Physiological Regulation Research Articles

Antithrombotic and anticariogenic activity of peptide fractions from cowpea (Vigna unguiculata) protein hydrolysates.

Protein-derived peptide fractions can play a key role in the physiological and metabolic regulation and modulation of the body, which suggests that they could be used as functional ingredients to improve health and to reduce the risk of disease. This work aimed to evaluate the in vitro antithrombotic and anticariogenic bioactivity of hydrolysates and protein fractions obtained from cowpea (Vigna unguiculata) by biocatalysis. Cowpea protein concentrate was hydrolyzed by sequential action with two enzyme systems, Pepsin-Pancreatin or Alcalase-Flavourzyme. There was extensive enzymatic hydrolysis, with degrees of hydrolysis of 34.94% and 81.43% for Pepsin-Pancreatin and Alcalase-Flavourzyme, respectively. The degree of hydrolysis for the control treatments, without the addition of the enzymes Pepsin-Pancreatin and Alcalase-Flavourzyme was 1.1% and 1.2%, respectively. The hydrolysates were subjected to fractionation by ultrafiltration, with five cut-off points according to molecular weight (<1, 1-3, 3-5, 5-10 and >10 kDa). The Alcalase-Flavourzyme hydrolysate led to 100% inhibition of platelet aggregation, while the Pepsin-Pancreatin hydrolysate showed 77.41% inhibition, but this was approximately 100% in the ultrafiltered fractions. The highest anticariogenic activity was obtained with the Pepsin-Pancreatin system, with 61.55% and 56.07% for calcium and phosphorus demineralization, respectively. Hydrolysates and their peptide fractions from Vigna unguiculata exhibited inhibition of platelet aggregation and protection of tooth enamel and have the potential for use in the development of functional products with beneficial health effects. © 2024 Society of Chemical Industry.

Thyroid hormone receptor beta (THRB) dependent regulation of diurnal hepatic lipid metabolism in adult male mice

Thyroid hormones (THs) are critical regulators of systemic energy metabolism and homeostasis. In the liver, high TH action protects against steatosis by enhancing cholesterol and triglyceride turnover, with thyroid hormone receptor beta (THRB) signaling playing a pivotal role. This study probed the potential interaction between THRB action and another critical regulator of liver energy metabolism, the circadian clock. Liver transcriptome analysis of THRB deficient (THRBKO) mice under normal chow conditions revealed a modest impact of THRB deletion. Temporal transcriptome and lipidome profiling uncovered significant alterations in diurnal metabolic rhythms attributable to THRB deficiency pointing to a pro-steatotic state with elevated levels of cholesterol, tri- and diacylglycerides, and fatty acids. These findings were confirmed by THRB agonization in hepatocytes under steatosis-promoting conditions in vitro. Integration of transcriptome profiles from THRBKO mice and mice with induced high or low TH action identified a subset of TH responsive but THRB insensitive genes implicated in immune processes. In summary, our study reveals a complex time-of-day dependent interaction of different TH-related signals in the regulation of liver physiology indicating an opportunity for chronopharmacological approaches to TH/THRB manipulation in fatty liver diseases.

Antioxidant Potential of Exosomes in Animal Nutrition.

This review delves into the advantages of exosomes as novel antioxidants in animal nutrition and their potential for regulating oxidative stress. Although traditional nutritional approaches promote oxidative stress defense systems in mammalian animals, several issues remain to be solved, such as low bioavailability, targeted tissue efficiency, and high-dose by-effect. As an important candidate offering regulation opportunities concerned with cellular communication, disease prevention, and physiology regulation in multiple biological systems, the potential of exosomes in mediating redox status in biological systems has not been well described. A previously reported relationship between redox system regulation and circulating exosomes suggested exosomes as a fundamental candidate for both a regulator and biomarker for a redox system. Herein, we review the effects of oxidative stress on exosomes in animals and the potential application of exosomes as antioxidants in animal nutrition. Then, we highlight the advantages of exosomes as redox regulators due to their higher bioavailability and physiological heterogeneity-targeted properties, providing a theoretical foundation and feed industry application. Therefore, exosomes have shown great potential as novel antioxidants in the field of animal nutrition. They can overcome the limitations of traditional antioxidants in terms of dosage and side effects, which will provide unprecedented opportunities in nutritional management and disease prevention, and may become a major breakthrough in the field of animal nutrition.

