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Background. Breast cancer is an important cause of cancer-related death in women worldwide and represents the second most frequent cause of brain metastases after lung cancer. The aim of this study was to determine the characteristics and outcomes of triple-negative breast cancer (TNBC) patients with brain metastasis (BM). Methods. We retrospectively reviewed a cohort of patients diagnosed with TNBC at the “Instituto Nacional de Enfermedades Neoplasicas” (period 2000–2014) to evaluate patients who developed BM. Survival rates were assessed by the Kaplan–Meier method, and prognostic factors were identified with the Cox regression analysis. Results. Of a total of 2007 TNBC patients, 193 (9.62%) developed BM. Of these, 169 stages I–III patients with a median age of 45 years (range:21–78) were included. The stage in this cohort was 4 (2.4%) clinical stage (CS) I, 23 (13.6%) with CS II and 142 (84.0%) with CS III. Most of these patients presented ECOG ≥2 (68.6%). The most common symptom was headache (74.0%), followed by nausea-vomiting (46.7%). Imaging showed that 80 patients (53.0%) had ≥1 metastatic brain lesion. Regarding the treatment of BM in this cohort, 132 patients (84.6%) received radiotherapy (RT), 2 (1.5%) surgery, and 6 (4.5%) surgery plus RT. The overall survival (OS) rate of BM was 59.8%, 37.3%, and 15.0% at 3, 6, and 12 months, respectively. A multivariate analysis showed RT to be the only factor with a positive impact on the OS of BM (hazard ratio (HR) = 0.48, 95% confidence interval (CI):0.30-0.77, and p=0.002), while ECOG ≥2 was associated with a worse OS (HR = 1.69, 95%CI:1.15–2.48, and p=0.007). Conclusion. Despite the poor prognosis of TNBC patients who develop BM, RT showed a benefit in OS rates, while ECOG ≥2 was the only prognostic factor associated with a worse OS. These results may be useful for multidisciplinary teams for treatment planning in patients with TNBC and BM.

BackgroundEvidence regarding differences in survival associated with the site of metastasis in triple-negative breast cancer (TNBC) remains limited. Our aim was to analyze the overall survival (OS), distant relapse free survival (DRFS), and survival since the diagnosis of the relapse (MS), according to the side of metastasis.MethodsThis was a retrospective study of TNBC patients with distant metastases at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru) from 2000 to 2014. Prognostic factors were determined by multivariate Cox regression analysis.ResultsIn total, 309 patients were included. Regarding the type of metastasis, visceral metastasis accounted for 41% and the lung was the most frequent first site of metastasis (33.3%). With a median follow-up of 10.2 years, the 5-year DRFS and OS were 10% and 26%, respectively. N staging (N2-N3 vs. N0, HR = 1.49, 95%CI: 1.04-2.14), metastasis in visceral sites (vs. bone; HR = 1.55, 95%CI: 0.94-2.56), the central nervous system (vs. bone; HR = 1.88, 95% CI: 1.10-3.22), and multiple sites (vs. bone; HR = 2.55, 95%CI:1.53-4.25) were prognostic factors of OS whereas multiple metastasis (HR = 2.30, 95% CI: 1.42-3.72) was a predictor of MS. In terms of DRFS, there were no differences according to metastasis type or solid organ.ConclusionTNBC patients with multiple metastasis and CNS metastasis have an increased risk of death compared to those with bone metastasis in terms of OS and MS.

Previous reports have already estimated the overall number of abortions and the number of unsafe abortions in Latin America. Conversely, there are few reliable data from this region to inform public policies aiming to meet women’s needs. In this context, the Latin American Centre of Perinatology (Centro Latinoamericano de Perinatología (CLAP)) created a network specialising in the care of women in an abortion situation (CLAP MUSA-Network) in an attempt to strengthen healthcare surveillance in Latin America by using the Perinatal Information System (Sistema Informático Perinatal (SIP)). This system was developed by the CLAP with a special module named SIP Abortion (SIP-A), a data collection tool designed by Latin American experts to be routinely used in cases of legal and incomplete abortions. The SIP-A follows the standards established by WHO, allowing investigators to systematise information, generate local reports and monitor changes after training and follow-up interventions based on national guidelines. This network promotes collaborative work between institutions to strengthen epidemiological surveillance, cooperative investigation and development of a critical mass of professionals skilled in sexual and reproductive health. Currently, 29 sentinel centres from 13 countries jointly work exchanging information to improve surveillance of healthcare indicators of women in an abortion situation. Latin America was the first region in the world to have a network of sentinel centres that continuously monitors healthcare provision to these women. Data collected by this network are already being used to design, implement and evaluate public policies.

Abstract Background Adiposity is a major component of the metabolic syndrome (MetS), low muscle strength has also been identified as a risk factor for MetS and for cardiovascular disease. We describe the prevalence of MetS and evaluate the relationship between muscle strength, anthropometric measures of adiposity, and associations with the cluster of the components of MetS, in a middle-income country. Methods MetS was defined by the International Diabetes Federation criteria. To assess the association between anthropometric variables (waist circumference (WC), waist-to-hip ratio (W/H), body mass index (BMI)), strength (handgrip/kg bodyweight (HGS/BW)) and the cluster of MetS, we created a MetS score. For each alteration (high triglycerides, low HDLc, dysglycemia, or high blood pressure) one point was conferred. To evaluate the association an index of fat:muscle and MetS score, participants were divided into 9 groups based on combinations of sex-specific tertiles of WC and HGS/BW. Results The overall prevalence of MetS in the 5,026 participants (64% women; mean age 51.2 years) was 42%. Lower HGS/BW, and higher WC, BMI, and W/H were associated with a higher MetS score. Amongst the 9 HGS/BW:WC groups, participants in the lowest tertile of HGS/BW and the highest tertile of WC had a higher MetS score (OR = 4.69 in women and OR = 8.25 in men;p

