RESUMEN
Bioactive peptides from brewer's spent grain (BSG) and brewer's spent yeast (BSY), two by-products of the brewing industry, have great potential as functional food ingredients, dietary supplements or nutraceuticals to reduce the risk of numerous pathological conditions. Nevertheless, the oral administration of these peptides poses great challenges since peptides must undergo gastrointestinal digestion, intestinal absorption and hepatic metabolism, which can affect their bioavailability and, therefore, the expected outcomes. This review provides a comprehensive and critical analysis of the potential impact of the oral route on the bioactivity of BSG/BSY peptides as assessed by in vitro assays and identifies research gaps that require novel approaches/methodologies. The data collected indicate that in addition to the significant influence of gastrointestinal digestion, intestinal absorption and hepatic metabolism also have a major impact on the bioactivity of brewing peptides. The major gap identified was the insufficient evidence regarding hepatic metabolism, which points for the need of employing in vitro assays in this research field to provide such clarification. Thus, to reach the market, the impact of the oral route on the bioactivities of BSG/BSY peptides must be properly studied in vitro to allow adequate/effective administration (dosage/frequency) with a beneficial impact on the population health.
RESUMEN
This work compared the metabolic profile of a parental MDA-MB-231 cisplatin-sensitive triple negative breast cancer (TNBC) cell line with that of a derived cisplatin-resistant line, to characterize inherent metabolic adaptations to resistance, as a means for marker and new TNBC therapies discovery. Supported by cytotoxic, microscopic and biochemical characterization of both lines, Nuclear Magnetic Resonance (NMR) metabolomics was employed to characterize cell polar extracts for the two cell lines, as a function of time (0, 24 and 48 h), and identify statistically relevant differences both between sensitive and resistant cells and their time course behavior. Biochemical results revealed a slight increase in activation of the NF-κB pathway and a marked decrease of the ERK signaling pathway in resistant cells. This was accompanied by lower glycolytic and glutaminolytic activities, possibly linked to glutamine being required to increase stemness capacity and, hence, higher survival to cisplatin. The TCA cycle dynamics seemed to be time-dependent, with an apparent activation at 48 h preferentially supported by anaplerotic aromatic amino acids, leucine and lysine. A distinct behavior of leucine, compared to the other branched-chain-amino-acids, suggested the importance of the recognized relationship between leucine and in mTOR-mediated autophagy to increase resistance. Suggested markers of MDA-MB-231 TNBC cisplatin-resistance included higher phosphocreatine/creatine ratios, hypotaurine/taurine-mediated antioxidant protective mechanisms, a generalized marked depletion in nucleotides/nucleosides, and a distinctive pattern of choline compounds. Although the putative hypotheses generated here require biological demonstration, they pave the way to the use of metabolites as markers of cisplatin-resistance in TNBC and as guidance to develop therapies.
RESUMEN
BACKGROUND: Increasing cesarean section (CS) rates are a global concern because they are related to higher maternal and neonatal complication rates and do not provide positive childbirth experiences. In 2019, Brazil ranked second globally, given its overall CS rate of 57%. According to the World Health Organization (WHO), populational CS rates of 10-15% are associated with decreased maternal, neonatal, and infant mortality rates. This study aimed to investigate whether multidisciplinary care following evidence-based protocols associated with a high motivation of both women and professionals for a vaginal birth leads to less overuse of CS in a Brazilian private practice (PP). METHODS: This cross-sectional study evaluated CS rates by Robson group for women who sought vaginal birth in a private practice in Brazil comparing with Swedish data. Collaborative care of midwives and obstetricians who adopted evidence-based guidelines was offered. CS rates, overall and by Robson group, contribution of each Robson group to the overall CS rate, clinical and nonclinical interventions, vaginal birth, pre-labor CS, and intrapartum CS proportions were estimated. The expected CS rate was calculated using the World Health Organization C-model tool. The analysis used Microsoft Excel and R Studio (version 1.2.1335. 2009-2019). RESULTS: The PP overall CS rate was 15.1% (95%CI, 13.4-17.1%) versus the 19.8% (95%CI, 14.8-24.7%) rate expected by the WHO C-model tool. The population included 43.7% women in Robson Group 1 (nulliparous, single, cephalic, at term, spontaneous labor), 11.4% in Group 2 (nulliparous, single, cephalic, at term, induced labor or CS before labor), and 14.9% in Group 5 (multiparous women with previous CS), the greatest contributors to higher CS rates (75.4% of them). The Swedish overall CS rate was 17.9% (95%CI, 17.6-18.1%) in a population of 27% women in Robson Group 1, 10.7% in Group 2, and 9.2% in Group 5. CONCLUSIONS: Multidisciplinary care following evidence-based protocols, associated with high motivation of both women and professionals for vaginal birth, may lead to a significant and safe reduction of CS rates even in contexts such as Brazil, with high medicalization of obstetric care and excess CS.
