Asunto(s)

Biomarcadores , Lesiones Traumáticas del Encéfalo , Péptidos y Proteínas de Señalización Intercelular , Humanos , Lesiones Traumáticas del Encéfalo/sangre , Estudios de Casos y Controles , Péptidos y Proteínas de Señalización Intercelular/sangre , Biomarcadores/sangre , Proteínas Sanguíneas/análisis , Péptidos/sangre

RESUMEN

Systemic vasculitis is a group of rare diseases that share an essential characteristic: inflammation of blood vessel walls. This injury occurs during the disease course, but specific features vary for each entity. In this paper, we will address relevant aspects of the newest monogenic mutation vasculitis, such as deficiency of adenosine deaminase 2 (ADA2) and VEXAS syndrome (UBA1), and other relevant vasculitis, such as Cogan syndrome and Susac syndrome that may share some similarities with them.

Asunto(s)

Adenosina Desaminasa , Enfermedades Raras , Humanos , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Síndrome de Cogan/complicaciones , Síndrome de Susac/complicaciones , Síndrome de Susac/diagnóstico , Vasculitis Sistémica/diagnóstico , Agammaglobulinemia/complicaciones , Mutación , Vasculitis , Péptidos y Proteínas de Señalización Intercelular

RESUMEN

The present study utilized the spared nerve injury (SNI) to create a mouse model of depression to investigate the impact of esketamine on depressive-like behaviors, on the expression of PSD-95 and CRMP2 proteins, and on changes in neuronal dendritic spine plasticity in the prefrontal cortex (PFC). Depressive-like behavioral tests were performed 1 h after esketamine treatment, and the PFC tissues were obtained on the fourth day after completing the behavioral tests. Then, dendritic spine density and morphology in the PFC were measured using Golgi staining, and CRMP2 and PSD-95 proteins were obtained from PFC tissue by western blotting. The results of this study showed that esketamine significantly increased the immobility time in the forced swimming test and tail suspension test. In the open field test, esketamine increased the time spent in the open arms, the time spent in the central area, and the total distance covered. It also increased the protein expression levels of CRMP2 and PSD-95 in addition to the total and mature dendritic spine density of the PFC in SNI-depressed mice. Esketamine can significantly improve depression-like behaviors in SNI-depressed mice and promote an increase in dendritic spine density and maturation in the PFC. These effects may be associated with changes in CRMP2 and PSD-95 expression.

Asunto(s)

Espinas Dendríticas , Depresión , Modelos Animales de Enfermedad , Ketamina , Plasticidad Neuronal , Corteza Prefrontal , Animales , Corteza Prefrontal/efectos de los fármacos , Ketamina/farmacología , Plasticidad Neuronal/efectos de los fármacos , Masculino , Espinas Dendríticas/efectos de los fármacos , Ratones , Depresión/tratamiento farmacológico , Proteínas del Tejido Nervioso/metabolismo , Homólogo 4 de la Proteína Discs Large/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Neuronas/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Western Blotting

RESUMEN

OBJECTIVE: It has been determined that adropin has a role in tissue healing. This study aimed to determine the effects of head trauma on the tissues and blood levels of patients admitted to the emergency department. METHODS: The study group was divided into two to compare the adropin level in healthy individuals and patients with head trauma. Blood tests from patients and healthy volunteers were compared using the adropin kit. Adropin levels, Glasgow Coma Scale, and revised scores of trauma patients were recorded and analyzed. RESULTS: All patients in the trauma group had significantly higher adropin levels than the control group. Among these patients, the adropin level of the discharged patients was higher than the others. In addition, patients with high Glasgow Coma Scale and normal blood pressure were found to have higher adropin levels than the others. CONCLUSION: Although adropin cannot make a sharp distinction in determining the prognosis, the increase in its level in trauma patients shows that it triggers a protective mechanism.

Asunto(s)

Biomarcadores , Proteínas Sanguíneas , Lesiones Traumáticas del Encéfalo , Escala de Coma de Glasgow , Péptidos y Proteínas de Señalización Intercelular , Péptidos , Humanos , Estudios de Casos y Controles , Péptidos y Proteínas de Señalización Intercelular/sangre , Lesiones Traumáticas del Encéfalo/sangre , Masculino , Femenino , Proteínas Sanguíneas/análisis , Adulto , Persona de Mediana Edad , Péptidos/sangre , Biomarcadores/sangre , Pronóstico , Adulto Joven