Abstract Background Current South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African. Individual variation in relative proportions of each of these ancestries may be confounded with socio-economic factors due to population stratification. Therefore, ancestry is a potential confounder variable that should be considered in epidemiologic studies and in public health plans. However, there are few studies that have assessed the ancestry of the current admixed Chilean population. This is partly due to the high cost of genome-scale technologies commonly used to estimate ancestry. In this study we have designed a small panel of SNPs to accurately assess ancestry in the largest sampling to date of the Chilean mestizo population (n = 3349) from eight cities. Our panel is also able to distinguish between the two main Amerindian components of Chileans: Aymara from the north and Mapuche from the south. Results A panel of 150 ancestry-informative markers (AIMs) of SNP type was selected to maximize ancestry informativeness and genome coverage. Of these, 147 were successfully genotyped by KASPar assays in 2843 samples, with an average missing rate of 0.012, and a 0.95 concordance with microarray data. The ancestries estimated with the panel of AIMs had relative high correlations (0.88 for European, 0.91 for Amerindian, 0.70 for Aymara, and 0.68 for Mapuche components) with those obtained with AXIOM LAT1 array. The country’s average ancestry was 0.53 ± 0.14 European, 0.04 ± 0.04 African, and 0.42 ± 0.14 Amerindian, disaggregated into 0.18 ± 0.15 Aymara and 0.25 ± 0.13 Mapuche. However, Mapuche ancestry was highest in the south (40.03%) and Aymara in the north (35.61%) as expected from the historical location of these ethnic groups. We make our results available through an online app and demonstrate how it can be used to adjust for ancestry when testing association between incidence of a disease and nongenetic risk factors. Conclusions We have conducted the most extensive sampling, across many different cities, of current Chilean population. Ancestry varied significantly by latitude and human development. The panel of AIMs is available to the community for estimating ancestry at low cost in Chileans and other populations with similar ancestry.

Background: Chronic non-communicable diseases are prevalent conditions in developing countries, such as Colombia. Several socioeconomic and educational factors have been associated with these pathologies. However, there is little country-specific information regarding the self-reported prevalence of chronic diseases and their association with the aforementioned factors in Colombia. Objectives: To evaluate the current situation of chronic non-transmissible diseases in Colombia by self-report and to analyze its potential relationship with sociodemographic, economic and educational factors. Methods: This is a cross-sectional baseline sub-analysis from the prospective, standardized collaborative PURE study in Colombia. Participants were recruited between 2005 to 2009, in 11 departments of the country, and included 7,485 subjects of 35 to 70 years old. Questionnaires of self-reported chronic non-communicable diseases, and demographic, socioeconomic and educational variables were applied. Results: Hypertension was the most prevalent chronic condition reported with a prevalence of 22.2% (21.2%–23.1%, 95% CI), followed by diabetes with a prevalence of 5.7% (5.1%–6.2%, 95% CI), asthma 2.7% (2.2%–3.0%, 95% CI), coronary heart disease 2.4% (2.0%–2.7%, 95% CI), stroke and heart failure 1.5% (1.2%–1.8%, 95% CI) each, chronic obstructive pulmonary disease 1.2% (0.6%–1.5%, 95% CI), and cancer 1.2% (1.0%–1.5%, 95% CI). Among the study sample, 23.3% (22.4%–24.3%, 95% CI) reported having one chronic NCDs, and 6.4% (5.9%–7.0%, 95% CI) reported having multiple chronic NCDs. The prevalence of multiple NCDs increased significantly with age, was more common in those from households with higher income, whereas it was significantly lower in persons with high education. The central and central-east regions of the country are those with the higher prevalence of self-reported NCDs. Conclusion: The results of the current study indicate the presence of socioeconomic and educational inequalities in the distribution of chronic NCDs in the Colombian population.

Objectives. This study seeks to determine the prevalence of chronic diseases and analyze the association between multimorbidity and all-cause mortality by sex. Methods. This is a 16-year longitudinal study of follow-up. We used sample data of the SABE (Health, Well-Being and Aging) study cohort and mortality data obtained through the Mortality Information Improvement Program of the City of São Paulo (PRO-AIM) from the 2000–2016 period. Survival analysis was performed using Cox proportional hazard models. Results. Hypertension (HT) was the most prevalent disease in older adults (52.93%), followed by musculoskeletal disorders (MSDs) (27.09%), cardiovascular diseases (CD) (17.79%), diabetes mellitus (DM) (16.95%), mental disorders (MD) (15.43%), and respiratory diseases (RD) (9.72%). The highest mortality rate in women was observed in the combination of HT/MSDs/DM/MD (HR = 6.15, 95% CI = 2.32, 16.32), while in men was in the combination of HT/CD/MSDs/DM (HR = 5.72, 95% CI = 1.72, 19.06). Conclusion. Similar to previous studies carried out in developed countries, we found that all-cause mortality increased as diseases are added to an individual. Women and men presented different mortality patterns according to multimorbidity. Therefore, we suggest that additional longitudinal studies should be performed in order to analyze mortality by sex.

