Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.827.744
Filtrar
1.
Bol. latinoam. Caribe plantas med. aromát ; 23(4): 487-515, jul. 2024. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1538020

RESUMO

Myrtus communis L., commonly known as true myrtle, is a medicinal plant native to the Mediterranean area. Since ancient times, the inhabitant s of this area have been using it for its cultural and medicinal properties. Because of the vast diversity of biomolecules in its aerial parts, it exhibits several biological properties, including antioxidant, antimicrobial, and anticancer properties. This review retrospect the research on the source, biological activities with empirical evidence, chemical composition, applications, and cellular targets of extracts and essential oils obtained from M. communis leaves, which provides a perspective for further studies on the applications and formulations of extract and EO of M. communis leaves. The efficacy of constituents' individually, in association with other bioactive constituents, or in combination with available commercial drugs would provide insights in to the development of these bio - actives as future drugs and their evolving future potential applications in the pharmaceutical, food, and aroma industries.


Myrtus communis L., comúnmente conocido como arrayán verdadero, es una planta medicinal originaria de la zona mediterránea. Desde la antigüedad, los habitantes de esta zona lo utilizan por sus propiedades culturales y medicinales. Debido a la gran div ersidad de biomoléculas en sus partes aéreas, exhibe varias propiedades biológicas, incluidas propiedades antioxidantes, antimicrobianas y anticancerígenas. Esta revisión retrospectiva de la investigación sobre la fuente, las actividades biológicas con evi dencia empírica, la composición química, las aplicaciones y los objetivos celulares de los extractos y aceites esenciales obtenidos de las hojas de M. communis , lo que brinda una perspectiva para futuros estudios sobre las aplicaciones y formulaciones de l os extractos y EO de M. communis . La eficacia de los componentes individualmente, en asociación con otros componentes bioactivos o en combinación con medicamentos comerciales disponibles proporcionaría información sobre el desarrollo de estos bioactivos co mo medicamentos futuros y sus futuras aplicaciones potenciales en las industrias farmacéutica, alimentaria y aromática


Assuntos
Myrtus communis/farmacologia , Plantas Medicinais , Óleos Voláteis/metabolismo , Óleos Voláteis/farmacologia , Folhas de Planta/metabolismo , Antibacterianos , Antifúngicos , Antioxidantes
2.
Bol. latinoam. Caribe plantas med. aromát ; 23(4): 523-533, jul. 2024. tab
Artigo em Inglês | LILACS | ID: biblio-1538056

RESUMO

Leaves of Croton stipulaceuswere extracted (EHex, ECHCl3and EEtOH extracts) to assesstheir antioxidant potential, anti-inflammatory activity in murine models and acute toxicity. EEtOH showed the highest effect in DPPH (37.80% inhibition), FRAP (1065.00 ± 55.30 µmolFe2+) and total polyphenols (231.24 ± 9.05 meq AG/gM). EHex was the most active, ~ 50% inhibition of TPA-induced ear edema; while EEtOH (dose of 2 mg/ear) showed the highest inhibition in the chronic model (97% inhibition), and inhibited MPO activity (48%). In carrageenan-induced edema, ECHCl3(dose 500 mg/kg) was the most active. None of the extracts showed acute toxicity (LD50) at 2 g/kg (p.o.). This work is the first report that supports the traditional use of C. stipulaceusas an anti-inflammatory.


De las hojas de Croton stipulaceusse obtuvieron diferentes extractos (EHex, ECHCl3y EEtOH) evaluando el potencial antioxidante y la actividad antiinflamatoria en modelos murinos y la toxicidad aguda. El EEtOH mostró mayor efecto en DPPH (37.80% inhibición), FRAP (1065.00 ± 55.30 µmolFe2+) y polifenolestotales (231.24 ± 9.05 meq AG/gM). El EHex fue el más activo, cercano al 50% de inhibición del edema auricular inducido con TPA; mientras que el EEtOH (dosis de 2 mg/oreja) mostró la mayor inhibición en el modelo crónico (97% inhibición), e inhibió la actividad de la MPO (48%). En el edema inducido con carragenina, el ECHCl3(dosis 500 mg/kg) fue el más activo. Ninguno de los extractos mostró una toxicidad aguda (DL50) mayor a 2 g/kg (p.o). Este trabajo es el primer reporte que sustenta el uso tradicional de C. stipulaceuscomo antiinflamatorio.


