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The R230C variant of the ATP-binding cassette transporter A1 (ABCA1) gene has been consistently associated with decreased HDL-cholesterol (HDL-C) concentrations in several studies in the Mexican mestizo population. However, information on how diet composition modifies the effect of the ABCA1-R230C variant on HDL-C concentrations is very scarce. The aim of the present study was to analyze whether the effect of ABCA1-R230C on HDL-C concentrations is modulated by dietary factors in a nationwide population sample of 3591 adults from the National Health and Nutrition Survey conducted by the State's Employees' Social Security and Social Services Institute. All participants answered a validated questionnaire to assess health status and weekly food consumption. Fasting blood samples were drawn for biochemical analysis and DNA extraction, and the ABCA1-R230C variant was genotyped using TaqMan assays. Statistical analyses consisted of simple linear and multiple regression modeling adjusting for age, BMI, smoking, and alcohol consumption. The overall C risk allele frequency was 9.3% and the variant was significantly associated with low HDL-C concentrations in both sexes. A significant negative correlation between carbohydrate consumption and HDL-C concentrations was observed in women bearing the R230C variant (P = 0.021) and a significant gene-diet interaction was found only in premenopausal women (P = 0.037). In conclusion, the effect of the ABCA1-R230C gene variant on HDL-C concentrations is modulated by carbohydrate intake in premenopausal women. This finding may help design optimized dietary interventions according to sex and ABCA1-R230C genotype. [ABSTRACT FROM AUTHOR]

Betalains in beetroots offer notable colouring properties and health benefits, including antioxidant, anti-inflammatory, hepatoprotective, and antitumorous activities. However, they degrade due to processing and storage conditions like temperature, pH, oxygen, and light-exposure. Traditional betalain determination methods are resource-intensive solid-liquid extractions. This study proposes a novel approach using a smart polymer to rapidly quantify betalains in processed beetroots. The polymer, containing N,N-dimethylaminoethyl methacrylate, selectively interacts with compounds like betalains. Characterization shows thermal stability over 250 °C and suitable mechanical properties. The film changes to colour upon interaction with betalains, allowing quantification via smartphone. The sensory polymer's efficacy was validated across 27 beetroot samples, showing no significant differences compared to traditional methods. Combining the smart polymer with a colour analysis app, "Colorimetric Titration," provides a robust and efficient means of quantifying total betalains in beetroot puree, reducing the quantification time from 180 to 90 min, promising implications for routine food industry quality assessments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Calcium ion (Ca 2+ ) homeostasis is crucial for neuron function and neurotransmission. This study focused on the actions mediated by the CB 1 receptor (CB 1 R), the most abundant G protein-coupled receptor (GPCR) in central nervous system (CNS) neurons, over by the AT 1 R, which is one of the few G protein-coupled CNS receptors able to regulate cytoplasmic Ca 2+ levels. A functional interaction suggesting a direct association between these receptors was detected. AT 1 -CB 1 receptor heteromers (AT 1 CB 1 Hets) were identified in HEK-293T cells by bioluminescence resonance energy transfer (BRET 2 ). Functional interactions within the AT 1 -CB 1 complex and their potential relevance in Parkinson's disease (PD) were assessed. In situ proximity ligation assays (PLA) identified AT 1 CB 1 Hets in neurons, in which an important finding was that Ca 2+ level increase upon AT 1 R activation was reduced in the presence of cannabinoids acting on CB 1 Rs. AT 1 CB 1 Het expression was quantified in samples from the 6-hydroxydopamine (6-OHDA) hemilesioned rat model of PD in which a lower expression of AT 1 CB 1 Hets was observed in striatal neurons from lesioned animals (versus non-lesioned). AT 1 CB 1 Het expression changed depending on both the lesion and the consequences of levodopa administration, i.e., dyskinesias versus lack of involuntary movements. A partial recovery in AT 1 CB 1 Het expression was detected in lesioned animals that developed levodopa-induced dyskinesias. These findings support the existence of a compensatory mechanism mediated by AT 1 CB 1 Hets that modulates susceptibility to levodopa-induced dyskinesias in PD. Therefore, cannabinoids may be useful in reducing calcium dyshomeostasis in dyskinesia., Competing Interests: Competing interests The authors declare no competing interests. Ethical approval Animal handling, sacrifice, and further experiments were conducted according to the guidelines set in Directive 2010/63/EU of the European Parliament and the Council of the European Union that are enforced in Spain by National and Regional organisms; the 3R rule (replace, refine, reduce) for animal experimentation was also considered. The rat PD model was generated and handled using a protocol approved by the Ethical Committee of the University of Santiago de Compostela (Protocol 14715012/2021/012; last revision 16 April 2021). According to the current legislation, protocol approval is unnecessary if animals are sacrificed to obtain a specific tissue as in this work to obtain primary neurons., (© 2024. The Author(s).)

Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor (hMP) high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM/PN accelerates muscle regeneration in vivo by stimulating MuSCs, increases muscle strength during recovery, and overcomes MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously decline during aging in model organisms and inter-independently associate with muscle mass and walking speed in a human cohort of 186 aged people. Collectively, our results establish NAM/PN as a new nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.

This study focuses on the "El Lavadero" tailings deposit, a mining environmental liability (MEL) located near the town of San Felipe de Jesús, Sonora, in northwest Mexico. The objective was to determine the total arsenic (As) content, its granulometric and geochemical distribution, as well as its mobilization capacity and bioavailability. The results from oxidized and unoxidized tailings showed low potential of hydrogen (pH) values (2.4-5.7) and high concentrations of total arsenic (8235-36,004 mg kg -1 ), predominantly in the finer granulometric fractions (< 0.05 mm). Arsenic also prevails in the finest fraction of agricultural soil (> 2 mm). These fine particles could present adverse environmental effects due to their potential to be transported by leaching and water suspension. In contrast, arsenic in the effluent sediments is primarily found in the coarser fraction (> 2 mm). A significant proportion of arsenic in the tailings (5-40%) was found in the non-residual geochemical fractions (I + II + III) (1106-7675 mg kg -1 ), indicating potential for mobilization and bioavailability. Depending on environmental conditions (redox potential and pH), arsenic can redissolve and exhibit high mobility in abiotic media, which may ultimately impact the environment and human health. Therefore, it is crucial to rehabilitate the "El Lavadero" MEL to prevent further environmental damage. This study provides useful information to understand some phenomena in other global mining environmental liabilities, such as mobilization and bioavailability of arsenic and its possible impact on the surrounding environment and biota, contributing to the worldwide research of ecosystems polluted by mining activity, especially in arid and semi-arid climates., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Human phosphoglycerate kinase 1(hPGK1) is a key glycolytic enzyme that regulates the balance between ADP and ATP concentrations inside the cell. Phosphorylation of hPGK1 at S203 and S256 has been associated with enzyme import from the cytosol to the mitochondria and the nucleus respectively. These changes in subcellular locations drive tumorigenesis and are likely associated with site-specific changes in protein stability. In this work, we investigate the effects of site-specific phosphorylation on thermal and kinetic stability and protein structural dynamics by hydrogen-deuterium exchange (HDX) and molecular dynamics (MD) simulations. We also investigate the binding of 3-phosphoglycerate and Mg-ADP using these approaches. We show that the phosphomimetic mutation S256D reduces hPGK1 kinetic stability by 50-fold, with no effect of the mutation S203D. Calorimetric studies of ligand binding show a large decrease in affinity for Mg-ADP in the S256D variant, whereas Mg-ADP binding to the WT and S203D can be accurately investigated using protein kinetic stability and binding thermodynamic models. HDX and MD simulations confirmed the destabilization caused by the mutation S256D (with some long-range effects on stability) and its reduced affinity for Mg-ADP due to the strong destabilization of its binding site (particularly in the apo-state). Our research provides evidence suggesting that modifications in protein stability could potentially enhance the translocation of hPGK1 to the nucleus in cancer. While the structural and energetic basis of its mitochondrial import remain unknown., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Cancer-associated fibroblasts (CAFs) are the most abundant stromal cellular component in the tumor microenvironment (TME). CAFs contribute to tumorigenesis and have been proposed as targets for anticancer therapies. Similarly, dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to tumorigenesis and drug resistance in various cancers, including breast cancer. We explored the role of SUMOylation in breast CAFs and evaluated its potential as a therapeutic strategy in breast cancer., Methods: We used pharmacological and genetic approaches to analyse the functional crosstalk between breast tumor cells and CAFs. We treated breast CAFs with the SUMO1 inhibitor ginkgolic acid (GA) at two different concentrations and conditioned media was used to analyse the proliferation, migration, and invasion of breast cancer cells from different molecular subtypes. Additionally, we performed quantitative proteomics (SILAC) to study the differential signalling pathways expressed in CAFs treated with low or high concentrations of GA. We confirmed these results both in vitro and in vivo. Moreover, we used samples from metastatic breast cancer patients to evaluate the use of GA as a therapeutic strategy., Results: Inhibition of SUMOylation with ginkgolic acid (GA) induces death in breast cancer cells but does not affect the viability of CAFs, indicating that CAFs are resistant to this therapy. While CAF viability is unaffected, CAF-conditioned media (CM) is altered by GA, impacting tumor cell behaviour in different ways depending on the overall degree to which SUMO1-SUMOylated proteins are dysregulated. Breast cancer cell lines exhibited a concentration-dependent response to conditioned media (CM) from CAFs. At a low concentration of GA (10 µM), there was an increase in proliferation, migration and invasion of breast cancer cells. However, at a higher concentration of GA (30 µM), these processes were inhibited. Similarly, analysis of tumor development revealed that at 10 µM of GA, the tumors were heavier and there was a greater degree of metastasis compared to the tumors treated with the higher concentration of GA (30 µM). Moreover, some of these effects could be explained by an alteration in the activity of the GTPase Rac1 and the activation of the AKT signalling pathway. The results obtained using SILAC suggest that different concentrations of GA affected cellular processes differentially, possibly influencing the secretome of CAFs. Treatment of metastatic breast cancer with GA demonstrated the use of SUMOylation inhibition as an alternative therapeutic strategy., Conclusion: The study highlights the importance of SUMOylation in the tumor microenvironment, specifically in cancer-associated fibroblasts (CAFs). Targeting SUMOylation in CAFs affects their signalling pathways and secretome in a concentration-dependent manner, regulating the protumorigenic properties of CAFs., (© 2024. The Author(s).)