Introducción. Tacna es una región de muy alto riesgo de transmisión de tuberculosis. Sin embargo, se ha encontrado que el rendimiento diagnóstico de la baciloscopia en sus establecimientos de salud es del 1,5%. Objetivo. Describir los conocimientos, percepciones y prácticas sobre detección de sintomáticos respiratorios (SR). Diseño. Estudio transversal. Lugar. Establecimientos de salud de la Dirección Regional de Salud de Tacna. Participantes. Profesionales de salud (médicos y enfermeras). Intervenciones. Cuestionario estructurado auto-administrado y anónimo, elaborado por los autores del estudio en base a la vigente “Norma Técnica de Salud para la Atención Integral de las Personas Afectadas por Tuberculosis”. Principales medidas de resultado. Frecuencia absoluta y relativa de conocimientos adecuados, percepciones y prácticas sobre detección de sintomáticos respiratorios. Resultados. De 178 profesionales de salud (médicos y enfermeras), 89,9% conocían la definición de SR; 93,3% sabía que debe solicitarse dos muestras de esputo a los SR; 22,5% conocía el indicador que evalúa la calidad de detección de SR, y 28,1%, el indicador que evalúa la capacidad del personal para realizar la baciloscopia entre los sintomáticos respiratorios identificados; 49,4% sabía que la meta del indicador de intensidad de búsqueda es 5 por 100 atenciones en mayores de 15 años y 60,8% señaló haber leído la norma técnica vigente. Conclusiones. En el estudio, existió una brecha en el conocimiento de médicos y enfermeras en la detección de sintomáticos respiratorios. Esta brecha fue mayor en el conocimiento sobre los indicadores operacionales de detección.

An operational study was conducted to evaluate the tuberculosis detection indicators established in the Technical Standard for Comprehensive Care of Persons Affected by Tuberculosis. Three networks of first level of care facilities with very high risk of tuberculosis transmission from the Tacna region were selected. Using the registry of respiratory symptomatic patients, we analyzed 14,595 respiratory symptomatic subjects (RSS), of which we examined (ExRSS) 14,486 (99.3%). Of the total of ExRSS, 1.5% were BK (+).The average direct smears per RSS was 2.0 and search intensity (ratio between RSS and number of health care visits in more than 15 years) was 2.8%. Males were more likely to have at least one positive smear compared to women, OR 2.0 (95% CI: 1.5 to 2.6). It is concluded that the diagnostic performance of direct smears in respiratory symptomatic subjects is low.

Objetivo. Determinar las características del perfil epidemiológico de los accidentes de tránsito (AT) en el Perú, en el periodo 2005 -2009. Materiales y métodos. Estudio descriptivo, retrospectivo, se analizó fuentes secundarias de información de AT de la Policía Nacional del Perú y la Estrategia Sanitaria Nacional de Accidentes de Tránsito (ESNAT) del Ministerio de Salud. Resultados. En el quinquenio estudiado se produjeron 404 120 AT, el 63,8% de éstos sucedió en Lima. Los automóviles y las camionetas representan los tipos de vehículo más veces involucrados en estos accidentes. El exceso de velocidad y la imprudencia del conductor son las principales causas de la siniestralidad. El tipo de accidente más común es el choque (57%). Los varones de 20 a 34 años son la población más vulnerable. Los AT han provocado 17 025 muertos y 235 591 lesionados en el Perú durante este periodo. Conclusiones. Los AT son un problema emergente de salud pública en el Perú. La tendencia de las cifras de mortalidad y morbilidad por accidentes de tránsito en el Perú ha seguido una curva ascendente entre los años 2005 y 2008; sin embargo, estas cifras durante el 2009 se han reducido de manera muy poco significativa. Los sistemas de información deben integrarse para proporcionar información confiable a las instituciones nacionales involucradas en esta problemática, de manera que sirvan de referencia para futuras decisiones políticas.Objective. To determine the characteristics and epidemiological profile of road traffic injuries (RTI) in Peru during the period 2005-2009. Materials and methods. Descriptive, retrospective study, secondary sources of information on RTI from the National Police of Peru and the National Sanitary Strategy for the Control of Traffic Accidents (ESNAT) of the Ministry of Health were analyzed. Results. During the 5 years of study, there were 404120 TA, of which 63.8% occurred in Lima. Cars and vans are the types of vehicle most frequently involved in these accidents. Speed excess and driver`s senselessness are the main causes of accidents. The most common type of accident is the crash (57%). Males from 20 to 34 years old are the most vulnerable population. Conclusions. The RTI are an emerging public health problem in Peru. The trend of the mortality and morbidity rates due to traffic accidents in Peru has followed an increasing curve between the years 2005 and 2008; however these numbers during 2009 have been decreasing but not really significantly. Information systems must be integrated in order to give reliable information to the national institutions involved in these problematic, so that it can be used as a reference for future political decisions.

Objetivo: Determinar el nivel de conocimientos sobre el VIH/SIDA y las prácticas sexuales de los escolares de 14 a 17 años de la ciudad de Tacna, Perú. Materiales y métodos: Estudio transversal realizado entre septiembre y noviembre del 2004, se realizó un muestreo probabilística bietápico por conglomerados en instituciones educativas nacionales y privadas. Se incluyeron 399 escolares que respondieron a una encuesta autoaplicada, el nivel de conocimientos fue clasificado en inadecuado, regular y adecuado según el puntaje obtenido. Se establecieron las diferencias usando chi2 y U de Mann-Withney según correspondía. Resultados: El nivel de conocimiento fue regular para la mayoría de adolescentes (46,4%), los varones tuvieron mayor puntaje que las mujeres (p

Se revisa la información de la literatura respecto de la estructura de las membranas ovulares, describiendo la zona de morfología alterada extrema, los mecanismos fisiopatológicos involucrados en la rotura prematura de membranas (destacando el proceso de apoptosis), relacionados a infección, isquemia placentaria, distensión de membranas, hemorragia coriodecidual, tabaquismo, relaxina, prolactina, hormona paratiroídeaThe information in literature about the structure of the membranes is reviwed, describing the zone of the extremely alterated morphology, the pathophysiologic mechanism involved in the premature rupture of the membranes (emphasizing the process of apoptosis), related to infections, placentary ischemia, membranes strain, choridecidual hemorrhage, tobacco, relaxin, prolactin, parathyroid hormone

Se presenta un caso clínico de neurofibromatosis tipo I diagnosticada a las 28 semanas de embarazo con evolución materna y fetal satisfactoriaA clinical case of neurofibromatosis type I is presented with diagnosis at 28 weeks of pregnancy with satisfactory maternal fetal evolution

