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1.
Proc Natl Acad Sci U S A ; 119(28): e2206415119, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35867768

RESUMO

Chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem without therapeutic options. Using the platinum-based chemotherapy cisplatin to model CICI, we revealed robust elevations in the adenosine A2A receptor (A2AR) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A2AR inhibition by the Food and Drug Administration-approved A2AR antagonist KW-6002 prevented cisplatin-induced impairments in neural progenitor proliferation and dendrite morphogenesis of adult-born neurons, while improving memory and anxiety-like behavior, without affecting tumor growth or cisplatin's antitumor activity. Collectively, our study identifies A2AR signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Antineoplásicos , Comprometimento Cognitivo Relacionado à Quimioterapia , Cisplatino , Neurogênese , Purinas , Receptor A2A de Adenosina , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Comprometimento Cognitivo Relacionado à Quimioterapia/prevenção & controle , Cisplatino/efeitos adversos , Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/fisiologia , Neurogênese/efeitos dos fármacos , Purinas/administração & dosagem , Purinas/uso terapêutico , Receptor A2A de Adenosina/metabolismo
2.
J Lipid Res ; 65(3): 100516, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38320654

RESUMO

The gold-standard diagnostic test for peroxisomal disorders (PDs) is plasma concentration analysis of very long-chain fatty acids (VLCFAs). However, this method's time-consuming nature and limitations in cases which present normal VLCFA levels necessitates alternative approaches. The analysis of C26:0-lysophosphatydylcholine (C26:0-LPC) in dried blood spot samples by tandem-mass spectrometry (MS/MS) has successfully been implemented in certain newborn screening programs to diagnose X-linked adrenoleukodystrophy (ALD). However, the diagnostic potential of very long-chain LPCs concentrations in plasma remains poorly understood. This study sought to evaluate the diagnostic performance of C26:0-LPC and other very long-chain LPCs, comparing them to VLCFA analysis in plasma. The study, which included 330 individuals affected by a peroxisomal ß-oxidation deficiency and 407 control individuals, revealed that C26:0- and C24:0-LPC concentrations demonstrated the highest diagnostic accuracy (98.8% and 98.4%, respectively), outperforming VLCFA when C26:0/C22:0 and C24:0/C22:0 ratios were combined (98.1%). Combining C24:0- and C26:0-LPC gave the highest sensitivity (99.7%), with ALD females exhibiting notably higher sensitivity compared with the VLCFA ratio combination (98.7% vs. 93.5%, respectively). In contrast, C22:0-LPC exhibited suboptimal performance, primarily due to its low sensitivity (75%), but we identified a potential use to help distinguish between ALD and Zellweger spectrum disorders. In summary, MS/MS analysis of plasma C24:0- and C26:0-LPC concentrations represents a rapid and straightforward approach to diagnose PDs, demonstrating superior diagnostic accuracy, particularly in ALD females, compared with conventional VLCFA biomarkers. We strongly recommend integrating very-long chain LPC plasma analysis in the diagnostic evaluation of individuals suspected of having a PD.


Assuntos
Adrenoleucodistrofia , Lisofosfatidilcolinas , Recém-Nascido , Feminino , Humanos , Espectrometria de Massas em Tandem , Adrenoleucodistrofia/diagnóstico , Triagem Neonatal/métodos , Biomarcadores , Ácidos Graxos não Esterificados , Ácidos Graxos
3.
Rev Physiol Biochem Pharmacol ; 183: 45-101, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-32715321

RESUMO

The expression and function of many ion channels and transporters in cancer cells display major differences in comparison to those from healthy cells. These differences provide the cancer cells with advantages for tumor development. Accordingly, targeting ion channels and transporters have beneficial anticancer effects including inhibition of cancer cell proliferation, migration, invasion, metastasis, tumor vascularization, and chemotherapy resistance, as well as promoting apoptosis. Some of the molecular mechanisms associating ion channels and transporters with cancer include the participation of oxidative stress, immune response, metabolic pathways, drug synergism, as well as noncanonical functions of ion channels. This diversity of mechanisms offers an exciting possibility to suggest novel and more effective therapeutic approaches to fight cancer. Here, we review and discuss most of the current knowledge suggesting novel therapeutic approaches for cancer therapy targeting ion channels and transporters. The role and regulation of ion channels and transporters in cancer provide a plethora of exceptional opportunities in drug design, as well as novel and promising therapeutic approaches that may be used for the benefit of cancer patients.