Asunto(s)
Cesárea , Parto , Embarazo , Lactante , Recién Nacido , Femenino , Humanos , Masculino , Brasil/epidemiología , Estudios Transversales , Práctica PrivadaRESUMEN
Corema (C.) album is a shrub endemic to the Atlantic coast and has been described as yielding beneficial effects for human health. Nevertheless, studies concerning the bioactivity of C. album leaves are scarce. This study aims at investigating the anticancer potential and mode of action, of an hydroethanolic extract of C. album leaves (ECAL) on triple-negative breast cancer. This is a poor survival breast cancer subtype, owing to its high risk of distant reappearance, metastasis rates and the probability of relapse. The ECAL ability to prevent tumor progression through (i) the inhibition of cell proliferation (cell viability); (ii) the induction of apoptosis (morphological changes, TUNEL assay, caspase-3 cleaved) and (iii) the induction of DNA damage (PARP1 and γH2AX) with (iv) the involvement of NF-κB and of ERK1/2 pathways (AlphaScreen assay) was evaluated. ECAL activated the apoptotic pathway (through caspase-3) along with the inhibition of ERK and NF-κB pathways causing DNA damage and cell death. The large polyphenolic content of ECAL was presumed to be accountable for these effects. The extract of C. album leaves can target multiple pathways and, thus, can block more than one possible means of disease progression, evidencing the anticancer therapeutic potential from a plant source.
RESUMEN
Cisplatin (cDDP)-based chemotherapy is often limited by severe deleterious effects (nephrotoxicity, hepatotoxicity and neurotoxicity). The polynuclear palladium(II) compound Pd2Spermine (Pd2Spm) has emerged as a potential alternative drug, with favorable pharmacokinetic/pharmacodynamic properties. This paper reports on a Nuclear Magnetic Resonance metabolomics study to (i) characterize the response of mice brain and liver to Pd2Spm, compared to cDDP, and (ii) correlate brain-liver metabolic variations. Multivariate and correlation analysis of the spectra of polar and lipophilic brain and liver extracts from an MDA-MB-231 cell-derived mouse model revealed a stronger impact of Pd2Spm on brain metabolome, compared to cDDP. This was expressed by changes in amino acids, inosine, cholate, pantothenate, fatty acids, phospholipids, among other compounds. Liver was less affected than brain, with cDDP inducing more metabolite changes. Results suggest that neither drug induces neuronal damage or inflammation, and that Pd2Spm seems to lead to enhanced brain anti-inflammatory and antioxidant mechanisms, regulation of brain bioactive metabolite pools and adaptability of cell membrane characteristics. The cDDP appears to induce higher extension of liver damage and an enhanced need for liver regeneration processes. This work demonstrates the usefulness of untargeted metabolomics in evaluating drug impact on multiple organs, while confirming Pd2Spm as a promising replacement of cDDP.
Asunto(s)
Metabolómica , Espermina , Animales , Ratones , Encéfalo , Hígado , Cisplatino/farmacología , Espectroscopía de Resonancia MagnéticaRESUMEN
Fetal stress is known to increase susceptibility to cardiometabolic diseases and hypertension in adult age in a process known as fetal programming. This study investigated the relationship between vascular RAS, oxidative damage and remodeling in fetal programming. Six-month old Sprague-Dawley offspring from mothers that were fed ad libitum (CONTROL) or with 50% intake during the second half of gestation (maternal undernutrition, MUN) were used. qPCR or immunohistochemistry were used to obtain the expression of receptors and enzymes. Plasma levels of carbonyls were measured by spectrophotometry. In mesenteric arteries from MUN rats we detected an upregulation of ACE, ACE2, AT1 receptors and NADPH oxidase, and lower expression of AT2, Mas and MrgD receptors compared to CONTROL. Systolic and diastolic blood pressure and plasma levels of carbonyls were higher in MUN than in CONTROL. Vascular morphology evidenced an increased media/lumen ratio and adventitia/lumen ratio, and more connective tissue in MUN compared to CONTROL. In conclusion, fetal undernutrition indices RAS alterations and oxidative damage which may contribute to the remodeling of mesenteric arteries, and increase the risk of adverse cardiovascular events and hypertension.