The purpose of this article is to establish the answer to a clinical question regarding the effectiveness ofpreoperative hygiene with hand washing brush or without it. This first technique has been performed on the skinto reduce transient bacteria and to inhibit the growth of resident microorganisms as a common and required actbefore any surgical procedure. Despite this measure and others such as prophylactic antibiotics, the mainoperative complication continues to be the surgical wound infection. Today, it is as prevalent as in the past withthe consequent negative effects derived from it, both for the institutions and for patients. Being controversialtoday which one is the most effective and safe surgical hand washing method for the binomial: professionalsurgical team/ patient, this study is done under the criteria of the Evidence-Based Nursing.A question was builtin PICO format (Personal, Intervention, Comparison and Outcome). After this is done, continues informationsearch in the databases GOOGLE ACADÉMICO, Pub Med, Cochrane y Base de Datos para la Investigación enEnfermería (BDIE) We obtained 20 articles related to the topic of them 8, which fulfilled the set CASPe criteriato answer the clinical question, were analyzed. We conclude that washing hands with a brush is equally effectiveas without brush technique in terms of decreased of the superficial skin bacterial flora, although this technique hasadvantages over the traditional practice.

Se realizó una investigación operativa con el objetivo de evaluar los indicadores de detección de tuberculosis establecidos en la Norma Técnica para la Atención Integral de las Personas Afectadas por Tuberculosis. Se seleccionaron tres microrredes con muy alto riesgo de transmisión de tuberculosis de la región Tacna. Utilizando los libros de registro de sintomáticos respiratorios se analizaron los datos de 14 595 sintomáticos respiratorios identificados (SRI), de los cuales se examinaron (SREx) 14 486 (99,3%), del total de SREx 1,5% fueron BK (+). El promedio de baciloscopias directas por SRI fue de 2,0 y la intensidad de búsqueda (proporción de SRI entre las atenciones en > de 15 años) fue de 2,8%. Los varones tuvieron mayor probabilidad de presentar, al menos, una baciloscopía positiva que las mujeres, OR 2,0 (IC 95%: 1,5-2,6). Se concluye que el rendimiento de la baciloscopia diagnóstica en sintomáticos respiratorios es baja

Se realizó una investigación operativa con el objetivo de evaluar los indicadores de detección de tuberculosis establecidos en la Norma Técnica para la Atención Integral de las Personas Afectadas por Tuberculosis. Se seleccionaron tres microrredes con muy alto riesgo de transmisión de tuberculosis de la región Tacna. Utilizando los libros de registro de sintomáticos respiratorios se analizaron los datos de 14 595 sintomáticos respiratorios identificados (SRI), de los cuales se examinaron (SREx) 14 486 (99,3%), del total de SREx 1,5% fueron BK (+). El promedio de baciloscopias directas por SRI fue de 2,0 y la intensidad de búsqueda (proporción de SRI entre las atenciones en > de 15 años) fue de 2,8%. Los varones tuvieron mayor probabilidad de presentar, al menos, una baciloscopía positiva que las mujeres, OR 2,0 (IC 95%: 1,5-2,6). Se concluye que el rendimiento de la baciloscopia diagnóstica en sintomáticos respiratorios es baja

Survival rates for childhood cancer survivors (CCS) have improved, although they display a risk for early frailty due to the long-term effects of chemo/radiotherapy, including early aging. This study investigates antioxidant defenses and oxidative damage in mononuclear cells (MNCs) from CCS, comparing them with those from age-matched and elderly healthy individuals. Results show impaired antioxidant responses and increased oxidative stress in CCS MNCs, which exhibited uncoupled oxidative phosphorylation, leading to higher production of reactive oxygen species, similar to metabolic issues seen in elderly individuals. Key antioxidant enzymes, namely glucose-6-phosphate dehydrogenase, hexose-6-phosphate dehydrogenase, glutathione reductase, glutathione peroxidase, catalase, and superoxide dismutase, showed reduced activity, likely due to lower expression of nuclear factor erythroid 2-related factor 2 (Nrf2). This imbalance caused significant damage to lipids, proteins, and DNA, potentially contributing to cellular dysfunction and a higher risk of cancer recurrence. These oxidative and metabolic dysfunctions persist over time, regardless of cancer type or treatment. However, treatment with N-acetylcysteine improved Nrf2 expression, boosted antioxidant defenses, reduced oxidative damage, and restored oxidative phosphorylation efficiency, suggesting that targeting the redox imbalance could enhance long-term CCS health.