Assessing Children's Autonomic Nervous System Activity During Structured Tasks: A Feasibility and Reliability Study in Ghana.

The significance of physiological regulation in relation to behavioral and emotional regulation is well documented, but primarily in economically advantaged contexts. Few studies have been conducted in low- and middle-income countries. We investigated the feasibility and reliability of measuring autonomic nervous system (ANS) activity and behavior during challenge tasks in 30 children aged 8-10 years in Ghana during two visits, 1 week apart. Completeness of ANS data ranged from 80% to 100% across all tasks. There was low-to-moderate test-retest reliability of video mood induction (VMI) emotion ratings and balloon analog risk task (BART) pumps (r=0.34-0.52). VMI elicited higher targeted emotion ratings in Visit 2 than Visit 1. Respiratory sinus arrhythmia (RSA) was higher, and pre-ejection period (PEP) was longer at Visit 2 than Visit 1 for baseline and both tasks. RSA was higher at baseline than during the VMI anger scene at Visit 1, whereas PEP was shorter at baseline than during all VMI emotion scenes at Visit 2. RSA was higher at baseline than during BART at both visits. In conclusion, ANS data collection within evocative and arousing challenge tasks was feasible in Ghana, and the tasks were generally reliable and effective in eliciting target emotions and risk-taking behavior in this sample.

Relationships between boldness and fecal steroid hormone levels in captive alpine musk deer (Moschus chrysogaster) in China

Animals adapt to environmental changes through behavioral and physiological regulation, and there are individual differences in their ability to adapt to the environment, which are associated with individual personality. Boldness is a fundamental axis of animal personality, characterizing an animal's response to unfamiliar environments and threats. From June 1 to July 28, 2023, a personality assessment experiment utilizing a novel stimulus test with an unfamiliar human was conducted on 39 captive alpine musk deer (Moschus chrysogaster) at the Zhuanglang Musk Farm in Gansu Province, China. We recorded avoidance reaction indicators of musk deer in the presence of an unfamiliar human, and measured the level of the musk deer's boldness, influencing factors, and the relationships with fecal steroid hormone levels. Based on cluster analysis, 39 captive musk deer could be divided into bold (boldness score, BSS = 0.994 ± 0.008, n = 3) and shy groups (BSS = 0.327 ± 0.145, n = 36) and the average BSS in 39 musk deer was 0.378 ± 0.228. Factors such as age, sex, and density of enclosures did not have a significant effect on the boldness of musk deer. There was a significant negative correlation between the musk deer's boldness and the level of fecal cortisol metabolites. However, the correlations between boldness and testosterone levels in males and estradiol levels in females were not significant. Based on the results of our study, in the practice of musk deer farming, the measurement of the boldness can help predict the individual's adaptation to environmental stress, and it can also provide a new research perspective for the study of the boldness of solitary animals that are forced to live in groups.

Dynamics of diversified A-to-I editing in Streptococcus pyogenes is governed by changes in mRNA stability.

Adenosine-to-inosine (A-to-I) RNA editing plays an important role in the post-transcriptional regulation of eukaryotic cell physiology. However, our understanding of the occurrence, function and regulation of A-to-I editing in bacteria remains limited. Bacterial mRNA editing is catalysed by the deaminase TadA, which was originally described to modify a single tRNA in Escherichia coli. Intriguingly, several bacterial species appear to perform A-to-I editing on more than one tRNA. Here, we provide evidence that in the human pathogen Streptococcus pyogenes, tRNA editing has expanded to an additional tRNA substrate. Using RNA sequencing, we identified more than 27 editing sites in the transcriptome of S.pyogenes SF370 and demonstrate that the adaptation of S.pyogenes TadA to a second tRNA substrate has also diversified the sequence context and recoding scope of mRNA editing. Based on the observation that editing is dynamically regulated in response to several infection-relevant stimuli, such as oxidative stress, we further investigated the underlying determinants of editing dynamics and identified mRNA stability as a key modulator of A-to-I editing. Overall, our findings reveal the presence and diversification of A-to-I editing in S.pyogenes and provide novel insights into the plasticity of the editome and its regulation in bacteria.