Assuntos
Folhas de Planta/química , Croton/química , Extratos Vegetais/metabolismo , Extratos Vegetais/química , Estruturas Vegetais/metabolismo , Estruturas Vegetais/química , Folhas de Planta/metabolismo , Croton/metabolismo , Anti-Inflamatórios , Antioxidantes
3.
J Zhejiang Univ Sci B ; 25(4): 280-292, 2024 Apr 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38584091

RESUMO

Cells within tissues are subject to various mechanical forces, including hydrostatic pressure, shear stress, compression, and tension. These mechanical stimuli can be converted into biochemical signals through mechanoreceptors or cytoskeleton-dependent response processes, shaping the microenvironment and maintaining cellular physiological balance. Several studies have demonstrated the roles of Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ) as mechanotransducers, exerting dynamic influence on cellular phenotypes including differentiation and disease pathogenesis. This regulatory function entails the involvement of the cytoskeleton, nucleoskeleton, integrin, focal adhesions (FAs), and the integration of multiple signaling pathways, including extracellular signal-regulated kinase (ERK), wingless/integrated (WNT), and Hippo signaling. Furthermore, emerging evidence substantiates the implication of long non-coding RNAs (lncRNAs) as mechanosensitive molecules in cellular mechanotransduction. In this review, we discuss the mechanisms through which YAP/TAZ and lncRNAs serve as effectors in responding to mechanical stimuli. Additionally, we summarize and elaborate on the crucial signal molecules involved in mechanotransduction.


Assuntos
Mecanotransdução Celular , RNA Longo não Codificante , Mecanotransdução Celular/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Via de Sinalização Hippo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
4.
J Zhejiang Univ Sci B ; 25(4): 341-353, 2024 Apr 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38584095

RESUMO

Kidney fibrosis is an inevitable result of various chronic kidney diseases (CKDs) and significantly contributes to end-stage renal failure. Currently, there is no specific treatment available for renal fibrosis. ELA13 (amino acid sequence: RRCMPLHSRVPFP) is a conserved region of ELABELA in all vertebrates; however, its biological activity has been very little studied. In the present study, we evaluated the therapeutic effect of ELA13 on transforming growth factor-ß1 (TGF-ß1)-treated NRK-52E cells and unilateral ureteral occlusion (UUO) mice. Our results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum, and reduce the expression of fibrosis biomarkers confirmed by Masson staining, immunohistochemistry, real-time polymerase chain reaction (RT-PCR), and western blot. Inflammation biomarkers were increased after UUO and decreased by administration of ELA13. Furthermore, we found that the levels of essential molecules in the mothers against decapentaplegic (Smad) and extracellular signal-regulated kinase (ERK) pathways were reduced by ELA13 treatment in vivo and in vitro. In conclusion, ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.


Assuntos
Nefropatias , Obstrução Ureteral , Camundongos , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Nefropatias/patologia , Transdução de Sinais , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Fator de Crescimento Transformador beta1 , Rim/metabolismo , Fibrose , Biomarcadores/metabolismo
5.
Zhonghua Gan Zang Bing Za Zhi ; 32(3): 201-207, 2024 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-38584100

RESUMO

Objective: To investigate the effects of reduced nicotinamide adenine dinucleotide phosphooxidase 4 (NOX4) inhibitors GKT137831 and M2-type macrophages on oxidative stress markers NOX4, nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in the rat hepatic stellate cell line (HSC-T6). Methods: Rat bone marrow macrophages were extracted and induced using interleukin (IL)-4 to differentiate them into M2 phenotype macrophages. HSC-T6 activation was performed with 5 µg/L transforming growth factor ß1 (TGF-ß1). The proliferation condition of HSC-T6 cells stimulated by the NOX4 inhibitor GKT137831 at a concentration gradient of 5 to 80 µmol/L after 48 hours was detected using the Cell Counting Kit-8 (CCK-8) assay. The optimal drug concentration was chosen and divided into an HSC co-culture group (the control group) and five experimental groups: the TGF-ß1 stimulation group, the TGF-ß1 +GKT137831 stimulation group, the M2-type macrophage + HSC co-culture group, the M2-type macrophage +TGF-ß1 stimulation group, and the M2-type + TGF-ß1 + GKT137831 stimulation group. Reactive oxygen species (ROS) production level was detected in each cell using the DCFH-DA probe method. NOX4, α-smooth muscle actin (α-SMA), Nrf2, and HO-1 levels in each group of HSC cells were detected using the qRT-PCR method and the Western blot method. The t-test was used to compare the two groups. The one-way ANOVA method was used to compare multiple groups. Results: Intracellular ROS increased significantly following TGF-ß1 stimulation. ROS relative levels in each cell group were 1.03±0.11, 3.88±0.07, 2.90±0.08, 0.99±0.06, 3.30±0.05, 2.21±0.11, F = 686.1, P = 0.001, respectively. The mRNA and protein expressions of NOX4, α-SMA, Nrf2, and HO-1 were significantly increased (P < 0.05). After the addition of GKT137831, ROS, and NOX4, α-SMA mRNA and protein expression were comparatively decreased in the TGF-ß1 stimulation group (P < 0.05), while mRNA and protein expressions of Nrf2 and HO-1 were increased (P < 0.05). The expression of ROS and NOX4, as well as α-SMA mRNA and protein, produced by HSC were significantly decreased in the co-culture group compared to the single culture group after TGF-ß1 stimulation (P < 0.05). After the addition of GKT137831, ROS, NOX4, α-SMA mRNA, and protein expression were further reduced in the co-culture group compared with the single culture group (P < 0.05), while the mRNA and protein expression of Nrf2 and HO-1 were further increased (P < 0.05). Conclusion: NOX4 inhibitor GKT137831 can reduce RO, NOX4, and α-SMA levels while increasing Nrf2 and HO-1 levels in hepatic stellate cells. After M2-type macrophage co-culture, GKT137831 assists in lowering ROS, NOX4, and α-SMA levels while accelerating Nrf2 and HO-1 levels in hepatic stellate cells, which regulates the balance between oxidative stress and anti-oxidative stress systems, thereby antagonizing the fibrosis process.


