Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.300.592
Filtrar
1.
J Biomed Opt ; 29(Suppl 2): S22702, 2025 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38434231

RESUMO

Significance: Advancements in label-free microscopy could provide real-time, non-invasive imaging with unique sources of contrast and automated standardized analysis to characterize heterogeneous and dynamic biological processes. These tools would overcome challenges with widely used methods that are destructive (e.g., histology, flow cytometry) or lack cellular resolution (e.g., plate-based assays, whole animal bioluminescence imaging). Aim: This perspective aims to (1) justify the need for label-free microscopy to track heterogeneous cellular functions over time and space within unperturbed systems and (2) recommend improvements regarding instrumentation, image analysis, and image interpretation to address these needs. Approach: Three key research areas (cancer research, autoimmune disease, and tissue and cell engineering) are considered to support the need for label-free microscopy to characterize heterogeneity and dynamics within biological systems. Based on the strengths (e.g., multiple sources of molecular contrast, non-invasive monitoring) and weaknesses (e.g., imaging depth, image interpretation) of several label-free microscopy modalities, improvements for future imaging systems are recommended. Conclusion: Improvements in instrumentation including strategies that increase resolution and imaging speed, standardization and centralization of image analysis tools, and robust data validation and interpretation will expand the applications of label-free microscopy to study heterogeneous and dynamic biological systems.


Assuntos
Técnicas Histológicas , Microscopia , Animais , Citometria de Fluxo , Processamento de Imagem Assistida por Computador
2.
Clín. investig. arterioscler. (Ed. impr.) ; 36(2): 60-70, mar.-abr. 2024. tab, graf
Artigo em Inglês | IBECS | ID: ibc-231494

RESUMO

Background Combined oral contraceptives (COCs), use in individuals are associated with increased risk of thrombotic events. This highlights the significance of assessing the impact of COC on promoting coagulation and endothelial activation in high-fat diet (HFD)-fed Sprague Dawley rats. Methods Twenty (20) five-weeks-old female Sprague Dawley rats weighing between 150 and 200g were subjected to both LFD and HFD-feeding for 8-weeks to determine its influence on basic metabolic status, hemostatic profile, hemodynamic parameters (blood pressure and heart rate), as well as selected biomarkers of coagulation (tissue factor and D-dimer) and endothelial activation (Von Willebrand factor and nitric oxide). Thereafter HFD-fed animals were treated with receive high dose combined oral contraceptive (HCOC) and low dose combine oral contraceptive (LCOC) for 6 weeks. Results Our results showed that beyond weight gain, HFD-feeding was associated with hyperglycemia, increased mean arterial pressure, and reduced nitric oxide levels when compared with LFD group (p<0.05). Interestingly, treatment with high dose of COC for 6-weeks did not significantly alter atherothrombotic markers (p>0.05). However, this study is not without limitation as regulation of these markers remains to be confirmed within the cardiac tissues or endothelial cells of these animals. Conclusion HFD-feeding orchestrate the concomitant release of pro-coagulants and endothelial activation markers in rats leading to haemostatic imbalance and endothelial dysfunction. Short-term treatment with COC shows no detrimental effects in these HFD-fed rats. Although in terms of clinical relevance, our findings depict the notion that the risk of CVD in association with COC may depend on the dosage and duration of use among other factors especially in certain conditions. ... (AU)


Antecedentes El uso de anticonceptivos orales combinados (AOC) en individuos se asocia con un mayor riesgo de eventos trombóticos. Esto resalta la importancia de evaluar el impacto de los AOC en la promoción de la coagulación y la activación endotelial en ratas Sprague Dawley alimentadas con una dieta alta en grasas (HFD). Métodos Veinte (20) ratas Sprague Dawley hembra de 5semanas de edad con un peso entre 150-200g fueron tratadas mediante una alimentación con dieta baja en grasas (LFD) y alta en grasas (HFD) durante 8 semanas para determinar su influencia en el estado metabólico básico, perfil hemostático, parámetros hemodinámicos (presión arterial y frecuencia cardíaca), así como biomarcadores seleccionados de coagulación (factor tisular y D-dímero) y activación endotelial (factor de von Willebrand y óxido nítrico). Posteriormente, los animales alimentados con HFD fueron tratados con dosis alta de anticonceptivo oral combinado (AOC-AL) y dosis baja de anticonceptivo oral combinado (AOC-BL) durante 6 semanas. Resultados Nuestros resultados mostraron que, además del aumento de peso, la alimentación con HFD se asoció con hiperglucemia, aumento de la presión arterial media y niveles reducidos de óxido nítrico en comparación con el grupo LFD (p<0,05). Curiosamente, el tratamiento con dosis alta de AOC durante 6 semanas no alteró significativamente los marcadores aterotrombóticos (p>0,05). Sin embargo, este estudio no está exento de limitaciones, ya que la regulación de estos marcadores aún debe confirmarse en los tejidos cardíacos o las células endoteliales de estos animales. Conclusión La alimentación con HFD orquesta la liberación concomitante de procoagulantes y marcadores de activación endotelial en ratas, lo que conduce a un desequilibrio hemostático y disfunción endotelial. El tratamiento a corto plazo con AOC no muestra efectos perjudiciales en estas ratas alimentadas con HFD. ... (AU)


Assuntos
Animais , Feminino , Ratos , Anticoncepcionais Orais Combinados/efeitos adversos , Coagulação Sanguínea/efeitos dos fármacos , Fatores de Coagulação Sanguínea , Gorduras na Dieta/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Fatores de Crescimento Endotelial , Obesidade , Doenças Cardiovasculares
3.
Nefrología (Madrid) ; 44(2): 180-193, Mar-Abr. 2024. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-231568