Dietary fibre optimisation in support of global health.

The human gut microbiota influences its host via multiple molecular pathways, including immune system interactions, the provision of nutrients and regulation of host physiology. Dietary fibre plays a crucial role in maintaining a healthy microbiota as its primary nutrient and energy source. Industrialisation has led to a massive decrease of habitual fibre intake in recent times, and fibre intakes across the world are below the national recommendations. This goes hand in hand with other factors in industrialised societies that may negatively affect the gut microbiota, such as medication and increased hygiene. Non-communicable diseases are on the rise in urbanised societies and the optimisation of dietary fibre intake can help to improve global health and prevent disease. Early life interventions shape the developing microbiota to counteract malnutrition, both in the context of industrialised nations with an overabundance of cheap, highly processed foods, as well as in Low- and Middle-Income Countries (LMICs). Adequate fibre intake should, however, be maintained across the life course to promote health. Here we will discuss the current state of dietary fibre research in the global context and consider different intervention approaches.

Biomolecular condensates as stress sensors and modulators of bacterial signaling.

Microbes exhibit remarkable adaptability to environmental fluctuations. Signaling mechanisms, such as two-component systems and secondary messengers, have long been recognized as critical for sensing and responding to environmental cues. However, recent research has illuminated the potential of a physical adaptation mechanism in signaling-phase separation, which may represent a ubiquitous mechanism for compartmentalizing biochemistry within the cytoplasm in the context of bacteria that frequently lack membrane-bound organelles. This review considers the broader prospect that phase separation may play critical roles as rapid stress sensing and response mechanisms within pathogens. It is well established that weak multivalent interactions between disordered regions, coiled-coils, and other structured domains can form condensates via phase separation and be regulated by specific environmental parameters in some cases. The process of phase separation itself acts as a responsive sensor, influenced by changes in protein concentration, posttranslational modifications, temperature, salts, pH, and oxidative stresses. This environmentally triggered phase separation can, in turn, regulate the functions of recruited biomolecules, providing a rapid response to stressful conditions. As examples, we describe biochemical pathways organized by condensates that are essential for cell physiology and exhibit signaling features. These include proteins that organize and modify the chromosome (Dps, Hu, SSB), regulate the decay, and modification of RNA (RNase E, Hfq, Rho, RNA polymerase), those involved in signal transduction (PopZ, PodJ, and SpmX) and stress response (aggresomes and polyphosphate granules). We also summarize the potential of proteins within pathogens to function as condensates and the potential and challenges in targeting biomolecular condensates for next-generation antimicrobial therapeutics. Together, this review illuminates the emerging significance of biomolecular condensates in microbial signaling, stress responses, and regulation of cell physiology and provides a framework for microbiologists to consider the function of biomolecular condensates in microbial adaptation and response to diverse environmental conditions.

LAIR-1 and PECAM-1 function via the same signaling pathway to inhibit GPVI-mediated platelet activation

BackgroundInhibition of platelet responsiveness is important for controlling thrombosis. It is well established that platelet endothelial cell adhesion molecule-1 (PECAM-1) serves as a physiological negative regulator of platelet-collagen interactions. We recently demonstrated that leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a negative regulator of platelet production and reactivity. It is however not known if LAIR-1 and PECAM-1 function in the same or different inhibitory pathways. ObjectivesIn this study, we investigated the role of LAIR-1 alongside PECAM-1 in megakaryocyte development and platelet production and determined the functional redundancy through characterization of a LAIR-1/PECAM-1 double knockout (DKO) mouse model. MethodsLAIR-1 and PECAM-1 expression in megakaryocytes were evaluated by western blotting. Megakaryocyte ploidy and proplatelet formation were evaluated by flow cytometry and fluorescent microscopy. Platelet function and signalling were compared in wild-type, LAIR-1−/−, PECAM-1−/− and DKO mice using aggregometry, flow cytometry and western blotting. Thrombosis was evaluated using the FeCl3 carotid artery model. ResultsWe show that LAIR-1/PECAM-1 DKO mice exhibit a 17% increase in platelet count. Bone marrow-derived megakaryocytes from all 3 mouse models had normal ploidy in vitro, suggesting that neither LAIR-1 nor PECAM-1 regulates megakaryocyte development. Furthermore, relative to wild-type platelets, platelets derived from LAIR-1, PECAM-1, and DKO mice were equally hyperresponsive to collagen in vitro, indicating that LAIR-1 and PECAM-1 participate in the same inhibitory pathway. Interestingly, DKO mice exhibited normal thrombus formation in vivo due to DKO mouse platelets lacking the enhanced Src family kinase activation previously shown in platelets from LAIR-1-deficient mice. ConclusionFindings from this study reveal that LAIR-1 and PECAM-1 act to inhibit GPVI-mediated platelet activation via the same signaling pathway. Mice lacking LAIR-1 and PECAM-1 do not however exhibit an increase in thrombus formation despite minor increase in platelet count and reactivity to collagen. This study adds to the growing evidence that immunoreceptor tyrosine-based inhibition motif–containing receptors are important regulators of platelet count and function.