Assuntos
Neoplasias , Apoptose , Proliferação de Células , Humanos , Canais Iônicos , Neoplasias/patologia , Neovascularização Patológica
4.
Anal Biochem ; : 115600, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38964698

RESUMO

Foodborne pathogens are a grave concern for the for food, medical, environmental, and economic sectors. Their ease of transmission and resistance to treatments, such as antimicrobial agents, make them an important challenge. Food tainted with these pathogens is swiftly rejected, and if ingested, can result in severe illnesses and even fatalities. This review provides and overview of the current status of various pathogens and their metabolites transmitted through food. Despite a plethora of studies on treatments to eradicate and inhibit these pathogens, their indiscriminate use can compromise the sensory properties of food and lead to contamination. Therefore, the study of detection methods such as electrochemical biosensors has been proposed, which are devices with advantages such as simplicity, fast response, and sensitivity. However, these biosensors may also present some limitations. In this regard, it has been reported that nanomaterials with high conductivity, surface-to-volume ratio, and robustness have been observed to improve the detection of foodborne pathogens or their metabolites. Therefore, in this work, we analyze the detection of pathogens transmitted through food and their metabolites using electrochemical biosensors based on nanomaterials.

5.
Clin Chem Lab Med ; 62(3): 493-505, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-37794778

RESUMO

OBJECTIVES: Acylcarnitine and amino acid analyses of dried blood spot (DBS) samples using tandem mass spectrometry in newborn screening (NBS) programmes can generate false positive (FP) results. Therefore, implementation of second-tier tests (2TTs) using DBS samples has become increasingly important to avoid FPs. The most widely used 2TT metabolites include methylmalonic acid, 3-hydroxypropionic acid, methylcitric acid, and homocysteine. METHODS: We simultaneously measured 46 underivatised metabolites, including organic acids, acylglycine and acylcarnitine isomers, homocysteine, and orotic acid, in DBS samples using tandem mass spectrometry. To validate this method, we analysed samples from 147 healthy newborns, 160 patients with genetic disorders diagnosed via NBS, 20 patients with acquired vitamin B12 deficiency, 10 newborns receiving antibiotic treatment, and nine external quality control samples. RESULTS: The validation study revealed that 31 metabolites showed good analytical performance. Furthermore, this method detected key metabolites for all diseases associated with increased levels of the following acylcarnitines: C3, C4, C5, C4DC/C5OH, and C5DC. The sensitivity of this method to detect all diseases was 100 %, and the specificity was 74-99 %, except for glutaric aciduria type 1. This method can also be used to diagnose mitochondrial fatty acid ß-oxidation disorders (FAODs) and urea cycle defects (UCDs). CONCLUSIONS: We have described a 2TT panel of 31 metabolites in DBS samples based on an easy and rapid method without derivatisation. Its implementation allowed us to distinguish between different organic acidurias, some FAODs, and UCDs. This new strategy has increased the efficiency of our NBS programme by reducing FP and false negative results, second sample requests, and the time required for diagnosis.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Encefalopatias Metabólicas , Carnitina/análogos & derivados , Glutaril-CoA Desidrogenase/deficiência , Triagem Neonatal , Espectrometria de Massas em Tandem , Humanos , Recém-Nascido , Espectrometria de Massas em Tandem/métodos , Triagem Neonatal/métodos , Espanha , Cromatografia Líquida/métodos , Homocisteína , Teste em Amostras de Sangue Seco/métodos
6.
BMC Womens Health ; 24(1): 291, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38755575