RESUMEN

Skin wound healing is coordinated by a delicate balance between proinflammatory and anti-inflammatory responses, which can be affected by opportunistic pathogens and metabolic or vascular diseases. Several antimicrobial peptides (AMPs) possess immunomodulatory properties, suggesting their potential to support skin wound healing. Here, we evaluated the proregenerative activity of three recently described AMPs (Clavanin A, Clavanin-MO, and Mastoparan-MO). Human primary dermal fibroblasts (hFibs) were used to determine peptide toxicity and their capacity to induce cell proliferation and migration. Furthermore, mRNA analysis was used to investigate the modulation of genes associated with skin regeneration. Subsequently, the regenerative potential of the peptides was further confirmed using an ex vivo organotypic model of human skin (hOSEC)-based lesion. Our results indicate that the three molecules evaluated in this study have regenerative potential at nontoxic doses (i.e., 200 µM for Clavanin-A and Clavanin-MO, and 6.25 µM for Mastoparan-MO). At these concentrations, all peptides promoted the proliferation and migration of hFibs during in vitro assays. Such processes were accompanied by gene expression signatures related to skin regenerative processes, including significantly higher KI67, HAS2 and CXCR4 mRNA levels induced by Clavanin A and Mastoparan-MO. Such findings translated into significantly accelerated wound healing promoted by both Clavanin A and Mastoparan-MO in hOSEC-based lesions. Overall, the data demonstrate the proregenerative properties of these peptides using human experimental skin models, with Mastoparan-MO and Clavanin A showing much greater potential for inducing wound healing compared to Clavanin-MO.

Asunto(s)

Movimiento Celular , Proliferación Celular , Fibroblastos , Regeneración , Piel , Cicatrización de Heridas , Humanos , Cicatrización de Heridas/efectos de los fármacos , Piel/metabolismo , Piel/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regeneración/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos Antimicrobianos/farmacología , Células Cultivadas , Péptidos/farmacología

RESUMEN

OBJECTIVE: To explore the feasibility of injectable platelet-rich fibrin (i-PRF) in regenerative endodontics by comparing the effect of i-PRF and platelet-rich fibrin (PRF) on the biological behavior and angiogenesis of human stem cells from the apical papilla (SCAPs). METHODOLOGY: i-PRF and PRF were obtained from venous blood by two different centrifugation methods, followed by hematoxylin-eosin (HE) staining and scanning electron microscopy (SEM). Enzyme-linked immunosorbent assay (ELISA) was conducted to quantify the growth factors. SCAPs were cultured with different concentrations of i-PRF extract (i-PRFe) and PRF extract (PRFe), and the optimal concentrations were selected using the Cell Counting Kit-8 (CCK-8) assay. The cell proliferation and migration potentials of SCAPs were then observed using the CCK-8 and Transwell assays. Mineralization ability was detected by alizarin red staining (ARS), and angiogenesis ability was detected by tube formation assay. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to evaluate the expression of genes related to mineralization and angiogenesis. The data were subjected to statistical analysis. RESULTS: i-PRF and PRF showed a similar three-dimensional fibrin structure, while i-PRF released a higher concentration of growth factors than PRF ( P <.05). 1/4× i-PRFe and 1/4× PRFe were selected as the optimal concentrations. The cell proliferation rate of the i-PRFe group was higher than that of the PRFe group ( P <.05), while no statistical difference was observed between them in terms of cell mitigation ( P >.05). More importantly, our results showed that i-PRFe had a stronger effect on SCAPs than PRFe in facilitating mineralization and angiogenesis, with the consistent result of RT-qPCR ( P <.05). CONCLUSION: This study revealed that i-PRF released a higher concentration of growth factors and was superior to PRF in promoting proliferation, mineralization and angiogenesis of SCAPs, which indicates that i-PRF could be a promising biological scaffold for application in pulp regeneration.

Asunto(s)

Proliferación Celular , Ensayo de Inmunoadsorción Enzimática , Péptidos y Proteínas de Señalización Intercelular , Microscopía Electrónica de Rastreo , Neovascularización Fisiológica , Fibrina Rica en Plaquetas , Reacción en Cadena en Tiempo Real de la Polimerasa , Endodoncia Regenerativa , Humanos , Proliferación Celular/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Endodoncia Regenerativa/métodos , Células Cultivadas , Reproducibilidad de los Resultados , Movimiento Celular/efectos de los fármacos , Células Madre/efectos de los fármacos , Factores de Tiempo , Estudios de Factibilidad , Análisis de Varianza , Papila Dental/efectos de los fármacos , Papila Dental/citología , Valores de Referencia

