prompt treatment are essential to save the patient’s life. Currently, the treatment strategy focuses on restoring blood flow to the myocardium as quickly as possible. However, reperfusion activates several cellular cascades that contribute to organ dysfunction, resulting in the ischaemia/reperfusion (I/R) injury. The search for treatments against AMI and I/R injury is urgent due to the shortage of effective treatments at present. In this regard, histone deacetylase (HDAC) inhibitors emerge as a promising treatment against myocardial infarction. The objective of this systematic review is to analyse the effects of HDAC inhibitors on ventricular function, cardiac remodelling and infarct size, among other parameters, focusing on the signalling pathways that may mediate these cardiovascular effects and protect against AMI. Methods: Original experimental studies examining the effects of HDAC inhibitors on AMI were included in the review using the PubMed and Scopus databases. Non-experimental papers were excluded. The SYRCLE RoB tool was used to assess risk of bias and the results were summarised in a table and presented in sections according to the type of HDAC inhibitor used. Results: A total of 18 studies were included, 10 of them using trichostatin A (TSA) as an HDAC inhibitor and concluding that the treatment improved ventricular function, reduced infarct size, and inhibited myocardial hypertrophy and remodelling after AMI. Other HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), valproic acid (VPA), mocetinostat, givinostat, entinostat, apicidin, and RGFP966, were also analysed, showing antioxidant and anti-inflammatory effects, an improvement in cardiac function and remodelling, and a decrease in apoptosis, among other effects. Conclusions: HDAC inhibitors constitute a significant promise for the treatment of AMI due to their diverse cardioprotective effects. However, high risk of selection, performance, and detection bias in the in vivo studies means that their application in the clinical setting is still a long way off and more research is needed to better understand their benefits and possible side effects.

In previous studies, using transcriptomic analysis, we observed higher levels of aryl hydrocarbon receptor (AHR) gene expression in the peripheral blood cells of centenarians compared to octogenarians. This suggests the potential significance of this receptor in maintaining physiological balance and promoting healthy aging, possibly linked to its critical role in detoxifying xenobiotics. In our current study, we confirmed that AHR expression is indeed higher in centenarians. We employed C. elegans as a model known for its suitability in longevity studies to explore whether the AHR pathway has a significant impact on lifespan and healthspan. Our survival assays revealed that two different mutants of AHR-1 exhibited lower longevity. Additionally, we used a mouse model to examine whether supplementation with pomegranate extract modulates the expression of AHR pathway genes in the liver. Furthermore, we studied a nutritional strategy based on pomegranate extract administration to investigate its potential modulation of life- and healthspan in worms.

La asignatura de Fisiopatología del Grado de Farmacia consta de seminarios que tradicionalmente se han planteado como exposiciones orales grupales. Sin embargo, la amplia utilización de esta metodología en muchas asignaturas puede ser causa de una disminución en la motivación y rendimiento del alumnado en esta actividad. Además, esta estrategia podría no ser muy efectiva para incorporar los Objetivos de Desarrollo Sostenible (ODS). Por tanto, hemos implantado un cambio de la metodología, aplicando nuevas estrategias pedagógicas que potencian el uso de nuevas tecnologías de la información y la comunicación a través de dispositivos electrónicos, tales como elementos multimedia y herramientas de respuesta a audiencia. Nuestro objetivo es aumentar la atención, motivación y participación del alumnado y fomentar la adquisición de competencias que les permitan integrar los contenidos teóricos de la asignatura con su vertiente aplicada. Este proyecto de innovación docente, implantado en el curso 21-22 y optimizado en el 22-23, ha generado resultados prometedores que se ajustan a los previstos inicialmente, aumentando el rendimiento y la motivación del alumnado en el desarrollo de esta actividad y mejorando su percepción del aprovechamiento del tiempo en clase, la comprensión y la integración de los contenidos, así como la incorporación de los ODS.

Figure S4. Higher self-renewal capacity of sorted G03 patient-derived cell.

This is a narrative review about the mechanisms involved in bacterial sepsis in preterm infants, which is an illness with a high incidence, morbidity, and mortality. The role of the innate immune response and its relationship with oxidative stress in the pathogenesis are described as well as their potential implementation as early biomarkers. Moreover, we address the impact that all the mechanisms triggered by sepsis have on the dysbiosis and the changes on neonatal microbiota.

Figure S3. Reduced acetylation on H4K16 in KD-KANSL2 cells.

Activation of the aryl hydrocarbon receptor (AhR) has been shown to be important in physiological processes other than detoxification, including vascular homeostasis. Although AhR is highly expressed in the endothelium, its function has been poorly studied. This systematic review aims to summarise current knowledge on the AhR role in the endothelium and its cardiovascular implications. We focus on endogenous AhR agonists, such as some uremic toxins and other agonists unrelated to environmental pollutants, as well as studies using AhR knockout models. We conclude that AhR activation leads to vascular oxidative stress and endothelial dysfunction and that blocking AhR signalling could provide a new target for the treatment of vascular disorders such as cardiovascular complications in patients with chronic kidney disease or pulmonary arterial hypertension.

Insulin resistance is one of the main characteristics of metabolic syndrome (MetS) and the main cause of the development of type II diabetes. The high prevalence of this syndrome in recent decades has made it necessary to search for preventive and therapeutic agents, ideally of natural origin, with fewer side effects than conventional pharmacological treatments. Tea is widely known for its medicinal properties, including beneficial effects on weight management and insulin resistance. The aim of this study was to analyze whether a standardized extract of green and black tea (ADM® Complex Tea Extract (CTE)) prevents the development of insulin resistance in mice with MetS. For this purpose, C57BL6/J mice were fed for 20 weeks with a standard diet (Chow), a diet with 56% kcal from fat and sugar (HFHS) or an HFHS diet supplemented with 1.6% CTE. CTE supplementation reduced body weight gain, adiposity and circulating leptin levels. Likewise, CTE also exerted lipolytic and antiadipogenic effects in 3T3-L1 adipocyte cultures and in the C. elegans model. Regarding insulin resistance, CTE supplementation significantly increased plasma adiponectin concentrations and reduced the circulating levels of insulin and the HOMA-IR. Incubation of liver, gastrocnemius muscle and retroperitoneal adipose tissue explants with insulin increased the pAkt/Akt ratio in mice fed with Chow and HFHS + CTE but not in those fed only with HFHS. The greater activation of the PI3K/Akt pathway in response to insulin in mice supplemented with CTE was associated with a decrease in the expression of the proinflammatory markers Mcp-1, IL-6, IL-1β or Tnf-α and with an overexpression of the antioxidant enzymes Sod-1, Gpx-3, Ho-1 and Gsr in these tissues. Moreover, in skeletal muscle, mice treated with CTE showed increased mRNA levels of the aryl hydrocarbon receptor (Ahr), Arnt and Nrf2, suggesting that the CTE’s insulin-sensitizing effects could be the result of the activation of this pathway. In conclusion, supplementation with the standardized extract of green and black tea CTE reduces body weight gain, exerts lipolytic and antiadipogenic effects and reduces insulin resistance in mice with MetS through its anti-inflammatory and antioxidant effects.