RESUMO

BACKGROUND: Menstrual Regulation (MR) has been legal in Bangladesh since 1979 in an effort to reduce maternal mortality from unsafe abortion care. However, access to high-quality and patient-centered MR care remains a challenge. This analysis aimed to explore what clients know before going into care and the experience itself across a variety of service delivery sites where MR care is available. METHODS: We conducted 26 qualitative semi-structured interviews with MR clients who were recruited from three different service delivery sites in Dhaka, Bangladesh from January to March 2019. Interviews explored client expectations and beliefs about MR care, the experience of the care they received, and their perception of the quality of that care. We conducted a thematic content analysis using a priori and emergent codes. RESULTS: Clients overall lacked knowledge about MR care and held fears about the damage to their bodies after receiving care. Despite their fears, roughly half the clients held positive expectations about the care they would receive. Call center clients felt the most prepared by their provider about what to expect during their MR care. During counseling sessions, providers at in-facility locations reinforced the perception of risk of future fertility as a result of MR and commonly questioned clients on their need for MR services. Some even attempted to dissuade nulliparous women from getting the care. Clients received this type of questioning throughout their time at the facilities, not just from their medical providers. The majority of clients perceived their care as good and rationalized these comments from their providers as coming from a caring place. However, a handful of clients did report bad care and negative feelings about their interactions with providers and other clinical staff. CONCLUSION: Providers and clinical staff can play a key role in shaping the experience of clients accessing MR care. Training on accurate knowledge about the safety and effectiveness of MR, and the importance of client communication could help improve client knowledge and person-centered quality of MR care.


Assuntos
Pesquisa Qualitativa , Humanos , Feminino , Bangladesh , Adulto , Adulto Jovem , Gravidez , Menstruação/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Aborto Induzido/psicologia , Adolescente
7.
Acta Paediatr ; 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38922980

RESUMO

AIM: Our aim was to identify independent determinants of rapid weight gain in infants at 3-4, 6, and 12 months of age. METHODS: A cohort study was conducted on Mexican term infants in public and private settings between March 2021 and May 2023. Rapid weight gain was defined as a ≥0.67 SD change in weight-for-age-Z-score from birth to 3-4, 6, and 12 months of age. Maternal and infant characteristics were described, and infant feeding practices, appetitive traits, weight, and length were analysed at 3-4, 6, and 12 months of age. Rapid weight gain predictors were determined using generalised linear regression models. RESULTS: In total, 168 infants were recruited (55% boys). Small-for-gestational-age status increased rapid weight gain risk 1.5 times, whereas large-for-gestational-age status represented a 20%-30% decrease. Slowness in eating decreased the risk by 10%. Protective factors were older maternal age and higher educational level, whereas formula feeding, early complementary feeding, greater food enjoyment, and satiety responsiveness increased the risk. CONCLUSIONS: Small for gestational age, slowness in eating, and feeding practices can be rapid weight gain predictors across the first year of life.

8.
Chem Biodivers ; 21(2): e202301930, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38216544

RESUMO

The aim of this study was to screen sixteen meso-1 semi-synthetic derivatives bearing ether, esther, carbamate, phosphate or aminoether functional groups against five cancer cell lines: MCF-7 (breast), A549 (lung), HepG2 (liver), HeLa (cervix), and DU145 (prostate) at 25 µM using the MTT assay. Results from the screening showed that two derivatives had the lowest percentage of cell viability at 25 µM, the aminoether derivative meso-11 and the esther derivative meso-20 against A549 (44.15±0.78 %) and MCF-7 (41.60±0.92 %), respectively. Then, it was determined the IC50 value of each compound against their most sensitive cancer cell line. Results showed that aminoether derivative meso-11 showed potent cytotoxicity against A549 (IC50 =17.11±2.11 µM), whereas it resulted more cytotoxic against the LL-47 lung normal cell line (IC50 =9.49±1.19 µM) having a Selective Index (SI) of 0.55. On the other hand, the esther derivative meso-20 exhibited potent activity against MCF-7 (IC50 =18.20±1.98 µM), whereas it displayed moderate cytotoxicity against the MCF-10 breast normal cell line (IC50 =41.22±2.17 µM) with a SI of 2.2. Finally, studies on the mechanism of action of meso-20 indicated disruption of MCF-7 plasma membrane in vitro and the AMPK activation in silico.