RESUMO

Background: Contrast agents can directly or indirectly induce renal tubular ischemia and hypoxic damage. Given that cobalt chloride (CoCl2) can protect renal tubules, the protective effect and potential mechanism of action of CoCl2 on contrast-induced nephropathy (CIN) warrant investigation. Methods: A CIN mouse model was established to determine the protective effect of CoCl2 on renal injury in vivo. Then, TMT-based proteomics was performed to determine the differentially expressed proteins (DEPs), following which, enrichment analyses of gene ontology and the KEGG pathway were performed. In vitro, a CIN model was constructed with renal tubular epithelial cells (HK-2) to determine the effect of CoCl2 on potential targets and the role of the key protein identified from the in vivo experiments. Results: CoCl2 treatment decreased the levels of BUN and serum creatinine (sCr), while increasing the levels of urea and creatinine (Cr) in the urine of mice after CIN injury. Damage to the renal tubules in the CoCl2 treatment group was significantly less than in the CIN model group. We identified 79 DEPs after treating the in vivo model with CoCl2, and frequently observed ferroptosis-related GO and KEGG pathway terms. Of these, Hp (haptoglobin) was selected and found to have a strong renoprotective effect, even though its expression level in kidney tissue decreased after CoCl2 treatment. In HK-2 cells, overexpression of Hp reduced the ferroptosis caused by erastin, while knocking down Hp negated the attenuation effect of CoCl2 on HK-2 cell ferroptosis. Conclusion: CoCl2 attenuated kidney damage in the CIN model, and this effect was associated with the decrease in ferroptosis mediated by Hp.(AU)


Antecedentes: Los agentes de contraste pueden inducir isquemia tubular renal y daño hipóxico de manera directa o indirecta. Dado que el cloruro de cobalto (CoCl2) puede proteger los túbulos renales, el efecto protector y el mecanismo de acción potencial de CoCl2 en la nefropatía inducida por contraste (NIC) merecen ser investigados. Métodos: Se estableció un modelo de NIC en ratones para determinar el efecto protector de CoCl2 en la nefropatía in vivo. Seguidamente, se realizó un análisis proteómico por TMT para determinar las proteínas diferencialmente expresadas (DEP) y, a continuación, un análisis de enriquecimiento de ontología genética y vía KEGG. In vitro, se construyó un modelo NIC en células epiteliales de túbulos renales (HK-2) para determinar el efecto de CoCl2 en los objetivos potenciales y el rol de la proteína clave identificada en los experimentos in vivo. Resultados: El tratamiento con CoCl2 redujo los niveles de BUN y de creatinina sérica e incrementó, a la vez, los de urea y creatinina en la orina de los ratones, tras la lesión NIC. El daño a los túbulos renales en el grupo de tratamiento con CoCl2 fue significativamente menor que en el grupo de modelo NIC. Identificamos 79 DEP tras el tratamiento en el modelo in vivo con CoCl2 y observamos con frecuencia ontología genética relacionada con ferroptosis y términos de vías KEGG. De ellos, se seleccionó la haptoglobina (Hp) y se encontró que tenía un fuerte efecto renoprotector, aun cuando su nivel de expresión en el tejido renal se redujo tras el tratamiento con CoCl2. En las células HK-2, la sobreexpresión de Hp redujo la ferroptosis causada por erastina, a pesar de que el descenso de Hp negó el efecto atenuador de CoCl2 en la ferroptosis de las células HK-2. Conclusión: El CoCl2 atenuó el daño renal en el modelo NIC y se asoció este efecto al descenso de ferroptosis mediada por Hp.(AU)


Assuntos
Animais , Ratos , Nefropatias , Nefropatias/induzido quimicamente , Nefrologia
4.
Neurología (Barc., Ed. impr.) ; 39(3): 282-291, Abr. 2024. ilus
Artigo em Espanhol | IBECS | ID: ibc-VR-230

RESUMO

Introducción: La esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa, progresiva y de etiología desconocida caracterizada por la degeneración de motoneuronas superiores e inferiores. Aproximadamente el 90% de los casos de ELA son esporádicos, mientras que el 10% restante se consideran familiares. Independientemente de si son familiares o esporádicas, los pacientes desarrollan una debilidad progresiva, atrofia muscular con espasticidad y contracturas. Por lo general, la esperanza de vida en los pacientes de ELA es de 2 a 5 años. Desarrollo: Los modelos in vivo han ayudado a explicar la etiología y la patogénesis, así como los mecanismos de la ELA. Sin embargo, estos mecanismos no están del todo esclarecidos aún, por lo que los modelos experimentales son fundamentales para continuar con el estudio de los mismos, así como para la búsqueda de posibles dianas terapéuticas. A pesar de que el 90% de los casos son esporádicos, la mayoría de los modelos utilizados hasta la actualidad para estudiar la patogénesis están basados en las mutaciones genéticas asociadas a la enfermedad familiar, lo que provoca que la patogénesis de la ELA esporádica no sea aún conocida. Por tanto, sería fundamental el estudio de la enfermedad en modelos basados en la enfermedad esporádica. Conclusión: En el presente artículo se han revisado los principales modelos experimentales, tanto genéticos como esporádicos, utilizados en el estudio de esta enfermedad, enfocándonos en los que se han desarrollado utilizando el roedor como plataforma experimental.(AU)


Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose aetiology is unknown. It is characterised by upper and lower motor neuron degeneration. Approximately 90% of cases of ALS are sporadic, whereas the other 10% are familial. Regardless of whether the case is familial or sporadic, patients will develop progressive weakness, muscle atrophy with spasticity, and muscle contractures. Life expectancy of these patients is generally 2–5 years after diagnosis. Development: In vivo models have helped to clarify the aetiology and pathogenesis of ALS, as well as the mechanisms of the disease. However, as these mechanisms are not yet fully understood, experimental models are essential to the continued study of the pathogenesis of ALS, as well as in the search for possible therapeutic targets. Although 90% of cases are sporadic, most of the models used to study ALS pathogenesis are based on genetic mutations associated with the familial form of the disease; the pathogenesis of sporadic ALS remains unknown. Therefore, it would be critical to establish models based on the sporadic form. Conclusion: This article reviews the main genetic and sporadic experimental models used in the study of this disease, focusing on those that have been developed using rodents.(AU)


Assuntos
Humanos , Animais , Masculino , Feminino , Camundongos , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/tratamento farmacológico , Doenças Neurodegenerativas , Líquido Cefalorraquidiano , Neurologia , Doenças do Sistema Nervoso
5.
Psiquiatr. biol. (Internet) ; 31(1): [100439], ene.-mar 2024.
Artigo em Espanhol | IBECS | ID: ibc-231631

RESUMO

El aumento de la esperanza de vida ha llevado a un incremento en la incidencia de enfermedades crónicas como la demencia. Tratar los factores de riesgo de la demencia, como la depresión, podría reducir su incidencia. Sin embargo, el tratamiento con antidepresivos no ha sido eficaz en el manejo de este síntoma, lo que aumenta el riesgo de demencia en el futuro. Es fundamental investigar las causas y el tratamiento de la depresión, y el uso de modelos animales es importante en este sentido. Este estudio busca analizar la relación entre la depresión y el riesgo de desarrollar demencia, así como los modelos preclínicos más relevantes para estudiar la depresión en roedores. (AU)


The increase in life expectancy has led to a rise in the incidence of chronic diseases, such as dementia. Treating the risk factors of dementia, such as depression, could help reduce its occurrence. However, antidepressant treatment has not proven effective in managing this symptom, thereby increasing the risk of dementia in the future. It is essential to investigate the causes and treatment of depression, and in this regard, the use of animal models is of great significance. This study aims to analyze the evidence supporting the relationship between depression and the risk of developing dementia, while also providing an update on the most relevant preclinical models for studying depression in rodents. (AU)


Assuntos
Humanos , Animais , Demência/diagnóstico , Demência/prevenção & controle , Depressão/diagnóstico , Depressão/prevenção & controle , Fatores de Risco , Antidepressivos/efeitos adversos , Disfunção Cognitiva , Modelos Animais
6.
Gastroenterol. hepatol. (Ed. impr.) ; 47(3): 219-229, mar. 2024. tab, graf
Artigo em Inglês | IBECS | ID: ibc-231202

RESUMO

Background Hepatic fibrosis (HF) is a common result of the repair process of various chronic liver diseases. Hepatic stellate cells (HSCs) activation is the central link in the occurrence of HF. Methods ELISA and histological analysis were performed to detect the pathological changes of liver tissues. In vitro, HSCs were treated with TGF-β1 as HF cell model. Combination of GATA-binding protein 3 (GATA3) and miR-370 gene promoter was ensured by ChIP and luciferase reporter assay. Autophagy was monitored by observing the GFP-LC3 puncta formation. The interaction between miR-370 and high mobility group box 1 protein (HMGB1) was verified by luciferase reporter assay. Results CCl4-induced HF mice exhibited an increase of ALT and AST, and severe damage and fibrosis of liver tissues. GATA3 and HMGB1 were up-regulated, and miR-370 was down-regulated in CCl4-induced HF mice and activated HSCs. GATA3 enhanced expression of the autophagy-related proteins and activation markers in the activated HSCs. Inhibition of autophagy partly reversed GATA3-induced activation of HSCs and the promotion of GATA3 to hepatic fibrosis. Moreover, GATA3 suppressed miR-370 expression via binding with its promotor, and enhanced HMGB1 expression in HSCs. Increasing of miR-370 inhibited HMGB1 expression by directly targeting its mRNA 3′-UTR. The promotion of GATA3 to TGF-β1-induced HSCs autophagy and activation was abrogated by miR-370 up-regulation or HMGB1 knockdown. Conclusions This work demonstrates that GATA3 promotes autophagy and activation of HSCs by regulating miR-370/HMGB1 signaling pathway, which contributes to accelerate HF. Thus, this work suggests that GATA3 may be a potential target for prevention and treatment of HF. (AU)


Introducción La fibrosis hepática (IC) es un resultado común del proceso de reparación de diversas enfermedades hepáticas crónicas. La activación de las células estrelladas hepáticas (HSC) es el vínculo central en la aparición de insuficiencia cardíaca. Métodos Se realizaron ELISA y análisis histológicos para detectar los cambios patológicos de los tejidos hepáticos. In vitro, las HSC se trataron con TGF-1 como modelo de células HF. La combinación de la proteína 3 de unión a GATA (GATA3) y el promotor del gen miR-370 se aseguró mediante el ensayo ChIP y el indicador de luciferasa. La autofagia se controló observando la formación de puntos GFP-LC3. La interacción entre miR-370 y la proteína de la caja 1 del grupo de alta movilidad (HMGB1) se verificó mediante el ensayo indicador de luciferasa. Resultados Los ratones con HF inducida por CCl4 exhibieron un aumento de ALT y AST, y daño severo y fibrosis de los tejidos hepáticos. GATA3 y HMGB1 estaban regulados positivamente, y miR-370 estaba regulado negativamente en ratones HF inducidos por CCl4 y HSC activadas. GATA3 mejoró la expresión de las proteínas relacionadas con la autofagia y los marcadores de activación en las HSC activadas. La inhibición de la autofagia revirtió parcialmente la activación de HSC inducida por GATA3 y la promoción de GATA3 a la fibrosis hepática. Además, GATA3 suprimió la expresión de miR-370 mediante la unión con su promotor y mejoró la expresión de HMGB1 en HSC. El aumento de miR-370 inhibió la expresión de HMGB1 al apuntar directamente a su ARNm 3 -UTR. La promoción de GATA3 a la autofagia y activación de las HSC inducidas por TGF-1 fue anulada por la regulación positiva de miR-370 o la eliminación de HMGB1. Conclusiones Este trabajo demuestra que GATA3 promueve la autofagia y la activación de las HSC mediante la regulación de la vía de señalización de miR-370/HMGB1, lo que contribuye para acelerar la HF... (AU)