Asunto(s)
Desarrollo Fetal , Trastornos Nutricionales en el Feto/fisiopatología , Fenómenos Fisiologicos Nutricionales Maternos , Arterias Mesentéricas/patología , Estrés Oxidativo , Sistema Renina-Angiotensina , Remodelación Vascular , Animales , Presión Sanguínea , Femenino , Masculino , Arterias Mesentéricas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismoRESUMEN
BACKGROUND: Recent decreases in neonatal mortality have been slower than expected for most countries. This study aims to predict the risk of neonatal mortality using only data routinely available from birth records in the largest city of the Americas. METHODS: A probabilistic linkage of every birth record occurring in the municipality of São Paulo, Brazil, between 2012 e 2017 was performed with the death records from 2012 to 2018 (1,202,843 births and 447,687 deaths), and a total of 7282 neonatal deaths were identified (a neonatal mortality rate of 6.46 per 1000 live births). Births from 2012 and 2016 (N = 941,308; or 83.44% of the total) were used to train five different machine learning algorithms, while births occurring in 2017 (N = 186,854; or 16.56% of the total) were used to test their predictive performance on new unseen data. RESULTS: The best performance was obtained by the extreme gradient boosting trees (XGBoost) algorithm, with a very high AUC of 0.97 and F1-score of 0.55. The 5% births with the highest predicted risk of neonatal death included more than 90% of the actual neonatal deaths. On the other hand, there were no deaths among the 5% births with the lowest predicted risk. There were no significant differences in predictive performance for vulnerable subgroups. The use of a smaller number of variables (WHO's five minimum perinatal indicators) decreased overall performance but the results still remained high (AUC of 0.91). With the addition of only three more variables, we achieved the same predictive performance (AUC of 0.97) as using all the 23 variables originally available from the Brazilian birth records. CONCLUSION: Machine learning algorithms were able to identify with very high predictive performance the neonatal mortality risk of newborns using only routinely collected data.
Asunto(s)
Mortalidad Infantil , Muerte Perinatal , Certificado de Nacimiento , Brasil/epidemiología , Femenino , Humanos , Recién Nacido , Aprendizaje Automático , EmbarazoRESUMEN
Disrespectful and abusive treatment of women during childbirth is a worldwide problem. This research aimed to develop and implement a Mother Baby-Friendly Hospital Initiative (MBFHI) in an academic maternity hospital in Brazil and evaluate how change could be sustained. Change Laboratory principles guided a process of action research, which was conducted between 2017 and 2019. Clinicians and managers joined the researchers in discussion sessions to redesign routines and care pathways. Observation, interviews, focus groups, and historical and documentary analysis provided information about the existing activity system, which we analysed qualitatively using MBFHI criteria to identify themes. Evidence of inappropriate obstetric interventions and impersonal interactions between clinicians and patients stimulated us to devise innovative solutions. The challenges identified by this exercise included: poor infrastructure and ambience; difficulty adhering to evidence-based protocols; social and professional hierarchies; and clinicians being poorly educated about women's rights. Although challenges remained, positive changes included a friendlier environment, improved patient privacy, and fewer unnecessary procedures. Resources released by these changes allowed us, collaboratively, to track the further implementation and sustainability of change. We conclude that the Change Laboratory can help motivated clinicians and managers humanise patients' experiences, make care more evidence-based, and expand learning of mother-friendly maternity care. Tensions and contradictions between education and patient care reported here may resonate in settings other than maternity care.