Assuntos
Antineoplásicos , Guaiacol/análogos & derivados , Lignanas , Masculino , Humanos , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/farmacologia , Lignanas/farmacologia , Proliferação de Células , Estrutura Molecular , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Células MCF-7
9.
Int J Mol Sci ; 25(4)2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38397059

RESUMO

This study explores the impact of plasma treatment on Lavandin Grosso flowers and its influence on the extraction of essential oils (EOs) via hydrodistillation. Short plasma treatment times enhance the yield of EO extraction from 3.19% in untreated samples to 3.44%, corresponding to 1 min of plasma treatment, while longer treatment times (10 min) show diminishing returns to 3.07% of yield extraction. Chemical characterization (GC/MS and ATR-FTIR) indicates that plasma treatments do not significantly alter the chemical composition of the extracted EOs, preserving their aromatic qualities. Investigations into plasma-surface interactions reveal changes at the nanometer level, with XPS confirming alterations in the surface chemistry of Lavandin Grosso flowers by reducing surface carbon and increasing oxygen content, ultimately resulting in an increased presence of hydrophilic groups. The presence of hydrophilic groups enhances the interaction between the surface membrane of the glandular trichomes on Lavandin Grosso flowers and water vapor, consequently increasing the extraction of EOs. Furthermore, microscopic SEM examinations demonstrate that plasma treatments do not affect the morphology of glandular trichomes, emphasizing that surface modifications primarily occur at the nanoscale. This study underscores the potential of plasma technology as a tool to enhance EO yields from botanical sources while maintaining their chemical integrity.


Assuntos
Óleos Voláteis , Óleos Voláteis/química , Cromatografia Gasosa-Espectrometria de Massas , Flores/química , Vapor , Tecnologia
10.
Int J Mol Sci ; 25(6)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38542089

RESUMO

Glaucoma is a neurodegenerative disease that causes blindness. In this study, we aimed to evaluate the protective role of cilastatin (CIL), generally used in the treatment of nephropathologies associated with inflammation, in an experimental mouse model based on unilateral (left) laser-induced ocular hypertension (OHT). Male Swiss mice were administered CIL daily (300 mg/kg, i.p.) two days before OHT surgery until sacrifice 3 or 7 days later. Intraocular Pressure (IOP), as well as retinal ganglion cell (RGC) survival, was registered, and the inflammatory responses of macroglial and microglial cells were studied via immunohistochemical techniques. Results from OHT eyes were compared to normotensive contralateral (CONTRA) and naïve control eyes considering nine retinal areas and all retinal layers. OHT successfully increased IOP values in OHT eyes but not in CONTRA eyes; CIL did not affect IOP values. Surgery induced a higher loss of RGCs in OHT eyes than in CONTRA eyes, while CIL attenuated this loss. Similarly, surgery increased macroglial and microglial activation in OHT eyes and to a lesser extent in CONTRA eyes; CIL prevented both macroglial and microglial activation in OHT and CONTRA eyes. Therefore, CIL arises as a potential effective strategy to reduce OHT-associated damage in the retina of experimental mice.


Assuntos
Glaucoma , Doenças Neurodegenerativas , Hipertensão Ocular , Masculino , Camundongos , Animais , Doenças Neurodegenerativas/complicações , Glaucoma/etiologia , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/patologia , Pressão Intraocular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Cilastatina/uso terapêutico , Modelos Animais de Doenças
11.
Matern Child Nutr ; : e13672, 2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38853145