Tissue regeneration following an injury requires dynamic cell-state transitions that allow for establishing the cell identities required for the restoration of tissue homeostasis and function. Here, we present a biochemical intervention that induces an intermediate cell state mirroring a transition identified during normal differentiation of myoblasts and other multipotent and pluripotent cells to mature cells. When applied in somatic differentiated cells, the intervention, composed of one-carbon metabolites, reduces some dedifferentiation markers without losing the lineage identity, thus inducing limited reprogramming into a more flexible cell state. Moreover, the intervention enabled accelerated repair after muscle injury in young and aged mice. Overall, our study uncovers a conserved biochemical transitional phase that enhances cellular plasticity in vivo and hints at potential and scalable biochemical interventions of use in regenerative medicine and rejuvenation interventions that may be more tractable than genetic ones., Competing Interests: Declaration of interests Patent applications have been filed related to the subject matter of this publication. R.H.-B., C.W., C.Z., S.M., F.H., V.L., I.G., S.S., M.Y., Y.S., A.A.-V., C.R.E., P.R., S.H., and J.C.I.B. are employees of Altos Labs., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Transgenerational epigenetic inheritance in mammals remains a debated subject. Here, we demonstrate that DNA methylation of promoter-associated CpG islands (CGIs) can be transmitted from parents to their offspring in mice. We generated DNA methylation-edited mouse embryonic stem cells (ESCs), in which CGIs of two metabolism-related genes, the Ankyrin repeat domain 26 and the low-density lipoprotein receptor, were specifically methylated and silenced. DNA methylation-edited mice generated by microinjection of the methylated ESCs exhibited abnormal metabolic phenotypes. Acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprogramming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a concrete step toward demonstrating transgenerational epigenetic inheritance in mammals, which may have implications in our understanding of evolutionary biology as well as the etiology, diagnosis, and prevention of non-genetically inherited human diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abscisic acid (ABA) is a hormone with a very long evolutionary history, dating back to the earliest living organisms, of which modern (ABA-producing) cyanobacteria are likely the descendants, well before separation of the plant and animal kingdoms, with a conserved role as a signal regulating cell responses to environmental challenges. In mammals, nanomolar ABA controls the metabolic response to glucose availability by stimulating glucose uptake in skeletal muscle and adipose tissue with an insulin-independent mechanism and increasing energy expenditure in the brown and white adipose tissues. Activation by ABA of AMP-dependent kinase (AMPK), in contrast to the insulin-induced activation of AMPK-inhibiting Akt, is responsible for stimulation of GLUT4-mediated muscle glucose uptake, and for the browning effect on white adipocytes. Intake of micrograms per Kg body weight of ABA improves glucose tolerance in both normal and in borderline subjects and chronic intake of such a dose of ABA improves blood glucose, lipids and morphometric parameters (waist circumference and body mass index) in borderline subjects for prediabetes and the metabolic syndrome. This review summarizes the most recent results obtained in vivo with microgram amounts of ABA, the role of the receptor LANCL2 in the hormone's action and the significance of the endowment by mammals of two different hormones controlling the metabolic response to glucose availability. Finally, open issues in need of further investigation and perspectives for the clinical use of nutraceutical ABA are discussed.

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD + salvage pathway from nicotinamide. By controlling the biosynthesis of NAD + , NAMPT regulates the activity of NAD + -converting enzymes, such as CD38, poly-ADP-ribose polymerases, and sirtuins (SIRTs). SIRT6 is involved in the regulation of a wide number of metabolic processes. In this study, we investigated the ability of SIRT6 to regulate intracellular NAMPT activity and NAD(P)(H) levels. BxPC-3 cells and MCF-7 cells were engineered to overexpress a catalytically active or a catalytically inactive SIRT6 form or were engineered to silence endogenous SIRT6 expression. In SIRT6-overexpressing cells, NAD(H) levels were up-regulated, as a consequence of NAMPT activation. By immunopurification and incubation with recombinant SIRT6, NAMPT was found to be a direct substrate of SIRT6 deacetylation, with a mechanism that up-regulates NAMPT enzymatic activity. Extracellular NAMPT release was enhanced in SIRT6-silenced cells. Also glucose-6-phosphate dehydrogenase activity and NADPH levels were increased in SIRT6-overexpressing cells. Accordingly, increased SIRT6 levels reduced cancer cell susceptibility to H 2 O 2 -induced oxidative stress and to doxorubicin. Our data demonstrate that SIRT6 affects intracellular NAMPT activity, boosts NAD(P)(H) levels, and protects against oxidative stress. The use of SIRT6 inhibitors, together with agents inducing oxidative stress, may represent a promising treatment strategy in cancer.-Sociali, G., Grozio, A., Caffa, I., Schuster, S., Becherini, P., Damonte, P., Sturla, L., Fresia, C., Passalacqua, M., Mazzola, F., Raffaelli, N., Garten, A., Kiess, W., Cea, M., Nencioni, A., Bruzzone, S. SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells.

Lanthionine synthetase component C-like protein 2 (LANCL2) has been identified as the mammalian receptor mediating the functional effects of the universal stress hormone abscisic acid (ABA) in mammals. ABA stimulates insulin independent glucose uptake in myocytes and adipocytes via LANCL2 binding in vitro, improves glucose tolerance in vivo and induces brown fat activity in vitro and in vivo. The emerging role of the ABA/LANCL2 system in glucose and lipid metabolism makes it an attractive target for pharmacological interventions in diabetes mellitus and the metabolic syndrome. The aim of this study was to investigate the presence of ABA binding site(s) on LANCL2 and identify the amino acid residues involved in ABA binding. Equilibrium binding assays ([ 3 H]-ABA saturation binding and surface plasmon resonance analysis) suggested multiple ABA-binding sites, prompting us to perform a computational study that indicated one putative high-affinity and two low-affinity binding sites. Site-directed mutagenesis (single mutant R118I, triple mutants R118I/R22I/K362I and R118I/S41A/E46I) and equilibrium binding experiments on the mutated LANCL2 proteins identified a high-affinity ABA-binding site involving R118, with a K D of 2.6 nM ± 1.2 nM, as determined by surface plasmon resonance. Scatchard plot analysis of binding curves from both types of equilibrium binding assays revealed a Hill coefficient >1, suggesting cooperativity of ABA binding to LANCL2. Identification of the high-affinity ABA-binding site is expected to allow the design of ABA agonists/antagonists, which will help to understand the role of the ABA/LANCL2 system in human physiology and disease., (Copyright © 2018. Published by Elsevier Ltd.)

We evaluated the energy metabolism of human mesenchymal stem cells (MSC) isolated from umbilical cord (UC) of preterm (< 37 weeks of gestational age) and term (≥ 37 weeks of gestational age) newborns, using MSC from adult bone marrow as control. A metabolic switch has been observed around the 34th week of gestational age from a prevalently anaerobic glycolysis to the oxidative phosphorylation. This metabolic change is associated with the organization of mitochondria reticulum: preterm MSCs presented a scarcely organized mitochondrial reticulum and low expression of proteins involved in the mitochondrial fission/fusion, compared to term MSCs. These changes seem governed by the expression of CLUH, a cytosolic messenger RNA-binding protein involved in the mitochondria biogenesis and distribution inside the cell; in fact, CLUH silencing in term MSC determined a metabolic fingerprint similar to that of preterm MSC. Our study discloses novel information on the production of energy and mitochondrial organization and function, during the passage from fetal to adult life, providing useful information for the management of preterm birth.