Asunto(s)
Servicios de Salud Materna , Madres , Actitud del Personal de Salud , Brasil , Femenino , Humanos , Laboratorios , Embarazo , Relaciones Profesional-Paciente , Investigación CualitativaRESUMEN
The interest in palladium(II) compounds as potential new anticancer drugs has increased in recent years, due to their high toxicity and acquired resistance to platinum(II)-derived agents, namely cisplatin. In fact, palladium complexes with biogenic polyamines (e.g., spermine, Pd2Spm) have been known to display favorable antineoplastic properties against distinct human breast cancer cell lines. This study describes the in vivo response of triple-negative breast cancer (TNBC) tumors to the Pd2Spm complex or to cisplatin (reference drug), compared to tumors in vehicle-treated mice. Both polar and lipophilic extracts of tumors, excised from a MDA-MB-231 cell-derived xenograft mouse model, were characterized through nuclear magnetic resonance (NMR) metabolomics. Interestingly, the results show that polar and lipophilic metabolomes clearly exhibit distinct responses for each drug, with polar metabolites showing a stronger impact of the Pd(II)-complex compared to cisplatin, whereas neither drug was observed to significantly affect tumor lipophilic metabolism. Compared to cisplatin, exposure to Pd2Spm triggered a higher number of, and more marked, variations in some amino acids, nucleotides and derivatives, membrane precursors (choline and phosphoethanolamine), dimethylamine, fumarate and guanidine acetate, a signature that may be relatable to the cytotoxicity and/or mechanism of action of the palladium complex. Putative explanatory biochemical hypotheses are advanced on the role of the new Pd2Spm complex in TNBC metabolism.
Asunto(s)
Antineoplásicos/farmacología , Metaboloma/efectos de los fármacos , Paladio/química , Espermina/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Apoptosis , Proliferación Celular , Cisplatino/farmacología , Femenino , Humanos , Ratones , Ratones Desnudos , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Adenosinergic system regulates vascular tonicity through the complex system of adenosine, adenosine receptors (ARs) and nucleoside transporters. This work aimed at evaluating the impact of hypertension on adenosine bioavailability and expression/distribution profile of AR subtypes (A1, A2A, A2B, A3) and equilibrative nucleoside transporters (ENT1, ENT2, ENT3, ENT4). Adenosine was measured in vascular tissue extracts by HPLC (fluorescence detection); immunoreactivities (ARs/ENTs) in mesenteric arteries/veins from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were analyzed by histomorphometry. Significantly higher adenosine bioavailability occurred in arteries than in veins. Adenosine bioavailability was even more increased in SHR vessels. Expression/distribution of ARs and ENTs observed in all vascular layers (intima, media, adventitia), with more intensified expression in arteries than in veins. In SHR arteries, a downregulation of all ENT along with downregulated and punctuated distribution of A1 and A2B receptors occurred comparatively to WKY arteries. By contrast, expressions of ARs and ENTs were unaltered, exception for an A2A receptor upregulation, and ENT2 downregulation in SHR veins relatively to WKY veins. Our data evidenced clear alterations of adenosinergic dynamics occurring in hypertension, particularly in arterial vessels. An increased adenosine bioavailability was observed, for the first time, in hypertensive vascular tissues.
Asunto(s)
Adenosina/metabolismo , Hipertensión/metabolismo , Arterias Mesentéricas/metabolismo , Proteínas de Transporte de Nucleósidos/metabolismo , Receptores Purinérgicos P1/metabolismo , Animales , Disponibilidad Biológica , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
BACKGROUND: High rates of unnecessary cesareans and interventions in vaginal births contribute to stagnant maternal and neonatal mortality rates in Brazil. We used the Maternity Safety Thermometer (MST) to assess the prevalence of harm during maternity care. METHODS: This secondary analysis of the "Birth in Brazil" survey included a representative sample of 10 155 women who gave birth in public and private hospitals in southeastern Brazil. The main outcomes were perineal and abdominal trauma, maternal infection and hemorrhage, newborn vitality, and women's perception of safety. We calculated the odds ratios (OR) for the number of MST harms (dependent variable). RESULTS: About 81.6% of the women with vaginal births had sutures for perineal trauma (87.7% of these due to episiotomies). Poor perception of safety was reported by 83.1% of women, and 69.5% of all infants not admitted to the NICU were separated from their mother after birth. The overall rate of cesarean birth was 52.6%, and 7.5% of term infants were admitted to the NICU. In public settings, having an intrapartum cesarean significantly increased the chances of one (OR 2.21; 95% CI 1.20-4.07), or two or more (4.08 [2.27-7.32]) harms. In private settings, cesarean deliveries without labor were also associated with higher chances of one (4.26 [2.65-6.85]), or two or more (4.60 [2.35-9.02]) harms. Only 2% of the women had harm-free care. CONCLUSIONS: In southeastern Brazil, there is a high prevalence of preventable harm during maternity care.