RESUMO

This study aimed to investigate if the duration of breastfeeding and the method at initiation of complementary feeding affect eating behaviour in children aged 3-6 years. This is a cross-sectional analysis from the Childhood Obesity Risk Assessment Longitudinal Study project, an ongoing longitudinal cohort study that aims to identify childhood obesity risk factors in Spanish children. A total of 1215 children aged 3-6 years were included. Breastfeeding duration and the method of initiation of complementary feeding [baby-led weaning (BLW), traditional/spoon or mixed method] were evaluated. Eating behaviour at 3-6 years was assessed with the Child Eating Behaviour Questionnaire. Generalized linear models were fitted to assess the association between the aforementioned exposures and eating behaviour. Children breastfed for ≥4 months were less likely to be fussy eaters at 3-6 years compared to those breastfed for <1 month (OR: 0.86 95% CI: 0.76-0.98; p = 0.031). Compared to those children using the traditional/spoon-feeding method, those initiating complementary feeding through BLW or through a mixed approach were more likely to have higher scores on the enjoyment of food (EF) (OR, 95% CI: 1.33, 1.13-1.57; p = 0.001 and 1.17, 1.05-1.30; p = 0.002, respectively) and lower scores on food fussiness (FF) at 3-6 years (0.76, 0.62-0.91; p = 0.004 and 0.87, 0.78-0.98; p = 0.033, respectively). Breastfeeding for ≥4 months and initiation of complementary feeding with the BLW and a mixed approach were associated with greater EF and lower FF, which should endure practice.

12.
Rev Invest Clin ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38781946

RESUMO

Background: The 5th edition of the World Health Organization Classification of Hematolymphoid Tumors recently defined immune deficiency/dysregulation (IDD)-associated-lymphoid-proliferations in HIV settings, where information is scarce, often gone under or misdiagnosed. Objectives: To describe the clinical picture, histopathology, and outcomes of IDD-associated-lymphoidproliferations Epstein-Barr virus+ (EBV) in people living with HIV without organ transplantation, antiretroviral therapy (ART) treated. Materials and Methods: HIV+ patients diagnosed with IDD-associated-lymphoid-proliferations seen at an academic medical center in Mexico from 2016 to 2019 were included. Immunohistochemical studies, in situ hybridization, and polymerase chain reaction analysis for EBV and LMP1 gene deletions were performed and correlated with clinical data. Results: We included 27 patients, all men who have sex with men, median age 36 years (interquartile range [IQR] 22-54). The median baseline CD4+ T cells were 113/mL (IQR 89-243), the CD4+/CD8+ ratio was 0.15 (IQR: 0.09-0.22), and the HIV viral load was 184,280 copies/mL (IQR: 76,000-515,707). Twenty patients (74.07%) had IDD-associated-lymphoid-proliferations hyperplasia plasma cell type EBV+, 3 (11.1%) had hyperplasia mononucleosis-like type (IM-type), 1 patient (3.70%) had florid follicular hyperplasia, 3 (11.1%) IDD-associated-lymphoid-proliferations polymorphic type, and there were 22 cases (81.4%) of synchronic Kaposi Sarcoma. Two patients were diagnosed with Hodgkin lymphoma following a second positron emission tomography-computed tomography scan-guided biopsy. The median follow-up was 228 weeks (IQR 50-269); 6 patients died (22.2%) of causes unrelated to IDD-associated-lymphoid-proliferations related. Conclusion: IDD-associated-lymphoid-proliferations EBV+ occured in severely immunosuppressed HIV+ patients, a high percentage of whom had concomitant Kaposi sarcoma. The prognosis was good in patients treated only with ART.

13.
Glycobiology ; 33(11): 861-872, 2023 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-37399117

RESUMO

N-linked protein glycosylation is a post-translational modification that exists in all domains of life. It involves two consecutive steps: (i) biosynthesis of a lipid-linked oligosaccharide (LLO), and (ii) glycan transfer from the LLO to asparagine residues in secretory proteins, which is catalyzed by the integral membrane enzyme oligosaccharyltransferase (OST). In the last decade, structural and functional studies of the N-glycosylation machinery have increased our mechanistic understanding of the pathway. The structures of bacterial and eukaryotic glycosyltransferases involved in LLO elongation provided an insight into the mechanism of LLO biosynthesis, whereas structures of OST enzymes revealed the molecular basis of sequon recognition and catalysis. In this review, we will discuss approaches used and insight obtained from these studies with a special emphasis on the design and preparation of substrate analogs.