Abscisic acid (ABA) is a phytohormone involved in pivotal physiological functions in higher plants. Recently, ABA has been proven to be also secreted and active in mammals, where it stimulates the activity of innate immune cells, mesenchymal and hematopoietic stem cells, and insulin-releasing pancreatic β cells through a signaling pathway involving the second messenger cyclic ADP-ribose (cADPR). In addition to behaving like an animal hormone, ABA also holds promise as a nutraceutical plant-derived compound in humans. Many biological functions of ABA in mammals are mediated by its binding to the LANCL-2 receptor protein. A putative binding of ABA to GRP78, a key regulator of endoplasmic reticulum stress, has also been proposed. Here we investigated the role of exogenous ABA in modulating thrombopoiesis, the process of platelet generation. Our results demonstrate that expression of both LANCL-2 and GRP78 is up-regulated during hematopoietic stem cell differentiation into mature megakaryocytes (Mks). Functional ABA receptors exist in mature Mks because ABA induces an intracellular Ca 2+ increase ([Ca 2+ ] i ) through PKA activation and subsequent cADPR generation. In vitro exposure of human or murine hematopoietic progenitor cells to 10 μm ABA does not increase recombinant thrombopoietin (rTpo)-dependent Mk differentiation or platelet release. However, under conditions of cell stress induced by rTpo and serum deprivation, ABA stimulates, in a PKA- and cADPR-dependent fashion, the mitogen-activated kinase ERK 1/2, resulting in the modulation of lymphoma 2 (Bcl-2) family members, increased Mk survival, and higher rates of platelet production. In conclusion, we demonstrate that ABA is a prosurvival factor for Mks in a Tpo-independent manner., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Abscisic acid (ABA) is a plant hormone also present in animals, where it is involved in the regulation of innate immune cell function and of glucose disposal, through its receptor LANCL2. ABA stimulates glucose uptake by myocytes and pre-adipocytes in vitro and oral ABA improves glycemic control in rats and in healthy subjects. Here we investigated the role of the ABA/LANCL2 system in the regulation of glucose uptake and metabolism in adipocytes. Silencing of LANCL2 abrogated both the ABA- and insulin-induced increase of glucose transporter-4 expression and of glucose uptake in differentiated 3T3-L1 murine adipocytes; conversely, overexpression of LANCL2 enhanced basal, ABA- and insulin-stimulated glucose uptake. As compared with insulin, ABA treatment of adipocytes induced lower triglyceride accumulation, CO 2 production and glucose-derived fatty acid synthesis. ABA per se did not induce pre-adipocyte differentiation in vitro, but stimulated adipocyte remodeling in terminally differentiated cells, with a reduction in cell size, increased mitochondrial content, enhanced O 2 consumption, increased transcription of adiponectin and of brown adipose tissue (BAT) genes. A single dose of oral ABA (1μg/kg body weight) increased BAT glucose uptake 2-fold in treated rats compared with untreated controls. One-month-long ABA treatment at the same daily dose significantly upregulated expression of BAT markers in the WAT and in WAT-derived preadipocytes from treated mice compared with untreated controls. These results indicate a hitherto unknown role of LANCL2 in adipocyte sensitivity to insulin-stimulated glucose uptake and suggest a role for ABA in the induction and maintenance of BAT activity., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Abscisic acid (ABA) is a hormone conserved from cyanobacteria to higher plants, where it regulates responses to environmental stimuli. ABA also plays a role in mammalian physiology, pointedly in inflammatory responses and in glycemic control. As the animal ABA receptor is on the intracellular side of the plasma membrane, a transporter is required for the hormone's action. Here we demonstrate that ABA transport in human nucleated cells occurs via the anion exchanger AE2. Together with the recent demonstration that ABA influx into human erythrocytes occurs via Band 3, this result identifies the AE family members as the mammalian ABA transporters., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Abscisic acid (ABA), a long known phytohormone, has been recently demonstrated to be present also in humans, where it targets cells of the innate immune response, mesenchymal and hemopoietic stem cells and cells involved in the regulation of systemic glucose homeostasis. LANCL2, a peripheral membrane protein, is the mammalian ABA receptor. We show that N-terminal glycine myristoylation causes LANCL2 localization to the plasmamembrane and to cytoplasmic membrane vesicles, where it interacts with the α subunit of a Gi protein and starts the ABA signaling pathway via activation of adenylate cyclase. Demyristoylation of LANCL2 by chemical or genetic means triggers its nuclear translocation. Nuclear enrichment of native LANCL2 is also induced by ABA treatment. Therefore human LANCL2 is a non-transmembrane G protein-coupled receptor susceptible to hormone-induced nuclear translocation.

In recent years, Abscisic Acid (ABA) has been demonstrated to be involved in the regulation of glucose homeostasis in mammals as an endogenous hormone, by stimulating both insulin release and peripheral glucose uptake. In addition, ABA is released by glucose- or GLP-1-stimulated β-pancreatic cells. Here we investigated whether ABA can stimulate GLP-1 release. The human enteroendocrine L cell line hNCI-H716 was used to explore whether ABA stimulates in vitro GLP-1 secretion and/or transcription. ABA induced GLP-1 release in hNCI-H716 cells, through a cAMP/PKA-dependent mechanism. ABA also enhanced GLP-1 transcription. In addition, oral administration of ABA significantly increased plasma GLP-1 and insulin levels in rats. In conclusion, ABA can stimulate GLP-1 release: this result and the previous observation that GLP-1 stimulates ABA release from β -cells, suggest a positive feed-back mechanism between ABA and GLP-1, regulating glucose homeostasis. Type 2 diabetes treatments targeting the GLP-1 axis by either inhibiting its rapid clearance by dipeptidyl-peptidase IV or using GLP-1 mimetics are currently used. Moreover, the development of treatments aimed at stimulating GLP-1 release from L cells has been considered as an alternative approach. Accordingly, our finding that ABA increases GLP-1 release in vitro and in vivo may suggest ABA and/or ABA analogs as potential anti-diabetic treatments.