RESUMEN

Human alphaherpesvirus 1 (HSV-1) is a significantly widespread viral pathogen causing recurrent infections that are currently incurable despite available treatment protocols. Studies have highlighted the potential of antimicrobial peptides sourced from Vespula lewisii venom, particularly those belonging to the mastoparan family, as effective against HSV-1. This study aimed to demonstrate the antiviral properties of mastoparans, including mastoparan-L [I5, R8], mastoparan-MO, and [I5, R8] mastoparan, against HSV-1. Initially, Vero cell viability was assessed in the presence of these peptides, followed by the determination of antiviral activity, mechanism of action, and dose-response curves through plaque assays. Structural analyses via circular dichroism and nuclear magnetic resonance were conducted, along with evaluating membrane fluidity changes induced by [I5, R8] mastoparan using fluorescence-labeled lipid vesicles. Cytotoxic assays revealed high cell viability (>80%) at concentrations of 200 µg/mL for mastoparan-L and mastoparan-MO and 50 µg/mL for [I5, R8] mastoparan. Mastoparan-MO and [I5, R8] mastoparan exhibited over 80% HSV-1 inhibition, with up to 99% viral replication inhibition, particularly in the early infection stages. Structural analysis indicated an α-helical structure for [I5, R8] mastoparan, suggesting effective viral particle disruption before cell attachment. Mastoparans present promising prospects for HSV-1 infection control, although further investigation into their mechanisms is warranted.

Asunto(s)

Antivirales , Herpesvirus Humano 1 , Péptidos y Proteínas de Señalización Intercelular , Péptidos , Venenos de Avispas , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/fisiología , Antivirales/farmacología , Antivirales/química , Animales , Células Vero , Chlorocebus aethiops , Péptidos/farmacología , Péptidos/química , Venenos de Avispas/farmacología , Venenos de Avispas/química , Péptidos y Proteínas de Señalización Intercelular/farmacología , Péptidos y Proteínas de Señalización Intercelular/química , Supervivencia Celular/efectos de los fármacos , Humanos , Replicación Viral/efectos de los fármacos

RESUMEN

BACKGROUND: Ellis-van Creveld syndrome (EvCS) is a chondroectodermal dysplasia caused by germline pathogenic variants in ciliary complex subunit 1 and 2 genes (EVC, EVC2) on chromosome 4p16.2. This disease has a broad phenotype, and there are few described phenotype-genotype correlations. METHODS: Ethical Compliance: Written informed consent was obtained from the parents. Here, we report a genetically confirmed Mexican patient with EvCS having two inherited pathogenic variants in trans in EVC2: c.[1195C>T];[2161delC]. RESULTS: This patient allowed a genotypic-phenotypic comparison with another Mexican subject who presented a more attenuated phenotype; furthermore, our patient also presented cleft palate, a rarely reported feature. CONCLUSION: Our case shows the importance of comparing functional hemizygosity between patient's phenotypes when they share a variant, and our case also supports the association of alterations in the palate as part of the EvCS phenotype.

Asunto(s)

Fisura del Paladar , Síndrome de Ellis-Van Creveld , Fenotipo , Humanos , Fisura del Paladar/genética , Fisura del Paladar/patología , Síndrome de Ellis-Van Creveld/genética , Síndrome de Ellis-Van Creveld/patología , México , Masculino , Femenino , Péptidos y Proteínas de Señalización Intercelular

RESUMEN

BACKGROUND: Monogenic autoinflammatory disorders result in a diverse range of neurological symptoms in adults, often leading to diagnostic delays. Despite the significance of early detection for effective treatment, the neurological manifestations of these disorders remain inadequately recognized. METHODS: We conducted a systematic review searching Pubmed, Embase and Scopus for case reports and case series related to neurological manifestations in adult-onset monogenic autoinflammatory diseases. Selection criteria focused on the four most relevant adult-onset autoinflammatory diseases-deficiency of deaminase 2 (DADA2), tumor necrosis factor receptor associated periodic fever syndrome (TRAPS), cryopyrin associated periodic fever syndrome (CAPS), and familial mediterranean fever (FMF). We extracted clinical, laboratory and radiological features to propose the most common neurological phenotypes. RESULTS: From 276 records, 28 articles were included. The median patient age was 38, with neurological symptoms appearing after a median disease duration of 5 years. Headaches, cranial nerve dysfunction, seizures, and focal neurological deficits were prevalent. Predominant phenotypes included stroke for DADA2 patients, demyelinating lesions and meningitis for FMF, and meningitis for CAPS. TRAPS had insufficient data for adequate phenotype characterization. CONCLUSION: Neurologists should be proactive in diagnosing monogenic autoinflammatory diseases in young adults showcasing clinical and laboratory indications of inflammation, especially when symptoms align with recurrent or chronic meningitis, small vessel disease strokes, and demyelinating lesions.