Assuntos
Animais , Masculino , Camundongos , Cirrose Hepática , Fator de Transcrição GATA3 , Proteína HMGB1 , Células Estreladas do Fígado , Autofagia
7.
Biomater Sci ; 12(7): 1898-1913, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38426394

RESUMO

Masquelet's induced membrane (IM) technique is a promising treatment strategy for the repair of substantial bone defects. The formation of an IM around polymethylmethacrylate bone cement plays a crucial role in this technique. Several studies have indicated that IMs have bioactivity because they contain abundant blood vessels, a variety of cells, and biological factors. The bioactivity of an IM increases during the initial stages of formation, thereby facilitating bone regeneration and remodeling. Nevertheless, the precise mechanisms underlying the enhancement of IM bioactivity and the promotion of bone regeneration necessitate further investigation. In this study, we successfully developed a Masquelet IM model of critical femur defects in rats. By employing proteomics analysis and biological detection techniques, we identified fibromodulin (FMOD) as a pivotal factor contributing to angiogenesis and the enhanced bioactivity of the IM. A significant increase in angiogenesis and the expression of bioactive factors in the IM was also observed with the upregulation of FMOD expression. Furthermore, this effect is mediated through the inhibition of the transforming growth factor beta (TGF-ß)/SMAD signaling pathway. We also demonstrated that administering recombinant human FMOD enhanced osteogenesis in rat bone marrow mesenchymal stem cells and angiogenesis in human umbilical vein endothelial cells in vitro. Furthermore, the negative regulatory effect of the TGF-ß signaling pathway was verified. In conclusion, this study provides a novel theoretical basis for the application of IMs in bone-defect reconstruction and explores possible new mechanisms that may play an important role in promoting the bioactivity and osteogenic potential of IMs.


Assuntos
Osteogênese , Fator de Crescimento Transformador beta , Ratos , Humanos , Animais , Fibromodulina , Células Endoteliais da Veia Umbilical Humana/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Transdução de Sinais
8.
mSphere ; 9(3): e0077423, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38426801

RESUMO

Diabetic foot ulcers (DFUs) are the most common complications of diabetes resulting from hyperglycemia leading to ischemic hypoxic tissue and nerve damage. Staphylococcus aureus is the most frequently isolated bacteria from DFUs and causes severe necrotic infections leading to amputations with a poor 5-year survival rate. However, very little is known about the mechanisms by which S. aureus dominantly colonizes and causes severe disease in DFUs. Herein, we utilized a pressure wound model in diabetic TALLYHO/JngJ mice to reproduce ischemic hypoxic tissue damage seen in DFUs and demonstrated that anaerobic fermentative growth of S. aureus significantly increased the virulence and the severity of disease by activating two-component regulatory systems leading to expression of virulence factors. Our in vitro studies showed that supplementation of nitrate as a terminal electron acceptor promotes anaerobic respiration and suppresses the expression of S. aureus virulence factors through inactivation of two-component regulatory systems, suggesting potential therapeutic benefits by promoting anaerobic nitrate respiration. Our in vivo studies revealed that dietary supplementation of L-arginine (L-Arg) significantly attenuated the severity of disease caused by S. aureus in the pressure wound model by providing nitrate. Collectively, these findings highlight the importance of anaerobic fermentative growth in S. aureus pathogenesis and the potential of dietary L-Arg supplementation as a therapeutic to prevent severe S. aureus infection in DFUs.IMPORTANCES. aureus is the most common cause of infection in DFUs, often resulting in lower-extremity amputation with a distressingly poor 5-year survival rate. Treatment for S. aureus infections has largely remained unchanged for decades and involves tissue debridement with antibiotic therapy. With high levels of conservative treatment failure, recurrence of ulcers, and antibiotic resistance, a new approach is necessary to prevent lower-extremity amputations. Nutritional aspects of DFU treatment have largely been overlooked as there has been contradictory clinical trial evidence, but very few in vitro and in vivo modelings of nutritional treatment studies have been performed. Here we demonstrate that dietary supplementation of L-Arg in a diabetic mouse model significantly reduced duration and severity of disease caused by S. aureus. These findings suggest that L-Arg supplementation could be useful as a potential preventive measure against severe S. aureus infections in DFUs.