Asunto(s)
Servicios de Salud Materna , Seguridad del Paciente , Calidad de la Atención de Salud , Adolescente , Adulto , Brasil/epidemiología , Cesárea/estadística & datos numéricos , Niño , Estudios de Cohortes , Parto Obstétrico , Episiotomía , Femenino , Encuestas de Atención de la Salud , Humanos , Infecciones/epidemiología , Unidades de Cuidado Intensivo Neonatal , Admisión del Paciente/estadística & datos numéricos , Perineo/lesiones , Perineo/cirugía , Hemorragia Posparto/epidemiología , Embarazo , Suturas , Adulto JovenRESUMEN
The use of reproductive technologies has expanded beyond cases of infertility, and opportunities for individuals of different sexual orientations to use such technologies for conception have increased. The authors examined the challenges and limitations faced by women in same-sex relationships seeking conception services in São Paulo, Brazil. They interviewed 16 women in same-sex relationships who conceived children using reproductive technologies. Access to public health services for conception remains limited and exclusive to infertile heterosexual couples. Women in same-sex relationships are forced to select between costly medical treatments in the private sector, or self-insemination with sperm from a known donor. In this study, individuals reported that they experienced adverse effects of treatments; were treated with technologies for infertility when they were, in fact, fertile; and were exposed to unnecessary and invasive interventions. Growing political conservatism and the reduction of investment in public health services are factors that can directly affect sexual and reproductive health, including that of lesbians. Public policies that enable same-sex couples to conceive have yet to be developed in many countries, and a clearer articulation of the right to evidence-informed, rights-based care, consistent with national and international guidelines is a much-needed next step.
Asunto(s)
Fertilización/fisiología , Equidad en Salud , Accesibilidad a los Servicios de Salud , Homosexualidad Femenina/psicología , Técnicas Reproductivas , Adulto , Brasil , Femenino , Fertilidad , Humanos , Conducta SexualRESUMEN
Brazil is a middle-income country with universal maternity care, mostly by doctors. The experience of normal birth often includes rigid routines, aggressive interventions, and abusive, disrespectful treatment. In Brazil, this has been referred to as dehumanised care and, more recently, as obstetric violence. Since the early 1990s, social movements (SM) have struggled to change practices, public policies and provider training. The aim of this paper is to describe and analyse the role of SM in promoting change in maternity care, and in provider training. In this integrative review using a gender-oriented approach, we searched the Scielo database and the Ministry of Health's (MofH) publications and edicts for institutional and research papers on SM initiatives addressing disrespect and abuse in the last 25 years (1993-2018) in Brazil, and their impact on public policies and training programmes. We analyse these groups of interrelated initiatives: (1) political actions of SM resulting in changes in public policies and legislation; (2) events organised by SM for diffusion of information to the public; (3) MofH policies to humanise childbirth with participation of SM; and (4) initiatives to change providers' training, including legal actions based on obstetric violence reports. To promote real change in maternity care, the progression of policies and enabling environment of laws, regulations, and broad dissemination of information, need to go hand in hand with changes in all health providers' training - including a solid base in ethics, gender and human rights.