Identification of a magnesium-binding site at the primary allosteric calcium sensor of the sodium-calcium exchanger: Implications for physiological regulation.

Sodium-calcium exchanger (NCX) proteins are ubiquitously expressed and play a pivotal role in cellular calcium homeostasis by mediating uphill calcium efflux across the cell membrane. Intracellular calcium allosterically regulates the exchange activity by binding to two cytoplasmic calcium-binding domains, CBD1 and CBD2. However, the calcium-binding affinities of these domains are seemingly inadequate to sense physiological calcium oscillations. Previously, magnesium binding to either domain was shown to tune their affinity for calcium, bringing it into the physiological range. However, while the magnesium-binding site of CBD2 was identified, the identity of the CBD1 magnesium site remains elusive. Here, using molecular dynamics in combination with differential scanning fluorimetry and mutational analysis, we pinpoint the magnesium-binding site in CBD1. Specifically, among four calcium-binding sites (Ca1-Ca4) in this domain, only Ca1 can accommodate magnesium with an affinity similar to its free intracellular concentration. Moreover, our results provide mechanistic insights into the modulation of the regulatory calcium affinity by magnesium, which allows an adequate NCX activity level throughout varying physiological needs.

Methionine Improves Boar Sperm Quality by Promoting Mitochondrial Translation during Liquid Storage.

Boar sperm quality serves as an important indicator of reproductive efficiency, playing a direct role in enhancing the output of livestock production. It has been demonstrated that mitochondrial protein translation is present in sperm and plays a crucial role in regulating sperm motility, capacitation and in vitro fertilization rate. The present study aimed to determine whether methionine supplementation enhances mitochondrial translation in boar sperm, thereby improving sperm quality. The results showed a significant elevation in the abundance of mitochondrial methionyl-tRNA formyltransferase (MTFMT), a crucial enzyme for mitochondrial protein translation, and mitochondrial DNA-encoded cytochrome c oxidase subunit 1 (COX1) in boar sperm exhibiting high motility. Both amino acids and methionine supplementation significantly enhanced boar sperm motility during storage. Moreover, methionine supplementation mitigates the loss of acrosomal integrity, enhances the expression of COX1, and boosts mitochondrial activity. Furthermore, the positive impact of methionine was negated in the presence of the mitochondrial translation inhibitor chloramphenicol. Together, these findings suggest that boar sperm may utilize methionine as a protein translation substrate to enhance sperm motility by stimulating mitochondrial protein translation. The supplementation of methionine may enhance the quality of boar sperm, thereby providing guidance for the optimization of diluent formulations for liquid storage and the identification of physiological regulators that regulate sperm motility.

Anxiety is related to slower RSA oscillation during stress response and regulation.

Respiratory sinus arrhythmia (RSA), an index of the parasympathetic nervous system activity, has been considered indicative of stress response and emotion regulation. However, the relationship between RSA and anxiety remains inconclusive, partly because previous research has primarily focused on static RSA levels. In this nonclinical sample (N = 75, Mage = 20.89 ± 1.72 SD, 48 males), we used a damped oscillator model to characterize RSA dynamics across 30-s epochs while participants completed the Trier social stress test. Results showed that RSA constantly oscillated during the three periods of TSST (namely Rest, Stress, and Recovery). Importantly, slower RSA oscillation in the Stress period was related to elevated state anxiety, whereas in the Recovery period, it was related to higher trait anxiety. These findings demonstrated the dynamic nature of RSA during the whole course of stress response. Slower RSA oscillation may indicate inflexible and tardy physiological regulation which may give rise to anxiety issues.