Assuntos
Diabetes Mellitus , Pé Diabético , Infecções Estafilocócicas , Animais , Camundongos , Staphylococcus aureus , Virulência , Nitratos , Infecções Estafilocócicas/complicações , Pé Diabético/tratamento farmacológico , Pé Diabético/complicações , Pé Diabético/microbiologia , Fatores de Virulência , Suplementos Nutricionais
9.
Arch Toxicol ; 98(5): 1515-1532, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38427118

RESUMO

The combustion of traditional fuels in low-income countries, including those in sub-Saharan Africa, leads to extensive indoor particle exposure. Yet, the related health consequences in this context are understudied. This study aimed to evaluate the in vitro toxicity of combustion-derived particles relevant for Sub-Saharan household environments. Particles (< 2.5 µm) were collected using a high-volume sampler during combustion of traditional Ethiopian biomass fuels: cow dung, eucalyptus wood and eucalyptus charcoal. Diesel exhaust particles (DEP, NIST 2975) served as reference particles. The highest levels of particle-bound polycyclic aromatic hydrocarbons (PAHs) were found in wood (3219 ng/mg), followed by dung (618 ng/mg), charcoal (136 ng/mg) and DEP (118 ng/mg) (GC-MS). BEAS-2B bronchial epithelial cells and THP-1 derived macrophages were exposed to particle suspensions (1-150 µg/mL) for 24 h. All particles induced concentration-dependent genotoxicity (comet assay) but no pro-inflammatory cytokine release in epithelial cells, whereas dung and wood particles also induced concentration-dependent cytotoxicity (Alamar Blue). Only wood particles induced concentration-dependent cytotoxicity and genotoxicity in macrophage-like cells, while dung particles were unique at increasing secretion of pro-inflammatory cytokines (IL-6, IL-8, TNF-α). In summary, particles derived from combustion of less energy dense fuels like dung and wood had a higher PAH content and were more cytotoxic in epithelial cells. In addition, the least energy dense and cheapest fuel, dung, also induced pro-inflammatory effects in macrophage-like cells. These findings highlight the influence of fuel type on the toxic profile of the emitted particles and warrant further research to understand and mitigate health effects of indoor air pollution.


Assuntos
Poluentes Atmosféricos , Hidrocarbonetos Policíclicos Aromáticos , Animais , Feminino , Bovinos , Humanos , Material Particulado/toxicidade , Material Particulado/análise , Tamanho da Partícula , Carvão Vegetal , Biomassa , Macrófagos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/análise , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise
10.
Int Immunopharmacol ; 130: 111711, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38428145

RESUMO

Immune dysregulation has been summarized as a critical factor in the occurrence and development of Polycystic ovary syndrome (PCOS), but potential mediators and mechanisms remain unclear. Our previous study showed that CD19+ B cells were involved in the pathogenesis of dehydroepiandrosterone (DHEA)-induced PCOS mice. Here, we studied the therapeutic potential of anti-CD19 antibody (aCD19 Ab) on DHEA-induced PCOS mice. The results showed that aCD19 Ab treatment improved ovarian pathological structure and function of PCOS mice, manifested by an increased number of corpus luteum, a decreased number of cystic follicles and atretic follicles, and regular estrus cycles. The aCD19 Ab treatment reduced the proportion of splenic CD21+ CD23low marginal zone B cells as well as the level of serum IgM and decreased the percentage of peripheral blood and splenic neutrophils. In particular, aCD19 Ab treatment reduced the apoptosis of granulosa cells and macrophage infiltration in ovarian secondary follicles of PCOS mice, as well as the expression of TNF-α in ovarian tissue and serum TNF-α levels. Moreover, we confirmed that TNF-α induced the apoptosis of human ovarian granulosa tumor cell line cells in vitro. Thus, our work demonstrates that aCD19 Ab treatment improves ovarian pathological phenotype and function by reducing local and systemic inflammation in PCOS mice, which may provide a novel insight into PCOS therapy.


Assuntos
Anticorpos , Antígenos CD19 , Síndrome do Ovário Policístico , Animais , Feminino , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Desidroepiandrosterona , Folículo Ovariano/imunologia , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/terapia , Fator de Necrose Tumoral alfa/metabolismo , Antígenos CD19/imunologia , Anticorpos/uso terapêutico , Linfócitos B/imunologia , Camundongos Endogâmicos C57BL
11.
Int Immunopharmacol ; 130: 111762, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38428146

RESUMO

Drug-induced liver injury (DILI) is a common and severe adverse drug reaction that can result in acute liver failure. Previously, we have shown that Lycium barbarum L. (wolfberry) ameliorated liver damage in acetaminophen (APAP)-induced DILI. Nevertheless, the mechanism needs further clarification. Herein, we utilized APAP-induced DILI mice to investigate how wolfberry impacts the gut-liver axis to mitigate liver damage. We showed that the abundance of Akkermansia muciniphila (A. muciniphila) was decreased, and intestinal microbiota was disrupted, while the expression levels of YAP1 and FXR-mediated CYP7A1 were reduced in the liver of DILI mice. Furthermore, wolfberry increased the abundance of A. muciniphila and the number of goblet cells in the intestines, while decreasing AST, ALT, and total bile acids (TBA) levels in the serum. Interestingly, A. muciniphila promoted YAP1 and FXR expression in hepatocytes, leading to the inhibition of CYP7A1 expression and a decrease in TBA content. Notably, wolfberry did not exert the beneficial effects mentioned above after the removal of intestinal bacteria by antibiotics (ATB)-containing water. Additionally, Yap1 knockout downregulated FXR expression and enhanced CYP7A1 expression in the liver of hepatocyte-specific Yap1 knockout mice. Therefore, wolfberry stimulated YAP1/FXR activation and reduced CYP7A1 expression by promoting the balance of intestinal microbiota, thereby suppressing the overproduction of bile acids.