Asunto(s)

Síndromes Periódicos Asociados a Criopirina , Fiebre Mediterránea Familiar , Enfermedades Autoinflamatorias Hereditarias , Meningitis , Adulto Joven , Humanos , Adulto , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Neurólogos , Adenosina Desaminasa/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Fiebre Mediterránea Familiar/genética , Síndromes Periódicos Asociados a Criopirina/genética , Fiebre , Fenotipo

RESUMEN

Bovine mastitis is a frequent infection in lactating cattle, causing great economic losses. Staphylococcus aureus represents the main etiological agent, which causes recurrent and persistent intramammary infections because conventional antibiotics are ineffective against it. Mastoparan-like peptides are multifunctional molecules with broad antimicrobial potential, constituting an attractive alternative. Nevertheless, their toxicity to host cells has hindered their therapeutic application. Previously, our group engineered three mastoparan-L analogs, namely mastoparan-MO, mastoparan-R1, and [I5, R8] MP, to improve cell selectivity and potential. Here, we were interested in comparing the antibacterial efficacy of mastoparan-L and its analogs against bovine mastitis isolates of S. aureus strains, making a correlation with the physicochemical properties and structural arrangement changes promoted by the sequence modifications. As a result, the analog's hemolytic and/or antimicrobial activity was balanced. All the peptides displayed α-helical folding in hydrophobic and membrane-mimetic environments, as determined by circular dichroism. The peptide [I5, R8] MP stood out for its enhanced selectivity and antibacterial features related to mastoparan-L and the other derivatives. Biophysical approaches revealed that [I5, R8] MP rapidly depolarizes the bacterial membrane of S. aureus, causing cell death by subsequent membrane disruption. Our results demonstrated that the [I5, R8] MP peptide could be a starting point for the development of peptide-based drugs for the treatment of bovine mastitis, with the advantage of no residue in milk, which would help reduce the use of classical antibiotics.IMPORTANCEStaphylococcus aureus is a leading cause of mastitis, the world's most important dairy cattle disease. The multidrug resistance and zoonotic potential of S. aureus, besides the likelihood of antibiotic residues in milk, are of critical concern to public and animal health. Antimicrobial peptides offer a novel antimicrobial strategy. Here, we demonstrate that [I5, R8] MP is a potent and selective peptide, which acts on S. aureus by targeting the bacterial membrane. Therefore, understanding the physicochemical determinants and the modes of action of this class of antimicrobials opens novel prospects for peptide development with enhanced activities in the bovine mastitis context.

Asunto(s)

Antibacterianos , Péptidos y Proteínas de Señalización Intercelular , Mastitis Bovina , Pruebas de Sensibilidad Microbiana , Infecciones Estafilocócicas , Staphylococcus aureus , Animales , Bovinos , Mastitis Bovina/microbiología , Mastitis Bovina/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Femenino , Antibacterianos/farmacología , Antibacterianos/química , Péptidos y Proteínas de Señalización Intercelular/farmacología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/veterinaria , Infecciones Estafilocócicas/tratamiento farmacológico , Péptidos/farmacología , Péptidos/química , Venenos de Avispas/farmacología , Venenos de Avispas/química

RESUMEN

OBJECTIVE: To explore the value of serum Dickkopf-3 (sDKK3) in predicting Early Neurological Deterioration (END) and in-hospital adverse outcomes in acute ischemic stroke (AIS) patients. METHODS: AIS patients (n = 200) were included and assessed by the National Institutes of Health Stroke Rating Scale. Serum Dkk3 levels were assessed by ELISA. END was defined as an increase of ≥ 4 points in NIHSS score within 72h. The biological threshold of sDKK3 level and END occurrence were predicted based on X-tile software. Primary outcomes were END and all-cause death, and the secondary outcome was ICU admission during hospitalization. The logistic regression model and Cox risk regression model were applied to evaluate the relationship between DKK3 level and END incidence, all-cause in-hospital mortality, and in-hospital adverse outcomes (ICU admission). RESULTS: During hospitalization, the incidence of END in patients with AIS was 13.0 %, and the mortality rate within 7 days after END was 11.54 % (3/26). In patients below the serum DKK3 cutoff (93.0 pg/mL), the incidence of END was 43.5 % (20/48). Patients with lower sDKK3 levels were associated with a 1.188-fold increased risk of developing END (OR = 1.188, 95 % CI 1.055‒1.369, p < 0.0001). However, there was no significant association with admission to the ICU. sDKK3 below the threshold (93.0 pg/mL) was a risk factor for death. CONCLUSION: Predictive threshold levels of serum DKK3 based on X-tile software may be a potential predictive biomarker of in-hospital END in patients with AIS, and low levels of DKK3 are independently associated with increased in-hospital mortality.