Asunto(s)
Parto Obstétrico/psicología , Violencia de Género/prevención & control , Personal de Salud/educación , Activismo Político , Política Pública , Respeto , Actitud del Personal de Salud , Brasil , Cesárea/estadística & datos numéricos , Femenino , Educación en Salud/organización & administración , Humanos , Servicios de Salud Materna/organización & administración , Cultura Organizacional , Aceptación de la Atención de Salud/psicología , Embarazo , Mujeres Embarazadas/psicología , Sector Privado/estadística & datos numéricos , Relaciones Profesional-Paciente , Salud de la MujerRESUMEN
Adenosine is an adenine base purine with actions as a modulator of neurotransmission, smooth muscle contraction, and immune response in several systems of the human body, including the cardiovascular system. In the vasculature, four P1-receptors or adenosine receptors-A1, A2A, A2B and A3-have been identified. Adenosine receptors are membrane G-protein receptors that trigger their actions through several signaling pathways and present differential affinity requirements. Adenosine is an endogenous ligand whose extracellular levels can reach concentrations high enough to activate the adenosine receptors. This nucleoside is a product of enzymatic breakdown of extra and intracellular adenine nucleotides and also of S-adenosylhomocysteine. Adenosine availability is also dependent on the activity of nucleoside transporters (NTs). The interplay between NTs and adenosine receptors' activities are debated and a particular attention is given to the paramount importance of the disruption of this interplay in vascular pathophysiology, namely in hypertension., The integration of important functional aspects of individual adenosine receptor pharmacology (such as in vasoconstriction/vasodilation) and morphological features (within the three vascular layers) in vessels will be discussed, hopefully clarifying the importance of adenosine receptors/NTs for modulating peripheral mesenteric vascular resistance. In recent years, an increase interest in purine physiology/pharmacology has led to the development of new ligands for adenosine receptors. Some of them have been patented as having promising therapeutic activities and some have been chosen to undergo on clinical trials. Increased levels of endogenous adenosine near a specific subtype can lead to its activation, constituting an indirect receptor targeting approach either by inhibition of NT or, alternatively, by increasing the activity of enzymes responsible for ATP breakdown. These findings highlight the putative role of adenosinergic players as attractive therapeutic targets for cardiovascular pathologies, namely hypertension, heart failure or stroke. Nevertheless, several aspects are still to be explored, creating new challenges to be addressed in future studies, particularly the development of strategies able to circumvent the predicted side effects of these therapies.
Asunto(s)
Adenosina/química , Adenosina/farmacología , Sistema Cardiovascular/efectos de los fármacos , Receptores Purinérgicos P1/química , Humanos , Hipertensión/tratamiento farmacológico , Ligandos , Terapia Molecular Dirigida , Proteínas de Transporte de Nucleósidos/antagonistas & inhibidores , Proteínas de Transporte de Nucleósidos/metabolismo , S-Adenosilhomocisteína/química , S-Adenosilhomocisteína/metabolismo , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
Compounds with a heterocyclic isoxazole ring are well known for their diverse biologic activities encompassing antimicrobial, antipsychotic, immunosuppressive, antidiabetic and anticancer effects. Recent studies on hematological malignancies have also shown that some of the isoxazole-derived compounds feature encouraging cancer selectivity, low toxicity to normal cells and ability to overcome cancer drug resistance of conventional treatments. These characteristics are particularly promising because patients with hematological malignancies face poor clinical outcomes caused by cancer drug resistance or relapse of the disease. This review summarizes the knowledge on isoxazole-derived compounds toward hematological malignancies and provides clues on their mechanism(s) of action (apoptosis, cell cycle arrest, ROS production) and putative pharmacological targets (c-Myc, BET, ATR, FLT3, HSP90, CARM1, tubulin, PD-1/PD-L1, HDACs) wherever known.
Asunto(s)
Antineoplásicos , Neoplasias Hematológicas , Isoxazoles , Humanos , Neoplasias Hematológicas/tratamiento farmacológico , Isoxazoles/farmacología , Isoxazoles/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Terapia Molecular DirigidaRESUMEN
Cisplatin (cDDP) resistance is a matter of concern in triple-negative breast cancer therapeutics. We measured the metabolic response of cDDP-sensitive (S) and -resistant (R) MDA-MB-231 cells to Pd2Spermine(Spm) (a possible alternative to cDDP) compared to cDDP to investigate (i) intrinsic response/resistance mechanisms and (ii) the potential cytotoxic role of Pd2Spm. Cell extracts were analyzed by untargeted nuclear magnetic resonance metabolomics, and cell media were analyzed for particular metabolites. CDDP-exposed S cells experienced enhanced antioxidant protection and small deviations in the tricarboxylic acid cycle (TCA), pyrimidine metabolism, and lipid oxidation (proposed cytotoxicity signature). R cells responded more strongly to cDDP, suggesting a resistance signature of activated TCA cycle, altered AMP/ADP/ATP and adenine/uracil fingerprints, and phospholipid biosynthesis (without significant antioxidant protection). Pd2Spm impacted more markedly on R/S cell metabolisms, inducing similarities to cDDP/S cells (probably reflecting high cytotoxicity) and strong additional effects indicative of amino acid depletion, membrane degradation, energy/nucleotide adaptations, and a possible beneficial intracellular γ-aminobutyrate/glutathione-mediated antioxidant mechanism.