Risk of Fat Mass- and Obesity-Associated Gene-Dependent Obesogenic Programming by Formula Feeding Compared to Breastfeeding.

It is the purpose of this review to compare differences in postnatal epigenetic programming at the level of DNA and RNA methylation and later obesity risk between infants receiving artificial formula feeding (FF) in contrast to natural breastfeeding (BF). FF bears the risk of aberrant epigenetic programming at the level of DNA methylation and enhances the expression of the RNA demethylase fat mass- and obesity-associated gene (FTO), pointing to further deviations in the RNA methylome. Based on a literature search through Web of Science, Google Scholar, and PubMed databases concerning the dietary and epigenetic factors influencing FTO gene and FTO protein expression and FTO activity, FTO's impact on postnatal adipogenic programming was investigated. Accumulated translational evidence underscores that total protein intake as well as tryptophan, kynurenine, branched-chain amino acids, milk exosomal miRNAs, NADP, and NADPH are crucial regulators modifying FTO gene expression and FTO activity. Increased FTO-mTORC1-S6K1 signaling may epigenetically suppress the WNT/β-catenin pathway, enhancing adipocyte precursor cell proliferation and adipogenesis. Formula-induced FTO-dependent alterations of the N6-methyladenosine (m6A) RNA methylome may represent novel unfavorable molecular events in the postnatal development of adipogenesis and obesity, necessitating further investigations. BF provides physiological epigenetic DNA and RNA regulation, a compelling reason to rely on BF.

Macronutrient regulation in nymphs of the two-spotted cricket, Gryllus bimaculatus (Orthoptera: Gryllidae)

Crickets have been extensively studied in recent insect nutritional research, but it remains largely unexplored how they balance the intake of multiple nutrients. Here, we used the nutritional geometry framework to examine the behavioural and physiological regulation of dietary protein and carbohydrate in nymphs of the two-spotted cricket, Gryllus bimaculatus (Orthoptera: Gryllidae). Growth, intake, utilization efficiencies, and body composition were measured from the eighth instar nymphs that received either food pairs or single foods with differing protein and carbohydrate content. When food choices were available, crickets preferentially selected a carbohydrate-biased protein:carbohydrate (P:C) ratio of 1:1.74. During this nutrient selection, carbohydrate intake was more tightly regulated than protein intake. When confined to nutritionally imbalanced foods, crickets adopted a nutrient balancing strategy that maximized the nutrient intake regardless of the nutrient imbalance, reflecting their omnivorous feeding habit. Intake was significantly reduced when crickets were confined to the most carbohydrate-biased food (P:C = 1:5). When nutrients were ingested in excess of the requirements, the post-ingestive utilization efficiencies of these nutrients were down-regulated, thereby buffering the impacts of nutrient imbalances on body nutrient composition. Crickets reared on the most carbohydrate-biased food (P:C = 1:5) suffered delayed development and reduced growth. Our data provide the most accurate description of nutrient regulation in G. bimaculatus and lay the foundation for further nutritional research in this omnivorous insect.

MiR-223-3p in Cancer Development and Cancer Drug Resistance: Same Coin, Different Faces.