Assuntos
Acetaminofen , Akkermansia , Ácidos e Sais Biliares , Doença Hepática Induzida por Substâncias e Drogas , Microbioma Gastrointestinal , Lycium , Proteínas de Ligação a RNA , Proteínas de Sinalização YAP , Animais , Camundongos , Acetaminofen/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/microbiologia , Fígado , Lycium/química , Proteínas de Sinalização YAP/metabolismo , Proteínas de Ligação a RNA/metabolismo , Camundongos Knockout
12.
Biomed Pharmacother ; 173: 116341, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428309

RESUMO

Obesity is a significant risk factor for several chronic diseases. However, pre-menopausal females are protected against high-fat diet (HFD)-induced obesity and its adverse effects. The pregnane X receptor (PXR, NR1I2), a xenobiotic-sensing nuclear receptor, promotes short-term obesity-associated liver disease only in male mice but not in females. Therefore, the current study investigated the metabolic and pathophysiological effects of a long-term 52-week HFD in female wild-type (WT) and PXR-KO mice and characterized the PXR-dependent molecular pathways involved. After 52 weeks of HFD ingestion, the body and liver weights and several markers of hepatotoxicity were significantly higher in WT mice than in their PXR-KO counterparts. The HFD-induced liver injury in WT female mice was also associated with upregulation of the hepatic mRNA levels of peroxisome proliferator-activated receptor gamma (Pparg), its target genes, fat-specific protein 27 (Fsp27), and the liver-specific Fsp27b involved in lipid accumulation, apoptosis, and inflammation. Notably, PXR-KO mice displayed elevated hepatic Cyp2a5 (anti-obesity gene), aldo-keto reductase 1b7 (Akr1b7), glutathione-S-transferase M3 (Gstm3) (antioxidant gene), and AMP-activated protein kinase (AMPK) levels, contributing to protection against long-term HFD-induced obesity and inflammation. RNA sequencing analysis revealed a general blunting of the transcriptomic response to HFD in PXR-KO compared to WT mice. Pathway enrichment analysis demonstrated enrichment by HFD for several pathways, including oxidative stress and redox pathway, cholesterol biosynthesis, and glycolysis/gluconeogenesis in WT but not PXR-KO mice. In conclusion, this study provides new insights into the molecular mechanisms by which PXR deficiency protects against long-term HFD-induced severe obesity and its adverse effects in female mice.


Assuntos
Dieta Hiperlipídica , Fígado , Masculino , Feminino , Camundongos , Animais , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Aumento de Peso , Obesidade/metabolismo , Inflamação/metabolismo , Camundongos Knockout
13.
Biomed Pharmacother ; 173: 116331, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428307

RESUMO

Farnesoid X receptor (FXR) plays a pivotal role in the regulation of bile acid homeostasis and is involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Although FXR agonists effectively alleviate pathological features of NASH, adverse effects such as disturbance of cholesterol homeostasis and occurrence of pruritus remain to be addressed. Here, we identified a novel FXR agonist, ID119031166 (ID166), and explored the pharmacological benefits of ID166 in the treatment of NASH. ID166, a potent and selective non-bile acid FXR agonist, exhibits preferential distribution in the intestine and shows no agonist activity against potential itch receptors including Mas-related G protein-coupled receptor X4 (MRGPRX4). Interestingly, ID166 significantly attenuated total nonalcoholic fatty liver disease (NAFLD) activity and liver fibrosis in a free choice diet-induced NASH hamster model. In addition, ID166 drastically modulated the relative abundance of five gut microbes and reduced the increase in plasma total bile acid levels to normal levels in NASH hamsters. Moreover, long-term treatment with ID166 significantly improved key histological features of NASH and liver fibrosis in a diet-induced NASH mouse model. In the NASH mouse livers, RNA-seq analysis revealed that ID166 reduced the gene expression changes associated with both NASH and liver fibrosis. Notably, ID166 exhibited no substantial effects on scratching behavior and serum IL-31 levels in mice. Our findings suggest that ID166, a novel FXR agonist with improved pharmacological properties, provides a preclinical basis to optimize clinical benefits for NASH drug development.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fígado , Cirrose Hepática/metabolismo , Ácidos e Sais Biliares/metabolismo
14.
Biomed Pharmacother ; 173: 116340, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428308

RESUMO

The current study investigated the ameliorating impact of GA water extract (GAE) on CCl4-induced nephrotoxicity in renal cells and tissue by comparing its effectiveness with the Ketosteril (Ks) drug in restoring oxidative stress and necroinflammation. The cell morphology, necrosis, and redox state were evaluated in Vero cells. The influence of GAE on CCl4-induced oxidative stress, inflammation, and necrosis was examined in rats. The predicted inhibitory mechanism of GAE phenolic constituents against COX-2 and iNOS was also studied. The results revealed that GAE contains crucial types of phenolic acids, which are associated with its antiradical activities. GAE improved CCl4-induced Vero cell damage and restored renal architecture damage, total antioxidant capacity, ROS, TBARS, NO, GSH, GPX, SOD, and MPO in rats. GAE downregulated the gene expression of renal NF-κB, TNF-α, iNOS, and COX-2, as well as kidney injury molecule-1 (KIM-1) in rats. The GAE improved blood urea, creatinine, cholesterol, and reducing power. The computational analysis revealed the competitive inhibitory mechanism of selected phenolic composites of GAE on COX-2 and iNOS activities. The GAE exhibited higher potency than Ks in most of the studied parameters, as observed by the heatmap plots. Thus, GAE is a promising extract for the treatment of kidney toxicity.