Asunto(s)

Biomarcadores , Mortalidad Hospitalaria , Péptidos y Proteínas de Señalización Intercelular , Accidente Cerebrovascular Isquémico , Valor Predictivo de las Pruebas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/mortalidad , Biomarcadores/sangre , Péptidos y Proteínas de Señalización Intercelular/sangre , Proteínas Adaptadoras Transductoras de Señales/sangre , Factores de Riesgo , Pronóstico , Ensayo de Inmunoadsorción Enzimática , Quimiocinas/sangre , Anciano de 80 o más Años , Factores de Tiempo , Valores de Referencia

RESUMEN

INTRODUCTION: Cardiac arrest or arrhythmia caused by bupivacaine may be refractory to treatment. Apelin has been reported to directly increase the frequency of spontaneous activation and the propagation of action potentials, ultimately promoting cardiac contractility. This study aimed to investigate the effects of apelin-13 in reversing cardiac suppression induced by bupivacaine in rats. METHODS: A rat model of cardiac suppression was established by a 3-min continuous intravenous infusion of bupivacaine at the rate of 5 mg.kg-1.min-1, and serial doses of apelin-13 (50, 150 and 450 µg.kg-1) were administered to rescue cardiac suppression to identify its dose-response relationship. We used F13A, an inhibitor of Angiotensin Receptor-Like 1 (APJ), and Protein Kinase C (PKC) inhibitor chelerythrine to reverse the effects of apelin-13. Moreover, the protein expressions of PKC, Nav1.5, and APJ in ventricular tissues were measured using Western blotting and immunofluorescence assay. RESULTS: Compared to the control rats, the rats subjected to continuous intravenous administration of bupivacaine had impaired hemodynamic stability. Administration of apelin-13, in a dose-dependent manner, significantly improved hemodynamic parameters in rats with bupivacaine-induced cardiac suppression (p < 0.05), and apelin-13 treatment also significantly upregulated the protein expressions of p-PKC and Nav1.5 (p < 0.05), these effects were abrogated by F13A or chelerythrine (p < 0.05). CONCLUSION: Exogenous apelin-13, at least in part, activates the PKC signaling pathway through the apelin/APJ system to improve cardiac function in a rat model of bupivacaine-induced cardiac suppression.

Asunto(s)

Bupivacaína , Cardiotoxicidad , Péptidos y Proteínas de Señalización Intercelular , Ratas Sprague-Dawley , Animales , Bupivacaína/toxicidad , Ratas , Masculino , Péptidos y Proteínas de Señalización Intercelular/farmacología , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Cardiotoxicidad/etiología , Cardiotoxicidad/prevención & control , Proteína Quinasa C/metabolismo , Relación Dosis-Respuesta a Droga , Anestésicos Locales/farmacología , Modelos Animales de Enfermedad , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5/efectos de los fármacos , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Apelina , Benzofenantridinas

RESUMEN

Wnt signaling plays an important role in adult brain function, and its dysregulation has been implicated in the loss of neuronal homeostasis. Despite the existence of many studies on the participation of the Wnt pathway in adult neurons, its regulation in astrocytes has been scarcely explored. Several reports point to the presence of Wnt ligands in astrocytes and their possible impact on neuronal plasticity or neuronal death. We aimed to analyze the effect of the neurotransmitter glutamate and the inflammatory cytokine TNFα on the mRNA and protein levels of the canonical Wnt agonist Wnt7a and the antagonist Dkk1 in cultured astrocytes. Primary astrocyte cultures from rat cerebral cortices were exposed to glutamate or TNFα. Wnt7a and Dkk1 expression was analyzed by RT-qPCR and its protein abundance and distribution was assessed by immunofluorescence. We found high basal expression and protein levels of Wnt7a and Dkk1 in unstimulated astrocytes and overproduction of Dkk1 mRNA induced by the two stimuli. These results reveal the astrocytic source of the canonical Wnt ligands Wnt7a and Dkk1, whose levels are differentially regulated by glutamate and TNFα. Astrocytes are a significant source of Wnt ligands, the production of which can be differentially regulated under excitatory or proinflammatory conditions, thereby impacting neuronal function.