Assuntos
Hexosiltransferases , Glicosilação , Hexosiltransferases/metabolismo , Lipopolissacarídeos/metabolismo , Polissacarídeos , Glicosiltransferases/metabolismo
14.
FASEB J ; 36(4): e22222, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35218573

RESUMO

Cellular uptake of vitamin B12 in humans is mediated by the endocytosis of the B12 carrier protein transcobalamin (TC) via its cognate cell surface receptor TCblR, encoded by the CD320 gene. Because CD320 expression is associated with the cell cycle and upregulated in highly proliferating cells including cancer cells, this uptake route is a potential target for cancer therapy. We developed and characterized four camelid nanobodies that bind holo-TC (TC in complex with B12 ) or the interface of the human holo-TC:TCblR complex with nanomolar affinities. We determined X-ray crystal structures of these nanobodies bound to holo-TC:TCblR, which enabled us to map their binding epitopes. When conjugated to the model toxin saporin, three of our nanobodies caused growth inhibition of HEK293T cells and therefore have the potential to inhibit the growth of human cancer cells. We visualized the cellular binding and endocytic uptake of the most potent nanobody (TC-Nb4) using fluorescent light microscopy. The co-crystal structure of holo-TC:TCblR with another nanobody (TC-Nb34) revealed novel features of the interface of TC and the LDLR-A1 domain of TCblR, rationalizing the decrease in the affinity of TC-B12 binding caused by the Δ88 mutation in CD320.


Assuntos
Anticorpos Monoclonais/química , Imunoconjugados/farmacologia , Receptores de Superfície Celular/metabolismo , Saporinas/química , Anticorpos de Domínio Único/química , Transcobalaminas/metabolismo , Vitamina B 12/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Camelídeos Americanos , Ciclo Celular , Proliferação de Células , Células HEK293 , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Imunotoxinas/química , Imunotoxinas/farmacologia , Receptores de Superfície Celular/química , Receptores de Superfície Celular/genética , Saporinas/imunologia , Anticorpos de Domínio Único/biossíntese , Anticorpos de Domínio Único/imunologia
15.
Synapse ; 77(1): e22252, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36099479

RESUMO

Previous studies demonstrated that in vitro preparations of the isolated vestibular system of diverse animal species still exhibit stable resting electrical activity and mechanically evoked synaptic transmission between hair cells and primary afferent endings. However, there are no reports related to their neurodevelopment. Therefore, this research aimed to examine whether NMDA receptors mediate these electrical signals in an isolated preparation of the chicken vestibular system at three developmental stages, E15, E18, and E21. We found that the spontaneous and mechanically evoked discharges from primary afferents of the posterior semicircular canal were modulated by agonists NMDA and glycine, but not by the agonist d-serine applied near the synapses. Moreover, the individually applied by bath perfusion of three NMDA receptor antagonists (MK-801, ifenprodil, and 2-naphthoic acid) or high Mg2+ decreased the resting discharge rate, the NMDA response, and the discharge rate of mechanically evoked activity from these primary afferents. Furthermore, we found that the vestibular ganglion shows a stage-dependent increase in the expression of NMDA receptor subunits GluN1, GluN2 (A-C), and GluN3 (A-B), being greater at E21, except for GluN2D, which was inversely related to the developmental stage. However, in the crista ampullaris, the expression pattern remained constant throughout development. This could suggest the possible existence of presynaptic NMDA receptors. Our results highlight that although the NMDA receptors are functionally active at the early embryonic stages of the vestibular system, NMDA and glycine reach their mature functionality to increase NMDA responses close to hatching (E21).


Assuntos
Galinhas , Receptores de N-Metil-D-Aspartato , Animais , Receptores de N-Metil-D-Aspartato/metabolismo , Galinhas/metabolismo , N-Metilaspartato , Sistema Vestibular , Glicina
16.
Nephrol Dial Transplant ; 38(3): 679-690, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-35561741