Assuntos
NF-kappa B , Insuficiência Renal , Chlorocebus aethiops , Ratos , Animais , NF-kappa B/metabolismo , Tetracloreto de Carbono/toxicidade , Goma Arábica , Células Vero , Ciclo-Oxigenase 2/metabolismo , Antioxidantes/farmacologia , Estresse Oxidativo , Insuficiência Renal/metabolismo , Oxirredução , Rim/metabolismo , Necrose/metabolismo
15.
Biomed Pharmacother ; 173: 116343, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428311

RESUMO

Therapeutic neovascularization is a strategy to promote blood vessel growth and improve blood flow, which is critical to tissue repair and regeneration in ischemic diseases. Here, we investigated the role of endothelial progenitor cell - derived exosomes (EPC-Exos) in therapeutic neovascularization and clarified the mechanism of hsa_circ_0093884 in EPC-Exos mediated neovascularization. Injection of EPC-Exos improved mouse ischemic hindlimb perfusion, promoted angiogenesis in Matrigel plugs and mouse skin wound healing. In vitro coculture with EPC-Exos improved HUVEC proliferation, angiogenic and migration ability, while alleviated hypoxia-induced apoptosis. hsa_circ_0093884 was identified from eleven types of circRNA derived from SIRT1 and proved to be enriched in EPC-Exos. Overexpression of hsa_circ_0093884 in EPC-Exos further enhanced the angiogenic capacity, while knockdown of hsa_circ_0093884 abolished the benefits. Mechanistically, EPC-Exos mediated shuttling of hsa_circ_0093884 induced cytoplasmic sponge of miR-145, thereby releasing repression of SIRT1. In vitro co-transfection indicated silence of miR-145 further strengthened the angiogenic effect of hsa_circ_0093884, while overexpression of miR-145 inhibited hsa_circ_0093884 mediated angiogenesis and abolished the beneficial effect of EPC-Exos. Furthermore, in vivo experiments using endothelial specific SIRT1 conditional knockout mice indicated hsa_circ_0093884 overexpressing EPC-Exos failed to promote therapeutic neovascularization in SIRT1cKO mice. Collectively, our results demonstrated that EPC-Exos promoted therapeutic neovascularization through hsa_circ_0093884/miR-145/SIRT1 axis.


Assuntos
Células Progenitoras Endoteliais , MicroRNAs , Camundongos , Animais , Células Progenitoras Endoteliais/metabolismo , MicroRNAs/metabolismo , Sirtuína 1/genética , Neovascularização Fisiológica/genética , Neovascularização Patológica/genética , Proliferação de Células/genética
16.
Biomed Pharmacother ; 173: 116361, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428310

RESUMO

Gynura procumbens (Lour.) Merr., utilized in traditional Chinese medicine, is known for its liver-protective, liver-soothing, and depression-alleviating properties. This research examines the antidepressant and anti-hyperprolactinemia potentials of an ethanol extract from G. procumbens stems (EEGS) and specific metabolites. To model depression and hyperprolactinemia, chronic unpredictable mild stress (CUMS) was induced in mice and risperidone was administered to rats, respectively. Treatments involved administering low (5 mg/kg), medium (25 mg/kg), and high (125 mg/kg) doses of EEGS and certain metabolites to both models. Behavioral assessments were conducted in the CUMS-induced mice, while the CA3 neuronal damage in mice and histopathological alterations in rat mammary glands were evaluated using Nissl and Hematoxylin & Eosin staining techniques, respectively. EEGS decreased immobility times in the forced swimming and tail suspension tests in mice, enhancing their exploration of the central zone. It elevated the serum levels of 5-hydroxytryptamine, norepinephrine, estradiol, luteinizing hormone (LH), and testosterone in mice. Moreover, EEGS restored the neuronal cell arrangement in the CA3 area, reduced interleukin-1beta mRNA production, and increased the expression of interleukin-10 and beta-catenin mRNA. In the context of risperidone-induced hyperprolactinemia, EEGS lowered blood prolactin levels, reduced the dimensions of rat nipples, and enhanced LH, progesterone, and dopamine levels, alongside mitigating mammary hyperplasia. Among the EEGS selected metabolites, the combined effect of chlorogenic acid and trans-p-coumaric acid was found to be more effective than the action of each compound in isolation. Collectively, the findings indicate that EEGS and its selected metabolites offer promising antidepressant benefits while counteracting hyperprolactinemia.


Assuntos
Asteraceae , Hiperprolactinemia , Ratos , Camundongos , Animais , Hiperprolactinemia/induzido quimicamente , Hiperprolactinemia/tratamento farmacológico , Risperidona/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , RNA Mensageiro , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Estresse Psicológico
17.
Biomed Pharmacother ; 173: 116346, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428312

RESUMO

BACKGROUND: This study aimed to investigate the effects of the combination of Epimedii Folium (EF) and Ligustri Lucidi Fructus (LLF) on regulating apoptosis and autophagy in senile osteoporosis (SOP) rats. METHODS: Firstly, we identified the components in the decoction and drug-containing serum of EL (EF&LLF) by Ultra performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS). Secondly, SOP rats were treated with EF, LLF, EL and caltrate to evaluate the advantages of EL. Finally, H2O2-, chloroquine-, and MHY1485-induced osteoblasts were treated with different doses of EL to reveal the molecular mechanism of EL. We detected bone microstructure, oxidative stress levels, ALP activity and the expressions of Bax, Bcl-2, caspase3, P53, Beclin-1, p-PI3K, PI3K, p-Akt, Akt, p-mTOR, mTOR, and LC3 in vivo and in vitro. RESULTS: 36 compounds in EL decoction and 23 in EL-containing serum were identified, including flavonoids, iridoid terpenoids, phenylethanoid glycosides, polyols and triterpenoids. EL could inhibit apoptosis activity and increase ALP activity. In SOP rats and chloroquine-inhibited osteoblasts, EL could improve bone tissue microstructure and osteoblasts functions by upregulating Bcl-2, Beclin1, and LC3-II/LC3-I, while downregulating p53 in all treatment groups. In H2O2-induced osteoblasts, EL could upregulate the protein and mRNA expressions of Bcl-2 while downregulate LC3-II/LC3-I, p53 and Beclin1. Besides, EL was able to down-regulate PI3K/AKT/mTOR pathway which activated in SOP rats and MHY1485-induced osteoblasts. CONCLUSIONS: These findings demonstrate that EL with bone protective effects on SOP rats by regulating autophagy and apoptosis via PI3K/Akt/mTOR signaling pathway, which might be an alternative medicine for the treatment of SOP.