Asunto(s)

Astrocitos , Ácido Glutámico , Péptidos y Proteínas de Señalización Intercelular , Proteínas Proto-Oncogénicas , Factor de Necrosis Tumoral alfa , Proteínas Wnt , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Animales , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ácido Glutámico/metabolismo , Proteínas Wnt/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Células Cultivadas , Ratas , ARN Mensajero/metabolismo , Ratas Wistar , Corteza Cerebral/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/citología

RESUMEN

Celiac disease (CD) is an immune-driven disease characterized by tissue damage in the small intestine of genetically-susceptible individuals. We evaluated here a crucial immune regulatory pathway involving TYRO3, AXL, and MERTK (TAM) receptors and their ligands PROS1 and GAS6 in duodenal biopsies of controls and CD patients. We found increased GAS6 expression associated with downregulation of PROS1 and variable TAM receptors levels in duodenum tissue of CD patients. Interestingly, CD3+ lymphocytes, CD68+, CD11c+ myeloid and epithelial cells, showed differential expressions of TAM components comparing CD vs controls. Principal component analysis revealed a clear segregation of two groups of CD patients based on TAM components and IFN signaling. In vitro validation demonstrated that monocytes, T lymphocytes and epithelial cells upregulated TAM components in response to IFN stimulation. Our findings highlight a dysregulated TAM axis in CD related to IFN signaling and contribute to a deeper understanding of the pathophysiology of CD.

Asunto(s)

Tirosina Quinasa del Receptor Axl , Enfermedad Celíaca , Duodeno , Péptidos y Proteínas de Señalización Intercelular , Mucosa Intestinal , Proteína S , Proteínas Tirosina Quinasas Receptoras , Tirosina Quinasa c-Mer , Femenino , Humanos , Masculino , Tirosina Quinasa c-Mer/genética , Tirosina Quinasa c-Mer/metabolismo , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/metabolismo , Enfermedad Celíaca/genética , Duodeno/metabolismo , Duodeno/inmunología , Duodeno/patología , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Interferones/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Proteína S/metabolismo , Proteína S/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/inmunología , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismo

RESUMEN

Gut microbiota, or the collection of diverse microorganisms in a specific ecological niche, are known to significantly impact human health. Decreased gut microbiota production of short-chain fatty acids (SCFAs) has been implicated in type 2 diabetes mellitus (T2DM) disease progression. Most microbiome studies focus on ethnic majorities. This study aims to understand how the microbiome differs between an ethnic majority (the Dutch) and minority (the South-Asian Surinamese (SAS)) group with a lower and higher prevalence of T2DM, respectively. Microbiome data from the Healthy Life in an Urban Setting (HELIUS) cohort were used. Two age- and gender-matched groups were compared: the Dutch (n = 41) and SAS (n = 43). Microbial community compositions were generated via DADA2. Metrics of microbial diversity and similarity between groups were computed. Biomarker analyses were performed to determine discriminating taxa. Bacterial co-occurrence networks were constructed to examine ecological patterns. A tight microbiota cluster was observed in the Dutch women, which overlapped with some of the SAS microbiota. The Dutch gut contained a more interconnected microbial ecology, whereas the SAS network was dispersed, i.e., contained fewer inter-taxonomic correlational relationships. Bacteroides caccae, Butyricicoccus, Alistipes putredinis, Coprococcus comes, Odoribacter splanchnicus, and Lachnospira were enriched in the Dutch gut. Haemophilus, Bifidobacterium, and Anaerostipes hadrus discriminated the SAS gut. All but Lachnospira and certain strains of Haemophilus are known to produce SCFAs. The Dutch gut microbiome was distinguished from the SAS by diverse, differentially abundant SCFA-producing taxa with significant cooperation. The dynamic ecology observed in the Dutch was not detected in the SAS. Among several potential gut microbial biomarkers, Haemophilus parainfluenzae likely best characterizes the ethnic minority group, which is more predisposed to T2DM. The higher prevalence of T2DM in the SAS may be associated with the gut dysbiosis observed.

Asunto(s)

Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Humanos , Femenino , Etnicidad , Diabetes Mellitus Tipo 2/epidemiología , Adenosina Desaminasa , Grupos Minoritarios , Péptidos y Proteínas de Señalización Intercelular , Ácidos Grasos Volátiles