Assuntos
Células Estreladas do Fígado , Pirazolonas , Piridonas , Fator de Crescimento Transformador beta1 , Ratos , Animais , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Cirrose Hepática/induzido quimicamente , Estresse Oxidativo , Macrófagos/metabolismo , RNA Mensageiro/metabolismo
6.
J Zhejiang Univ Sci B ; 25(4): 354-358, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38584096

RESUMO

Glufosinate-ammonium herbicides are the most widely used broad-spectrum, non-selective herbicides in the world. Glufosinate-ammonium is a structural analogue of glutamate (Glu) which can irreversibly inhibit the activity of glutamine synthetase (GS) and Glu decarboxylase in plants, thereby blocking the synthesis of glutamine (Gln) from Glu and ammonia (Hoerlein, 1994). This causes the plants to die because of the nitrogen metabolism disorder and subsequent intracellular accumulation of ammonia. In humans, the characteristic features of glufosinate-ammonium herbicide poisoning include gastrointestinal symptoms and neurotoxicity (Watanabe and Sano, 1998). Currently, there are no antidotes for glufosinate-ammonium herbicide poisoning, and thus supportive care is the key treatment.


Assuntos
Amônia , Herbicidas , Humanos , Aminobutiratos/metabolismo , Convulsões
7.
Zhonghua Gan Zang Bing Za Zhi ; 32(3): 268-272, 2024 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-38584113

RESUMO

Short-chain fatty acids are metabolites of the intestinal flora and serve as the main energy source for intestinal epithelial cells. At the same time, as important signaling molecules, it regulate a variety of cellular inflammatory responses and homeostatic proliferation through receptor-dependent and independent pathways. Short-chain fatty acids regulate the gut-liver axis and thereby directly act on the liver, participating in the pathogenesis and transformation of various liver diseases, including alcoholic liver disease, metabolic dysfunction-related liver disease, autoimmune liver disease, liver fibrosis, and hepatocellular carcinoma. In addition, short-chain fatty acids can inhibit HBV DNA replication. This article reviews the research progress on the role of short-chain fatty acids in aspects of the pathogenesis and transformation of chronic liver diseases.


Assuntos
Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/patologia , Cirrose Hepática , Ácidos Graxos Voláteis/metabolismo
8.
Zhonghua Gan Zang Bing Za Zhi ; 32(3): 284-288, 2024 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-38584116

RESUMO

Pyroptosis is a newly discovered kind of cell death modality that, due to its association with innate immunity, plays a crucial role in cytolysis and inflammatory cytokine release during host defense against infection. In recent years, studies have shown that pyroptosis plays an important role in the occurrence and development of liver diseases. This article introduces and elaborates on the most recent research progress on pyroptosis in liver diseases based on the morphological features, molecular and pathophysiological mechanisms.