Abscisic acid (ABA) is a plant hormone involved in the response to environmental stress. Recently, ABA has been shown to be present and active also in mammals, where it stimulates the functional activity of innate immune cells, of mesenchymal and hemopoietic stem cells, and insulin-releasing pancreatic β-cells. LANCL2, the ABA receptor in mammalian cells, is a peripheral membrane protein that localizes at the intracellular side of the plasma membrane. Here we investigated the mechanism enabling ABA transport across the plasmamembrane of human red blood cells (RBC). Both influx and efflux of [(3)H]ABA occur across intact RBC, as detected by radiometric and chromatographic methods. ABA binds specifically to Band 3 (the RBC anion transporter), as determined by labeling of RBC membranes with biotinylated ABA. Proteoliposomes reconstituted with human purified Band 3 transport [(3)H]ABA and [(35)S]sulfate, and ABA transport is sensitive to the specific Band 3 inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. Once inside RBC, ABA stimulates ATP release through the LANCL2-mediated activation of adenylate cyclase. As ATP released from RBC is known to exert a vasodilator response, these results suggest a role for plasma ABA in the regulation of vascular tone., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

UV-B is an abiotic environmental stress in both plants and animals. Abscisic acid (ABA) is a phytohormone regulating fundamental physiological functions in plants, including response to abiotic stress. We previously demonstrated that ABA is an endogenous stress hormone also in animal cells. Here, we investigated whether autocrine ABA regulates the response to UV-B of human granulocytes and keratinocytes, the cells involved in UV-triggered skin inflammation. The intracellular ABA concentration increased in UV-B-exposed granulocytes and keratinocytes and ABA was released into the supernatant. The UV-B-induced production of NO and of reactive oxygen species (ROS), phagocytosis, and cell migration were strongly inhibited in granulocytes irradiated in the presence of a monoclonal antibody against ABA. Moreover, presence of the same antibody strongly inhibited release of NO, prostaglandin E2 (PGE(2)), and tumor necrosis factor-α (TNF-α) by UV-B irradiated keratinocytes. Lanthionine synthetase C-like protein 2 (LANCL2) is required for the activation of the ABA signaling pathway in human granulocytes. Silencing of LANCL2 in human keratinocytes by siRNA was accompanied by abrogation of the UV-B-triggered release of PGE(2), TNF-α, and NO and ROS production. These results indicate that UV-B irradiation induces ABA release from human granulocytes and keratinocytes and that autocrine ABA stimulates cell functions involved in skin inflammation., (Copyright © 2011 Wiley Periodicals, Inc.)

The phytohormone abscisic acid (ABA), in addition to regulating several important physiological functions in plants, is also produced and released by human granulocytes and monocytes where it stimulates cell activities involved in the innate immune response. Here we describe the properties of an ABA synthetic analog that competes with the hormone for binding to human granulocyte membranes and to purified recombinant LANCL2 (the human ABA receptor) and inhibits several ABA-triggered inflammatory functions of granulocytes and monocytes in vitro: chemotaxis, phagocytosis, reactive oxygen species production and release of prostaglandin E(2) (PGE(2)) by human granulocytes, release of PGE(2) and of monocyte chemoattractant protein-1 by human monocytes. This observation provides a proof of principle that ABA antagonists may represent a new class of anti-inflammatory agents., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The phytohormone abscisic acid (ABA) is the central regulator of abiotic stress in plants and plays important roles during plant growth and development. In animal cells, ABA was shown to be an endogenous hormone, acting as a stress signal and stimulating cell functions involved in inflammatory responses and in insulin release. Recently, we demonstrated that Lanthionine synthetase component C-like protein 2 (LANCL2) is required for ABA binding to the plasmamembrane of granulocytes and for the activation of the signaling pathway triggered by ABA in human granulocytes and in rat insulinoma cells. In order to investigate whether ABA activates LANCL2 via direct interaction, we performed specific binding studies on human LANCL2 recombinant protein using different experimental approaches (saturation binding, scintillation proximity assays, dot blot experiments and affinity chromatography). Altogether, results indicate that human recombinant LANCL2 binds ABA directly and provide the first demonstration of ABA binding to a mammalian ABA receptor., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Critical size segmental bone defects are still a major challenge in reconstructive orthopedic surgery. Transplantation of human mesenchymal stem cells (hMSC) has been proposed as an alternative to autogenous bone graft, as MSC can be expanded in vitro and induced to differentiate into bone-regenerating osteoblasts by several bone morphogenetic proteins (BMP). The aim of this study was to investigate whether the association of hMSC and BMP-7, with providing the necessary scaffold to fill the bone loss, improved bone regeneration in a rat model of critical size segmental bone defect, compared to treatment with either hMSC or BMP-7 and the matrix. In addition, we tested whether pre-treatment of hMSC with cyclic ADP-ribose (cADPR), an intracellular Ca2+ mobilizer previously shown to accelerate the in vitro expansion of hMSC (Scarfì S et al, Stem Cells, 2008), affected the osteoinductive capacity of the cells in vivo. X-ray analysis, performed 2, 10 and 16 weeks after transplantation, revealed a significantly higher score in the rats treated with hMSC and BMP-7 compared to controls, receiving either hMSC or BMP-7. Microtomography and histological analysis, performed 16weeks after transplantation, confirmed the improved bone regeneration in the animals treated with the association of hMSC and BMP-7 compared to controls. Pre-treatment with cADPR to stimulate hMSC proliferation in vitro did not affect the bone regenerating capacity of the cells in vivo. These results indicate that the association of in vitro expanded hMSC with BMP-7 provide a better osteoinductive graft compared to either hMSC or BMP-7 alone. Moreover, cADPR may be used to stimulate hMSC proliferation in vitro in order to reduce the time required to obtain a transplantable number of cells, with no adverse effect on the bone regenerating capacity of hMSC., (2010 Elsevier Inc. All rights reserved.)