Assuntos
Medicamentos de Ervas Chinesas , Ligustrum , Osteoporose , Ratos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ligustrum/química , Ligustrum/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Beclina-1/metabolismo , Peróxido de Hidrogênio/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Osteoporose/tratamento farmacológico , Osteoblastos , Apoptose , Autofagia , Cloroquina/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
18.
Chemosphere ; 353: 141529, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428534

RESUMO

An important problem is the impact of photodegradation on product toxicity in biological tests, which may be complex and context-dependent. Previous studies have described the pharmacology of cefepime, but the toxicological effects of its photodegradation products remain largely unknown. Therefore, photodegradation studies were undertaken in conditions similar to those occurring in biological systems insilico, in vitro, in vivo and ecotoxicological experiments. The structures of four cefepime photodegradation products were determined by UPLC-MS/MS method. The calculated in silico ADMET profile indicates that carcinogenic potential is expected for compounds CP-1, cefepime, CP-2 and CP-3. The Cell Line Cytomotovity Predictor 2.0 tool was used to predict the cytotoxic effects of cefepime and related compounds in non-transformed and cancer cell lines. The results indicate that possible actions include: non-small cell lung cancer, breast adenocarcinoma, prostate cancer and papillary renal cell carcinoma. OPERA models were used to predict absorption, distribution, metabolism and excretion (ADME) endpoints, and potential bioactivity of CP-2, cefepime and CP-4. The results obtained in silico show that after 96h of exposure, cefepime, CP-1, CP-2, and CP-3 are moderately toxic in the zebrafish model, while CP-4 is highly toxic. On the contrary, cefepime is more toxic to T. platyurus (highly toxic) compared to the zebrafish model, similar to products CP-4, CP-3 and CP-2. In vitro cytotoxicity studies were performed by MTT assay and in vivo acute embryo toxicity studies using Danio rerio embryos and larvae. In vitro showed an increase in the cytotoxicity of products with the longest exposure period i.e. for 8 h. Additionally, at a concentration of 200 µg/mL, statistically significant changes in metabolic activity were observed depending on the irradiation time. In vivo studies conducted with Zebrafish showed that both cefepime and its photodegradation products have only low toxicity. Assessment of potential ecotoxicity included Microbiotests on invertebrates (Thamnotoxkit F and Daphtoxkit F), and luminescence inhibition tests (LumiMara). The observed toxicity of the tested solutions towards both Thamnocephalus platyurus and Daphnia magna indicates that the parent substance (unexposed) has lower toxicity, which increases during irradiation. The acute toxicity (Lumi Mara) of nonirradiated cefepime solution is low for all tested strains (<10%), but mixtures of cefepime and its photoproducts showed growth inhibition against all tested strains (except #6, Photobacterium phoreum). Generally, it can be concluded that after UV-Vis irradiation, the mixture of cefepime phototransformation products shows a significant increase in toxicity.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Masculino , Fotólise , Testes de Toxicidade/métodos , Peixe-Zebra , Cefepima/toxicidade , Cromatografia Líquida , Espectrometria de Massas em Tandem
19.
Int J Biol Macromol ; 263(Pt 2): 130423, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428760

RESUMO

Corn starch with slow thickening property may facilitate more efficient heat transfer and safety of corn starch-thickened foods. Partial substitution of normal corn starch (NCS) with slow-pasting behavior of cow cockle starch (CCS) was hypothesized to impart binary starch blend with slow-thickening effect during hydrothermal heating. To test hypothesis, a series of starch blend dispersions (with weight ratios of CCS to NCS = 75:25, 50:50, 25:75) were prepared at various starch concentrations (6 %, 8 %, 10 %, and 12 %) and subjected to the Rapid Viscosity Analysis (RVA). RVA viscographs of starch blends were compared with that of NCS, suggesting that nearly all starch blends at various concentrations showed longer time span of pasting and lower pasting rate. Although CCS and NCS blend gels exhibited lower Young's modulus and hardness based on textural profile analysis, the sensory panels revealed that 6 % and 8 % starch blend gels (with weight ratio of CCS to NCS = 25:75) showed the mouthfeel analogous to NCS gel. These findings highlight a viable non-chemical modification strategy that enables binary blends of CCS and NCS as a novel gelling agent with slow-pasting property and may aid in safety and high-quality processing of hydrogel foods.


Assuntos
Cardiidae , Amido , Animais , Bovinos , Amido/química , Zea mays/química , Viscosidade , Hidrogéis
20.
Sci Rep ; 14(1): 5088, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429466

RESUMO

Anti-vaccine trolling on video-hosting websites hinders efforts to increase vaccination rates by using toxic language and threatening claims to intimidate people and promote vaccine hesitancy. However, there is a shortage of research investigating the effects of toxic messages on these platforms. This study focused on YouTube anti-vaccine videos and examined the relationship between toxicity and fear in the comment section of these videos. We discovered that highly liked toxic comments were associated with a significant level of fear in subsequent comments. Moreover, we found complex patterns of contagion between toxicity and fear in the comments. These findings suggest that initial troll comments can evoke negative emotions in viewers, potentially fueling vaccine hesitancy. Our research bears essential implications for managing public health messaging and online communities, particularly in moderating fear-mongering messages about vaccines on social media.


Assuntos
Mídias Sociais , Ursidae , Vacinas , Humanos , Animais , Gravação em Vídeo , Vacinação/psicologia , Idioma
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...