Aim: Most patients experience barriers for becoming physical active post-heart transplantation. Therefore, identifying barriers and facilitators can help healthcare professionals in developing physical activity programs. This study aimed to explore the physical activity experiences, perceived barriers, and facilitators to perform physical activity of patients' post-heart transplantation., Methods and Results: A qualitative study was carried out using in-depth semi-structured interviews on 24 patients post-heart transplantation from October to December 2022. The data were analyzed using an inductive strategy for finding emerging themes. NVivo 12.0 software was used to analyze the data. The physical activity experiences included that (1) patients felt that they had to adapt to a new situation after the heart transplantation, (2) walking was a popular physical activity preferably outdoors, (3) participants preferred to perform physical activity regularly with others, and (4) they felt better since they perform physical activity. The facilitators were: (1) Desire to live; (2) Experiencing physical benefits; (3) Being physically active with others; (4) Use of mobility assistive devices resources. The barriers were: (1) Feeling not being able to perform former physical activity; (2) Complications and experiencing symptoms post-heart transplantation; (3) Unfavourable climate., Conclusions: Patients post-heart transplantation have various facilitators influencing their post-transplant experience to perform physical activity. Key facilitators include the desire to live, physical benefits, social activity, and external support. Yet, they also face barriers like lost abilities, post-transplant complications, and environmental challenges., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Pseudomonas poae PMA22 produces safracins, a family of compounds with potent broad-spectrum anti-bacterial and anti-tumor activities. The safracins' biosynthetic gene cluster (BGC sac) consists of 11 ORFs organized in two divergent operons ( sacABCDEFGHK and sacIJ ) that are controlled by P a and P i promoters. Contiguous to the BGC sac, we have located a gene that encodes a putative global regulator of the LysR family annotated as MexT that was originally described as a transcriptional activator of the MexEF-OprN multidrug efflux pump in Pseudomonas . Through both in vitro and in vivo experiments, we have demonstrated the involvement of the dual regulatory system MexT-MexS on the BGC sac expression acting as an activator and a repressor, respectively. The MexEF-OprN transport system of PMA22, also controlled by MexT, was shown to play a fundamental role in the metabolism of safracin. The overexpression of mexEF-oprN in PMA22 resulted in fourfold higher production levels of safracin. These results illustrate how a pleiotropic regulatory system can be critical to optimizing the production of tailored secondary metabolites, not only through direct interaction with the BGC promoters, but also by controlling their transport.

Background: Maternal childhood maltreatment (CM) has been repeatedly associated with negative offspring's emotional outcomes. The dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis has emerged as the main underlying physiological mechanism., Objective: To explore the association between maternal CM and newborns' physiological and neurobehavioral stress responses, considering the role of perinatal maternal depression and bonding., Participants and Setting: 150 healthy women were followed throughout pregnancy. 79 mother-infant dyads were included in the final analyses. Maternal CM was evaluated using the Childhood Trauma Questionnaire and depressive symptoms by the Edinburgh Postnatal Depression Scale (EPDS) at each trimester. At 7 weeks postpartum, the EPDS and the Postpartum Bonding Questionnaire were administered. Newborns' behavioral responses were assessed using "States Organization" (SO) and "States Regulation" (SR) subdomains of the Neonatal Behavioral Assessment Scale (NBAS). Newborns' salivary samples were collected before and after the NBAS to study cortisol reactivity., Methods: A cross-lagged panel model was employed., Results: Infants born to mothers with higher CM presented more optimal scores on SO (β (0.635) = 0.216, p 〈001) and SR (ß (0.273) = 0.195, p = .006), and a higher cortisol reactivity after NBAS handling (β(0.019) = 0.217, p = .009). Moreover, newborns of mothers with higher CM and postpartum depressive symptoms exhibited a poorer performance on SR (ß (0.156 = -0.288,p = .002). Analyses revealed non-significant relationships between mother-infant bonding, newborns' cortisol reactivity and SO., Conclusions: Newborns from mothers with greater CM present higher cortisol reactivity and more optimal behavioral responses, which may reflect a prenatal HPA axis sensitization. However, those exposed to maternal postnatal depressive symptoms present poorer stress recovery., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)