Asunto(s)
Antineoplásicos , Cisplatino , Resistencia a Antineoplásicos , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Femenino , Espermina/farmacología , Espermina/metabolismo , Paladio/química , Paladio/farmacologíaRESUMEN
In hypertension, vascular reactivity alterations have been attributed to numerous factors, including higher sympathetic innervation/adenosine. This study examined the modulation of adenosine receptors on vascular sympathetic nerves and their putative contribution to higher noradrenaline spillover in hypertension. We assessed adenosine receptors distribution in the adventitia through confocal microscopy, histomorphometry, and their regulatory function on electrically-evoked [(3)H]-noradrenaline overflow, using selective agonists/antagonists. We found that: i) A1-adenosine receptor agonist (CPA: 100 nM) inhibited tritium overflow to a lower extent in SHR (25% ± 3%, n = 14) compared to WKY (38% ± 3%, n = 14) mesenteric arteries; ii) A2A-adenosine receptor agonist (CGS 21680: 100 nM) induced a slight increase of tritium overflow that was similar in SHR (22% ± 8%, n = 8) and WKY (24% ± 5%, n = 8) mesenteric arteries; iii) A2B- and A3-adenosine receptors did not alter tritium overflow in either strain; iv) all adenosine receptors were present on mesenteric artery sympathetic nerves and/or some adventitial cells of both strains; and v) A1-adenosine receptor staining fractional area was lower in SHR than in WKY mesenteric arteries. We conclude that there is an impaired inhibitory function of vascular presynaptic A1-adenosine receptors in SHR, likely related to a reduced presence of these receptors on sympathetic innervation, which might lead to higher levels of noradrenaline in the synaptic cleft and contribute to hypertension in this strain.
Asunto(s)
Hipertensión/etiología , Arterias Mesentéricas/inervación , Arterias Mesentéricas/metabolismo , Receptor de Adenosina A1/fisiología , Sistema Nervioso Simpático/metabolismo , Animales , Hipertensión/metabolismo , Masculino , Microscopía Confocal , Imagen Molecular , Norepinefrina/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptor de Adenosina A1/metabolismo , Sinapsis/metabolismo , Tritio/metabolismoRESUMEN
OBJECTIVE: To analyze the quality of data collected during prenatal care recorded in the Integrated Health Care Management System (SIGA) of the Municipal Department of Health of São Paulo from 2012 to 2020. METHODS: Descriptive study using SIGA data and the variables: maternal height (cm), weight (kg) measured throughout pregnancy, gestational age at prenatal consultation, systolic (SBP) and diastolic (DBP) blood pressure (in mmHg), and body mass index (BMI) at the beginning of pregnancy (up to 8 weeks). Quality analysis was carried out by calculating the indicators: percentage of incompleteness and zero values of all variables studied, percentage of implausible values for height, weight, BMI; preference for terminal digit of weight and height, and normality of distributions. RESULTS: The database of pregnant women made available for analysis included 8,046,608 records and 1,174,115 women. The percentage of incompleteness and zero values was low (<1%) in all original variables of the system. There are more records at the end of pregnancy. For the four original variables of interest in the database (weight, height, SBP, DBP), there is a clear preference for the terminal digit. The variables of interest did not present an approximately normal distribution during the evaluated period. CONCLUSION: The quality analysis showed the need for improving the standardization of information collection and recording, the rounding of measurements and the need for encouraging pregnant women to start prenatal care as soon as possible, in such a way that it is important to invest in data quality, through educational resources for professionals who work in health care.