MicroRNAs (miRNAs) are mighty post-transcriptional regulators in cell physiology and pathophysiology. In this review, we focus on the role of miR-223-3p (henceforth miR-223) in various cancer types. MiR-223 has established roles in hematopoiesis, inflammation, and most cancers, where it can act as either an oncogenic or oncosuppressive miRNA, depending on specific molecular landscapes. MiR-223 has also been linked to either the sensitivity or resistance of cancer cells to treatments in a context-dependent way. Through this detailed review, we highlight that for some cancers (i.e., breast, non-small cell lung carcinoma, and glioblastoma), the oncosuppressive role of miR-223 is consistently reported in the literature, while for others (i.e., colorectal, ovarian, and pancreatic cancers, and acute lymphocytic leukemia), an oncogenic role prevails. In prostate cancer and other hematological malignancies, although an oncosuppressive role is frequently described, there is less of a consensus. Intriguingly, NLRP3 and FBXW7 are consistently identified as miR-223 targets when the miRNA acts as an oncosuppressor or an oncogene, respectively, in different cancers. Our review also describes that miR-223 was increased in biological fluids or their extracellular vesicles in most of the cancers analyzed, as compared to healthy or lower-risk conditions, confirming the potential application of this miRNA as a diagnostic and prognostic biomarker in the clinic.

Genome-wide identification of the EIN3/EIL gene family in Ginkgo biloba and functional study of a GbEIL in the ethylene signaling pathway

ETHYLENE-INSENSITIVE3 (EIN3) or EIN3-Like (EIL) proteins, play critical roles in integrating ethylene signaling and physiological regulation in plants by modulating the expression of various downstream genes, such as ethylene-response factors (ERFs). However, little is known about the characteristics of EIN3/EILs in the gymnosperm Ginkgo biloba. In the present study, a genome-wide comparative analysis of Ginkgo EIN3/EIL gene family was performed with those from an array of species, including bryophytes (Physcomitrella patens), gymnosperms (Cycas panzhihuaensis), and angiosperms (Arabidopsis thaliana, Gossypium raimondii, Gossypium hirsutum, Oryza sativa, and Brachypodium distachyon). Within the constructed phylogenetic tree for the 53 EIN3/EILs identified, 5 GbEILs from G. biloba, 2 PpEILs from P. patens, and 3 CpEILs from C. panzhihuaensis were assigned to one cluster, suggesting that their derivation occurred after the split of their ancestors and angiosperms. Although considerable divergence accumulated in amino acid sequences along with the evolutionary process, the specific EIN3_DNA-binding domains were evolutionarily conserved among the 53 EIN3/EILs. Collinearity analysis indicated that whole-genome or segmental duplication and subsequent purifying selection might have prompted the generation and evolution of EIN3/EIL multigene families. Based on the expression patterns of five GbEILs at the four developmental stages of Ginkgo ovules, one GbEIL gene (Gb_03292) was further investigated for its role in mediating ethylene signaling. The functional activity of Gb_03292 was closely related to ethylene signaling, as it complemented the triple response via ectopic expression in ein3eil1 double mutant Arabidopsis. Additionally, GbEIL likely modulates the expression of a Ginkgo ERF (Gb_15517) by directly binding to its promoter. These results demonstrated that the GbEIL gene could have participated in mediating ethylene signal transduction during ovule development in G. biloba. The present study also provides insights into the conservation of ethylene signaling across the gymnosperm G. biloba and angiosperm species.

FhMYB108 Regulates the Expression of Linalool Synthase Gene in Freesia hybrida and Arabidopsis.

Acting as the most abundant and widely distributed volatile secondary metabolites in plants, terpenoids play crucial roles in diverse physiological regulations and metabolic processes. Terpene synthases play a decisive role in determining the composition and diversity of terpenoids. Though the regulation of terpene synthases has been extensively investigated across various plant species, limited studies have focused on the upstream transcriptional regulation of terpene synthases. In this study, we have identified linalool as the predominant volatile compound that is released gradually from Freesia hybrida flowers throughout flower blooming. In the context of the transcriptome, a typical MYB transcription factor, FhMYB108, was screened based on homologous gene comparison. FhMYB108 is capable of regulating the expression of FhTPS1, and both their expression levels showed gradual increase during flower opening. Moreover, FhMYB108 exerts a stimulatory effect on the transcription of Arabidopsis thaliana AtTPS14, while no significant increase in AtTPS14 expression is observed upon the stabilization of FhMYB108 in A. thaliana. The highly expressed AtMYC2 in A. thaliana could interact with FhMYB108 to suppress the activation of AtTPS14 by FhMYB108. The present study not only elucidates the regulatory mechanism underlying linalool synthesis but also discovers the synergistic effect of MYB and bHLH transcription factors in governing the biosynthesis of volatile terpenoids.