Abscisic acid (ABA) is a plant hormone regulating fundamental physiological functions in plants, such as response to abiotic stress. Recently, ABA was shown to be produced and released by human granulocytes, by insulin-producing rat insulinoma cells, and by human and murine pancreatic beta cells. ABA autocrinally stimulates the functional activities specific for each cell type through a receptor-operated signal transduction pathway, sequentially involving a pertussis toxin-sensitive receptor/G-protein complex, cAMP, CD38-produced cADP-ribose and intracellular calcium. Here we show that the lanthionine synthetase C-like protein LANCL2 is required for ABA binding on the membrane of human granulocytes and that LANCL2 is necessary for transduction of the ABA signal into the cell-specific functional responses in granulocytes and in rat insulinoma cells. Co-expression of LANCL2 and CD38 in the human HeLa cell line reproduces the ABA-signaling pathway. Results obtained with granulocytes and CD38(+)/LANCL2(+) HeLa transfected with a chimeric G-protein (G alpha(q/i)) suggest that the pertussis toxin-sensitive G-protein coupled to LANCL2 is a G(i). Identification of LANCL2 as a critical component of the ABA-sensing protein complex will enable the screening of synthetic ABA antagonists as prospective new anti-inflammatory and anti-diabetic agents.

Abscisic acid (ABA) is a hormone involved in pivotal physiological functions in higher plants, such as response to abiotic stress and control of seed dormancy and germination. Recently, ABA was demonstrated to be autocrinally produced by human granulocytes, beta pancreatic cells, and mesenchymal stem cells (MSC) and to stimulate cell-specific functions through a signaling pathway involving the second messenger cyclic ADP-ribose (cADPR). Here we show that ABA expands human uncommitted hemopoietic progenitors (HP) in vitro, through a cADPR-mediated increase of the intracellular calcium concentration ([Ca(2+)](i)). Incubation of CD34(+) cells with micromolar ABA also induces transcriptional effects, which include NF-kappaB nuclear translocation and transcription of genes encoding for several cytokines. Human MSC stimulated with a lymphocyte-conditioned medium produce and release ABA at concentrations sufficient to exert growth-stimulatory effects on co-cultured CD34(+) cells, as demonstrated by the inhibition of colony growth in the presence of an anti-ABA monoclonal antibody. These results provide a remarkable example of conservation of a stress hormone and of its second messenger from plants to humans and identify ABA as a new hemopoietic growth factor involved in the cross-talk between HP and MSC.

Abscisic acid (ABA) is a phytohormone regulating important functions in higher plants, notably responses to abiotic stress. Recently, chemical or physical stimulation of human granulocytes was shown to induce production and release of endogenous ABA, which activates specific cell functions. Here we provide evidence that ABA stimulates several functional activities of the murine microglial cell line N9 (NO and tumor necrosis factor-alpha production, cell migration) through the second messenger cyclic ADP-ribose and an increase of intracellular calcium. ABA production and release occur in N9 cells stimulated with bacterial lipopolysaccharide, phorbol myristate acetate, the chemoattractant peptide f-MLP, or beta-amyloid, the primary plaque component in Alzheimer disease. Finally, ABA priming stimulates N9 cell migration toward beta-amyloid. These results indicate that ABA is a pro-inflammatory hormone inducing autocrine microglial activation, potentially representing a new target for anti-inflammatory therapies aimed at limiting microglia-induced tissue damage in the central nervous system.

Abscisic acid (ABA) is a phytohormone involved in fundamental processes in higher plants. Endogenous ABA biosynthesis occurs also in lower Metazoa, in which ABA regulates several physiological functions by activating ADP-ribosyl cyclase (ADPRC) and causing overproduction of the Ca(2+)-mobilizing second messenger cyclic ADP-ribose (cADPR), thereby enhancing intracellular Ca(2+) concentration ([Ca(2+)](i)). Recently, production and release of ABA have been demonstrated to take place also in human granulocytes, where ABA behaves as a proinflammatory hormone through the same cADPR/[Ca(2+)](i) signaling pathway described in plants and in lower Metazoa. On the basis of the fact that human mesenchymal stem cells (MSC) express ADPRC activity, we investigated the effects of ABA and of its second messenger, cADPR, on purified human MSC. Both ABA and cADPR stimulate the in vitro expansion of MSC without affecting differentiation. The underlying mechanism involves a signaling cascade triggered by ABA binding to a plasma membrane receptor and consequent cyclic AMP-mediated activation of ADPRC and of the cADPR/[Ca(2+)](i) system. Moreover, ABA stimulates the following functional activities of MSC: cyclooxygenase 2-catalyzed production of prostaglandin E(2) (PGE(2)), release of several cytokines known to mediate the trophic and immunomodulatory properties of MSC, and chemokinesis. Remarkably, ABA proved to be produced and released by MSC stimulated by specific growth factors (e.g., bone morphogenetic protein-7), by inflammatory cytokines, and by lymphocyte-conditioned medium. These data demonstrate that ABA is an autocrine stimulator of MSC function and suggest that it may participate in the paracrine signaling among MSC, inflammatory/immune cells, and hemopoietic progenitors. Disclosure of potential conflicts of interest is found at the end of this article.