RESUMO

BACKGROUND: Hypomagnesaemia with secondary hypocal-caemia (HSH) is a rare autosomal recessive disorder caused by pathogenic variants in TRPM6, encoding the channel-kinase transient receptor potential melastatin type 6. Patients have very low serum magnesium (Mg2+) levels and suffer from muscle cramps and seizures. Despite genetic testing, a subgroup of HSH patients remains without a diagnosis. METHODS: In this study, two families with an HSH phenotype but negative for TRPM6 pathogenic variants were subjected to whole exome sequencing. Using a complementary combination of biochemical and functional analyses in overexpression systems and patient-derived fibroblasts, the effect of the TRPM7-identified variants on Mg2+ transport was examined. RESULTS: For the first time, variants in TRPM7 were identified in two families as a potential cause for hereditary HSH. Patients suffer from seizures and muscle cramps due to magnesium deficiency and episodes of hypocalcaemia. In the first family, a splice site variant caused the incorporation of intron 1 sequences into the TRPM7 messenger RNA and generated a premature stop codon. As a consequence, patient-derived fibroblasts exhibit decreased cell growth. In the second family, a heterozygous missense variant in the pore domain resulted in decreased TRPM7 channel activity. CONCLUSIONS: We establish TRPM7 as a prime candidate gene for autosomal dominant hypomagnesaemia and secondary hypocalcaemia. Screening of unresolved patients with hypocalcaemia and secondary hypocalcaemia may further establish TRPM7 pathogenic variants as a novel Mendelian disorder.


Assuntos
Hipocalcemia , Canais de Cátion TRPM , Humanos , Magnésio , Canais de Cátion TRPM/metabolismo , Cãibra Muscular/complicações , Proteínas Serina-Treonina Quinases/metabolismo
17.
EMBO Rep ; 22(6): e51169, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34031962

RESUMO

Recent studies demonstrate that metabolic disturbance, such as augmented glycolysis, contributes to fibrosis. The molecular regulation of this metabolic perturbation in fibrosis, however, has been elusive. COUP-TFII (also known as NR2F2) is an important regulator of glucose and lipid metabolism. Its contribution to organ fibrosis is undefined. Here, we found increased COUP-TFII expression in myofibroblasts in human fibrotic kidneys, lungs, kidney organoids, and mouse kidneys after injury. Genetic ablation of COUP-TFII in mice resulted in attenuation of injury-induced kidney fibrosis. A non-biased proteomic study revealed the suppression of fatty acid oxidation and the enhancement of glycolysis pathways in COUP-TFII overexpressing fibroblasts. Overexpression of COUP-TFII in fibroblasts also induced production of alpha-smooth muscle actin (αSMA) and collagen 1. Knockout of COUP-TFII decreased glycolysis and collagen 1 levels in fibroblasts. Chip-qPCR revealed the binding of COUP-TFII on the promoter of PGC1α. Overexpression of COUP-TFII reduced the cellular level of PGC1α. Targeting COUP-TFII serves as a novel treatment approach for mitigating fibrosis in chronic kidney disease and potentially fibrosis in other organs.


Assuntos
Fator II de Transcrição COUP , Receptores Nucleares Órfãos , Animais , Fator II de Transcrição COUP/genética , Fator II de Transcrição COUP/metabolismo , Fibrose , Glicólise/genética , Rim , Camundongos , Camundongos Knockout , Miofibroblastos , Receptores Nucleares Órfãos/metabolismo , Proteômica
18.
Int J Eat Disord ; 56(3): 501-515, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36647184

RESUMO

OBJECTIVE: Eating disorders (ED) may be associated with an increased prevalence of non-suicidal self-injury (NSSI) and suicidal thoughts and behaviors (STBs) relative to healthy (HC) and psychiatric (PC) controls. However, precise estimates of differences in prevalence between individuals with EDs and controls are unclear. We compared the prevalence of NSSI, suicidal ideation (SI), suicide attempts (SA), and deaths by suicide in controls and individuals with EDs. METHOD: We searched MEDLINE, PsycINFO, EMBASE, and CINAHL for peer-reviewed publications reporting the prevalence of NSSI and/or STBs in EDs and HC or PC group (PROSPERO: CRD42021286754). A series of random-effects meta-analyses were conducted to estimate pooled odds ratios (ORs) for NSSI, SI, SA, and death by suicide in EDs. RESULTS: Across 32 studies, individuals with an ED had a significantly increased prevalence of NSSI (HC: OR = 6.85 [95% CI: 3.60, 13.04]; PC: OR = 2.74 [95% CI: 1.49, 5.06]), SI (HC: OR = 3.63 [95% CI: 2.43, 5.41]; PC: OR = 3.10 [95% CI: 2.01, 4.78]), and SA (HC: OR = 5.16 [95% CI: 4.27, 6.24]; PC: OR = 1.37 [95% CI: 0.37, 4.99]) relative to HC and PC groups. A 2.93-times increased odd of death by suicide did not achieve statistical significance. There was a high-level of heterogeneity between studies. DISCUSSION: Our findings indicate that ED populations have an increased prevalence of NSSI, SI, and SA but not death by suicide compared to controls and emphasize the need for effective clinical strategies to address these behaviors in ED populations. PUBLIC SIGNIFICANCE: This review provides evidence for an increased prevalence of non-suicidal self-injury, suicidal ideation, and suicide attempts in populations with eating disorders compared to controls. Our findings emphasize the need for effective clinical strategies to address these behaviors in patients with eating disorders.


Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos , Comportamento Autodestrutivo , Humanos , Ideação Suicida , Comportamento Autodestrutivo/psicologia , Tentativa de Suicídio/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Fatores de Risco
19.
Int J Behav Med ; 2023 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-37697141

RESUMO

BACKGROUND: Adolescent smoking is associated with significant health and social risks. Previous research has demonstrated the effectiveness of interventions based on behavior change theories in preventing adolescent smoking uptake. However, evidence from the theory-based perspective of evaluation is limited, especially for how such complex interventions work, and how they work when implemented in different contextual settings. METHOD: A comparative qualitative analysis was conducted to explore various influences on behavior change among participants taking part in two smoking prevention interventions in Northern Ireland and Bogotá. Twenty-seven focus groups were conducted in 12 schools (6 in Northern Ireland and 6 in Bogota, n = 195 pupils participated; aged 11-15 years). The Theoretical Domains Framework guided a content analysis of the data. RESULTS: We found similarities across settings in terms of knowledge, skills, and beliefs related to smoking or vaping behavior change, as well as differences in contextual resources and social influence. Different environmental resources included availability to purchase tobacco products in the neighborhoods and previous information about tobacco risk. Participants in both interventions perceived behavioral change outcomes related to personal skills and intention to not smoke or vape. CONCLUSION: These findings have highlighted how both individual factors and contextual resources influence behavior change for smoking prevention in practice. Local contextual factors and social influences affecting pupils should be taken into account in the implementation and evaluation of health behavior change interventions. In particular, this study supports using social and contextual influence strategies in interventions to reduce the onset of adolescent smoking and vaping.

20.
J Cutan Med Surg ; 27(4): 340-349, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37233603

RESUMO

BACKGROUND: Frontal fibrosing alopecia (FFA) is a scarring alopecia in which the exact etiopathogenesis has not been completely elucidated and the available treatments are not very effective. Plasma rich in growth factors (PRGF) has shown to induce folliculogenesis in hair loss related disorders. However, the scientific evidence when facing FFA is scarce. OBJECTIVES: The aim of this study was to retrospectively analyze the adjuvant use of PRGF compared to the conventional treatment in the management of FFA. METHODS: Participants with clinically diagnosed FFA who had been treated with either conventional therapy (Control Group) or conventional therapy combined with PRGF (PRGF Group) were identified from the center's medical records. The clinical assessment was based on the "Frontal Fibrosing Alopecia Severity Score" (FFASS), which was fulfilled during a period of two and 4 years. RESULTS: This study included 118 patients with clinically diagnosed FFA (Control Group: 57 and PRGF Group: 61). No adverse effects related to the treatments were observed. Both treatments showed to halt the steady progression of hair loss compared to baseline. PRGF treatment also induced significant hair regrowth compared to the Control Group. The scalp inflammation was reduced in response to treatments. The FFASS score indicated that PRGF Group improved the symptoms and severity of FFA in a significant manner. CONCLUSIONS: The adjuvant use of PRGF may exert long-term beneficial effects on hair loss reduction and might reduce the symptoms and severity of FFA.


Assuntos
Alopecia , Líquen Plano , Humanos , Estudos Retrospectivos , Alopecia/tratamento farmacológico , Cabelo , Líquen Plano/patologia , Couro Cabeludo/patologia
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