RESUMEN

BACKGROUND: The impact of treatments, suppressing the immune system, persistent hyperparathyroidism, and other risk factors on mineral and bone disorder (MBD) after kidney transplantation is well-known. However, there is limited knowledge about their effect on bone metabolism biomarkers. This study aimed to investigate the influence of kidney transplant on these markers, comparing them to patients undergoing hemodialysis and healthy individuals. METHODS: In this cross-sectional study, three groups were included: kidney transplant patients (n = 57), hemodialysis patients (n = 26), and healthy controls (n = 31). Plasma concentrations of various bone metabolism biomarkers, including Dickkopf-related protein 1, osteoprotegerin, osteocalcin, osteopontin, sclerostin, and fibroblast growth factor 23, were measured. Associations between these biomarkers and clinical and laboratory data were evaluated. RESULTS: A total of 114 patients participated. Transplant recipients had significantly lower levels of Dickkopf-related protein 1, osteoprotegerin, osteocalcin, osteopontin, sclerostin, and fibroblast growth factor 23 compared to hemodialysis patients. Alkaline phosphatase levels positively correlated with osteopontin (r = 0.572, p < 0.001), while fibroblast growth factor 23 negatively correlated with 25-hydroxyvitamin D (r = -0.531, p = 0.019). The panel of bone biomarkers successfully predicted hypercalcemia (area under the curve [AUC] = 0.852, 95% confidence interval [CI] = 0.679-1.000) and dyslipidemia (AUC = 0.811, 95% CI 0.640-0.982) in transplant recipients. CONCLUSION: Kidney transplantation significantly improves mineral and bone disorders associated with end-stage kidney disease by modulating MBD markers and reducing bone metabolism markers, such as Dickkopf-related protein 1, osteoprotegerin, osteocalcin, osteopontin, and sclerostin. Moreover, the panel of bone biomarkers effectively predicted hypercalcemia and dyslipidemia in transplant recipients.

Asunto(s)

Biomarcadores , Huesos , Factor-23 de Crecimiento de Fibroblastos , Trasplante de Riñón , Osteocalcina , Humanos , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores/sangre , Estudios Transversales , Adulto , Huesos/metabolismo , Osteocalcina/sangre , Osteoprotegerina/sangre , Diálisis Renal , Factores de Crecimiento de Fibroblastos/sangre , Osteopontina/sangre , Péptidos y Proteínas de Señalización Intercelular/sangre , Proteínas Adaptadoras Transductoras de Señales

RESUMEN

OBJECTIVE: The aim of our study was to assess if the addition of PRGF to healthy human sperm affects its motility and vitality. METHODS: This was a prospective study, with 44 sperm donors on whom sperm analysis was performed. Nine mL of blood was collected and PRGF was obtained using PRGF-Endoret® technology. The influence of different dilutions of PRGF (5%, 10%, 20%, 40%) applied to 15 sperm donors was compared, and sperm motility was assessed after 30 minutes. In the second part of the study, 29 sperm donors were studied to analyze the influence of 20% dilution of PRGF at 15, 30 and 45 minutes in fresh and thawed sperm samples. Motility was assessed after the addition of PRGF and after analysis each aliquot was frozen. After thawing, concentration and motility were assessed at the same time periods. RESULTS: There were no differences in sperm motility in fresh samples between dilutions of PRGF when assessed 30 minutes after administration, nor between them, nor when compared to the control group immediately prior to treatment. No trend was observed between motility and PRGF dilution in linear regression analysis. There were no significant differences in thawed samples. CONCLUSIONS: The administration of 20% PRGF dilution had no effect on sperm motility compared to samples without PRGF. In addition, there was no change in sperm vitality when comparing samples with and without PRGF. More studies focusing on subnormal sperm samples, analyzing different PRGF concentrations and increasing the number of study variables are needed.

Asunto(s)

Péptidos y Proteínas de Señalización Intercelular , Motilidad Espermática , Espermatozoides , Humanos , Masculino , Proyectos Piloto , Motilidad Espermática/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/farmacología , Espermatozoides/efectos de los fármacos , Espermatozoides/fisiología , Estudios Prospectivos , Criopreservación/métodos , Preservación de Semen/métodos , Adulto , Análisis de Semen , Plasma/química

RESUMEN

BACKGROUND: Fibrous scars frequently form at the sites of bone nonunion when attempts to repair bone fractures have failed. However, the detailed mechanism by which fibroblasts, which are the main components of fibrous scars, impede osteogenesis remains largely unknown. RESULTS: In this study, we found that fibroblasts compete with osteogenesis in both human bone nonunion tissues and BMP2-induced ectopic osteogenesis in a mouse model. Fibroblasts could inhibit the osteoblastic differentiation of mesenchymal stem cells (MSCs) via direct and indirect cell competition. During this process, fibroblasts modulated the nuclear-cytoplasmic shuttling of YAP in MSCs. Knocking down YAP could inhibit osteoblast differentiation of MSCs, while overexpression of nuclear-localized YAP-5SA could reverse the inhibition of osteoblast differentiation of MSCs caused by fibroblasts. Furthermore, fibroblasts secreted DKK1, which further inhibited the formation of calcium nodules during the late stage of osteogenesis but did not affect the early stage of osteogenesis. Thus, fibroblasts could inhibit osteogenesis by regulating YAP localization in MSCs and secreting DKK1. CONCLUSIONS: Our research revealed that fibroblasts could modulate the nuclear-cytoplasmic shuttling of YAP in MSCs, thereby inhibiting their osteoblast differentiation. Fibroblasts could also secrete DKK1, which inhibited calcium nodule formation at the late stage of osteogenesis.