Asunto(s)
Mujeres Embarazadas , Atención Prenatal , Embarazo , Humanos , Femenino , Brasil , Atención a la Salud , Inmunoglobulina A SecretoraRESUMEN
OBJECTIVE: To identify spatial variability of mortality from breast and cervical cancer and to assess factors associated in the city of São Paulo. METHODS: Between 2009 and 2016, 10,124 deaths from breast cancer and 2,116 deaths from cervical cancer were recorded in the Mortality Information System among women aged 20 years and over. The records were geocoded by address of residence and grouped according to Primary Health Care coverage areas. A spatial regression modeling was put together using the Bayesian approach with a Besag-York-Mollié structure to verify the association of deaths with selected indicators. RESULTS: Mortality rates from these types of cancer showed inverse spatial patterns. These variables were associated with breast cancer mortality: travel time between one and two hours to work (RR - relative risk: 0.97; 95%CI - credible interval: 0.93-1.00); women being the head of the household (RR 0.97; 95%CI 0.94-0.99) and deaths from breast cancer in private health institutions (RR 1.04; 95%CI 1.00-1.07). The following variables were associated with mortality from cervical cancer: travel time to work between half an hour and one hour (RR 0.92; 95%CI 0.87-0.98); per capita household income of up to 3 minimum wages (RR 1.27; 95%CI 1.18-1.37) and ratio of children under one year of age related to the female population aged 15 to 49 years (RR 1.09; 95%CI 1.01-1.18). CONCLUSION: The predicted RR for mortality from these cancers were calculated and associated with the socioeconomic conditions of the areas covered.
OBJETIVO: Identificar a variabilidade espacial da mortalidade por câncer de mama e colo do útero e avaliar fatores associados à mortalidade por esses cânceres no município de São Paulo. MÉTODOS: Entre 2009 e 2016 foram registrados, no Sistema de Informações sobre Mortalidade, 10.124 óbitos por câncer de mama e 2.116 óbitos por câncer do colo do útero em mulheres com 20 anos e mais. Os registros foram geocodificados por endereço de residência e agregados segundo território adstrito. Foram realizadas modelagens de regressão espacial utilizando-se a abordagem bayesiana com estrutura de Besag-York-Mollié para verificar a associação dos óbitos com indicadores selecionados. RESULTADOS: As taxas de mortalidade por esses cânceres apresentaram padrões espaciais inversos. As variáveis associadas à mortalidade por câncer de mama foram: tempo de deslocamento para o trabalho entre uma e duas horas (risco relativo RR 0,97; intervalo de credibilidade IC95% 0,931,00); mulheres responsáveis pelo domicílio (RR 0,97; IC95% 0,940,99) e óbitos por câncer de mama ocorridos em estabelecimentos privados (RR 1,04; IC95% 1,001,07). À mortalidade por câncer do colo do útero, estiveram associados: tempo de deslocamento para o trabalho entre meia e uma hora (RR 0,92; IC95% 0,870,98); rendimento domiciliar até três salários-mínimos (RR 1,27; IC95% 1,181,37); e razão de menores de um ano em relação à população feminina de 15 a 49 anos (RR 1,09; IC95% 1,011,18). CONCLUSÃO: Foram calculados os RR preditos para a mortalidade por esses cânceres, que estiveram associados às condições socioeconômicas das áreas de abrangência.
Asunto(s)
Neoplasias de la Mama , Neoplasias del Cuello Uterino , Niño , Humanos , Femenino , Teorema de Bayes , Brasil/epidemiología , Ciudades/epidemiología , Factores SocioeconómicosRESUMEN
OBJECTIVE: To identify factors associated with the definition of the gestational age (GA) estimation method recorded in the live birth certificate (LBC), and to compare the results obtained according to the method in the city of São Paulo (CSP), between 2012 and 2019. METHODS: Cross-sectional population-based study using the Live Birth Information System. Descriptive and comparative analysis was performed according to the GA estimation method, followed by a univariate and multivariate logistic regression model to identify the predictor variables of the method used. RESULTS: The estimation of GA by the date of the last menstrual period (LMP) (39.9%) was lower than that obtained by other methods (OM) (60.1%) - physical examination and ultrasound, between 2012-2019. LMP registration in the LBC increased with the mother's age, it was higher among women who were white, more educated and with partners, in cesarean sections and with private funding. In the logistic regression, public funding was 2.33 times more likely than private funding to use OM. The proportion of preterm infants (<37 weeks) with GA by LMP was 26.5% higher than that obtained by OM. Median birth weight was higher among preterm infants with GA estimated by LMP. CONCLUSION: Prematurity was higher with the GA estimated by LMP in the CSP, which may indicate overestimation by this method. The source of funding was the most explanatory variable for defining the GA estimator method at the LBC. The results point to the need for caution when comparing the GA obtained by different methods.