Neuroactive steroids fluctuate with regional specificity in the central and peripheral nervous system across the rat estrous cycle

Neuroactive steroids (i.e., sex steroid hormones and neurosteroids) are important physiological regulators of nervous function and potential neuroprotective agents for neurodegenerative and psychiatric disorders. Sex is an important component of such effects. However, even if fluctuations in sex steroid hormone level during the menstrual cycle are associated with neuropathological events in some women, the neuroactive steroid pattern in the brain across the ovarian cycle has been poorly explored. Therefore, we assessed the levels of pregnenolone, progesterone, and its metabolites (i.e., dihydroprogesterone, allopregnanolone and isoallopregnanolone), dehydroepiandrosterone, testosterone and its metabolites (i.e., dihydrotestosterone, 3α-diol and 17β-estradiol) across the rat ovarian cycle to determine whether their plasma fluctuations are similar to those occurring in the central (i.e., hippocampus and cerebral cortex) and peripheral (i.e., sciatic nerve) nervous system. Data obtained indicate that the plasma pattern of these molecules generally does not fully reflect the events occurring in the nervous system. In addition, for some neuroactive steroid levels, the pattern is not identical between the two brain regions and between the brain and peripheral nerves. Indeed, with the exception of progesterone, all other neuroactive steroids assessed here showed peculiar regional differences in their pattern of fluctuation in the nervous system during the estrous cycle. These observations may have important diagnostic and therapeutic consequences for neuropathological events influenced by the menstrual cycle.

Age as an Effect Modifier of the Effects of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) on Heart Rate Variability in Healthy Subjects.

Background: Evidence suggests that vagus nerve stimulation can modulate heart rate variability (HRV). However, there is a lack of mechanistic studies in healthy subjects assessing the effects of bilateral transcutaneous auricular vagus nerve stimulation (taVNS) on HRV. Our study aims to investigate how taVNS can influence the HRV response, including the influence of demographic variables in this response. Methods: Therefore, we conducted a randomized controlled study with 44 subjects, 22 allocated to active and 22 to sham taVNS. Results: Our results showed a significant difference between groups in the high-frequency (HF) metric. Active taVNS increased the HF metric significantly as compared to sham taVNS. Also, we found that age was a significant effect modifier of the relationship between taVNS and HF-HRV, as a larger increase in HF-HRV was seen in the older subjects. Importantly, there was a decrease in HF-HRV in the sham group. Conclusions: These findings suggest that younger subjects can adapt and maintain a constant level of HF-HRV regardless of the type of stimulation, but in the older subjects, only the active taVNS recipients were able to maintain and increase their HF-HRV. These results are important because they indicate that taVNS can enhance physiological regulation processes in response to external events.

Sex-specific epigenetic signatures of circulating urate and its increase after BCG vaccination.

Urate concentration and the physiological regulation of urate homeostasis exhibit clear sex differences. DNA methylation has been shown to explain a substantial proportion of serum urate variance, mediate the genetic effect on urate concentration, and co-regulate with cardiometabolic traits. However, whether urate concentration is associated with DNA methylation in a sex-dependent manner is unknown. Additionally, it is worth investigating if urate changes after perturbations, such as vaccination, are associated with DNA methylation in a sex-specific manner. We investigated the association between DNA methylation and serum urate concentrations in a Dutch cohort of 325 healthy individuals. Urate concentration and DNA methylation were measured before and after Bacillus Calmette-Guérin (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis. Validation of the identified CpG sites was conducted using three independent cohorts. 215 CpG sites were associated with serum urate in males, while 5 CpG sites were associated with serum urate in females, indicating sex-specific associations. Circulating urate concentrations significantly increased after BCG vaccination, and baseline DNA methylation was associated with differences in urate concentration before and after vaccination in a sex-specific manner. The CpG sites associated with urate concentration in males were enriched in neuro-protection pathways, whereas in females, the urate change-associated CpG sites were related to lipid and glucose metabolism. Our study enhances the understanding of how epigenetic factors contribute to regulating serum urate levels in a sex-specific manner. These insights have significant implications for the diagnosis, prevention, and treatment of various urate-related diseases and highlight the importance of personalized and sex-specific approaches in medicine.