Asunto(s)

Células Madre Mesenquimatosas , Osteogénesis , Animales , Humanos , Ratones , Calcio , Diferenciación Celular , Cicatriz , Fibroblastos , Péptidos y Proteínas de Señalización Intercelular , Osteoblastos , Osteogénesis/fisiología

RESUMEN

Studies in cows have reported that ovulation, steroidogenesis and angiogenesis are affected by stress and consequently fertility decreases. The purpose of this study was to evaluate the effects of ACTH administration during the preovulatory period on the expression of growth factors (CD-31, PDGF-A, PDGF-B, VEGFA-164, VEGFA-164b, VEGF-R1 and VEGF-R2) associated with the angiogenic process by immunohistochemistry in cows (n = 14). Results evidenced the expression of these growth factors in theca and granulosa cells from antral, atretic and dominant preovulatory follicles of ACTH-treated cows, suggesting that, under stress conditions, their expression continues to be required. VEGFA-164, VEGF-R1 and VEGF-R2 expression was greater in theca cells of dominant preovulatory follicles of the ACTH-treated group than in those of the control group. CD-31 protein expression was lower in the dominant preovulatory follicles of the ACTH-treated group than in those of the control group. PDGF-A and PDGF-B expression did not differ between groups, either in granulosa or in theca cells. These results suggest that VEGFA-164, its receptors and CD-31 are actors in the normal cycle of the ovaries and could have greater pathophysiological importance in the altered angiogenic process and other events that occur during anovulation and stress conditions. This dysregulation reinforces the importance of the angiogenic process in the pathophysiology of cystic ovarian disease in cows. This is the first report on the expression and localization of components of the VEGF and PDGF systems and CD-31 in cells from dominant preovulatory follicles after ACTH administration.

Asunto(s)

Folículo Ovárico , Factor A de Crecimiento Endotelial Vascular , Femenino , Bovinos , Animales , Folículo Ovárico/fisiología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Células de la Granulosa , Células Tecales , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Hormona Adrenocorticotrópica/farmacología , Hormona Adrenocorticotrópica/metabolismo

RESUMEN

Mastoparans are cationic peptides with multifunctional pharmacological properties. Mastoparan-R1 and mastoparan-R4 were computationally designed based on native mastoparan-L from wasps and have improved therapeutic potential for the control of bacterial infections. Here, we evaluated whether these peptides maintain their activity against Escherichia coli strains under a range of salt concentrations. We found that mastoparan-R1 and mastoparan-R4 preserved their activity under the conditions tested, including having antibacterial activities at physiological salt concentrations. The overall structure of the peptides was investigated using circular dichroism spectroscopy in a range of solvents. No significant changes in secondary structure were observed (random coil in aqueous solutions and α-helix in hydrophobic and anionic environments). The three-dimensional structures of mastoparan-R1 and mastoparan-R4 were elucidated through nuclear magnetic resonance spectroscopy, revealing amphipathic α-helical segments for Leu3-Ile13 (mastoparan-R1) and Leu3-Ile14 (mastoparan-R4). Possible membrane-association mechanisms for mastoparan-R1 and mastoparan-R4 were investigated through surface plasmon resonance and leakage studies with synthetic POPC and POPC/POPG (4:1) lipid bilayers. Mastoparan-L had the highest affinity for both membrane systems, whereas the two analogs had weaker association, but improved selectivity for lysing anionic membranes. This finding was also supported by molecular dynamics simulations, in which mastoparan-R1 and mastoparan-R4 were found to have greater interactions with bacteria-like membranes compared with model mammalian membranes. Despite having a few differences in their functional and structural profiles, the mastoparan-R1 analog stood out with the highest activity, greater bacteriostatic potential, and selectivity for lysing anionic membranes. This study reinforces the potential of mastoparan-R1 as a drug candidate.

Asunto(s)

Péptidos y Proteínas de Señalización Intercelular , Péptidos , Animales , Péptidos/farmacología , Venenos de Avispas/farmacología , Escherichia coli , Cloruro de Sodio , Computadores , Mamíferos