Assuntos
Hepatopatias , Piroptose , Humanos , Citocinas , Inflamassomos/metabolismo
9.
Zhonghua Gan Zang Bing Za Zhi ; 32(3): 257-261, 2024 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-38584111

RESUMO

Systemic treatment, including molecular targeted therapy, immunotherapy, and chemotherapy, is an important means of achieving long-term survival in patients with intermediate-and advanced-stage liver cancer. However, some patients are insensitive to treatment and even develop drug resistance. Mitochondria are the center of cellular energy metabolism and, at the same time, are the priority targets for systemic therapy. Mitochondrial homeostasis plays an important role in the treatment of liver cancer. The relationship between the two advances is elucidated so as to provide better ideas for the clinical treatment of liver cancer.


Assuntos
Neoplasias Hepáticas , Mitocôndrias , Humanos , Imunoterapia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/metabolismo , Homeostase
10.
Zhonghua Gan Zang Bing Za Zhi ; 32(3): 279-283, 2024 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-38584115

RESUMO

Hepatic sinusoidal obstruction syndrome (HSOS) is a type of secondary vascular disease of the liver that is mainly associated with the ingestion of pyrrole alkaloids (PAs) and hematopoietic stem cell transplantation (HSCT) treatment, resulting in severe liver dysfunction, multiple organ failure, and even death. Hepatic sinusoidal dilatation and obstruction, hepatocyte coagulative necrosis, and hepatic lobular inflammation are the main pathological manifestations of HSOS. The key initiating process for the pathogenesis of HSOS is damage to liver sinusoidal endothelial cells (LSECs). Currently, it is believed that LSECs are damaged by the involvement of multiple etiologies and mechanisms, and secondary coagulation and fibrinolysis disorders, oxidative stress, and inflammatory responses are the occurrence contributors to HSOS; however, the mechanism has not been fully elucidated. Therefore, the role of immune-inflammatory mechanisms has received increasing attention in LSEC damage. This article provides an overview of the epidemiology, etiology, and pathological changes of HSOS and reviews the physiological functions, common etiological damage mechanisms, and the key role of LSEC damage in the pathogenesis of HSOS, with a special focus on the role and research progress of immune-inflammatory mechanisms for LSEC damage in recent years. Furthermore, we believe that in-depth study and elucidation of the role of immune-inflammatory mechanisms in LSEC damage and the pathogenesis of HSOS and diagnosis will provide feasible research and development ideas for the screening and identification of new markers and drug treatment targets for HSOS.


Assuntos
Hepatopatia Veno-Oclusiva , Hepatopatias , Humanos , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/diagnóstico , Células Endoteliais , Hepatopatias/patologia , Fígado/patologia , Necrose/metabolismo , Necrose/patologia
11.
Eur J Endocrinol ; 190(4): 284-295, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38584335

RESUMO

OBJECTIVE: Glucocorticoid resistance is a rare endocrine disease caused by variants of the NR3C1 gene encoding the glucocorticoid receptor (GR). We identified a novel heterozygous variant (GRR569Q) in a patient with uncommon reversible glucocorticoid resistance syndrome. METHODS: We performed ex vivo functional characterization of the variant in patient fibroblasts and in vitro through transient transfection in undifferentiated HEK 293T cells to assess transcriptional activity, affinity, and nuclear translocation. We studied the impact of the variant on the tertiary structure of the ligand-binding domain through 3D modeling. RESULTS: The patient presented initially with an adrenal adenoma with mild autonomous cortisol secretion and undetectable adrenocorticotropin hormone (ACTH) levels. Six months after surgery, biological investigations showed elevated cortisol and ACTH (urinary free cortisol 114 µg/24 h, ACTH 10.9 pmol/L) without clinical symptoms, evoking glucocorticoid resistance syndrome. Functional characterization of the GRR569Q showed decreased expression of target genes (in response to 100 nM cortisol: SGK1 control +97% vs patient +20%, P < .0001) and impaired nuclear translocation in patient fibroblasts compared to control. Similar observations were made in transiently transfected cells, but higher cortisol concentrations overcame glucocorticoid resistance. GRR569Q showed lower ligand affinity (Kd GRWT: 1.73 nM vs GRR569Q: 4.61 nM). Tertiary structure modeling suggested a loss of hydrogen bonds between H3 and the H1-H3 loop. CONCLUSION: This is the first description of a reversible glucocorticoid resistance syndrome with effective negative feedback on corticotroph cells regarding increased plasma cortisol concentrations due to the development of mild autonomous cortisol secretion.


Assuntos
Glucocorticoides , Erros Inatos do Metabolismo , Receptores de Glucocorticoides , Receptores de Glucocorticoides/deficiência , Humanos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Glucocorticoides/metabolismo , Hidrocortisona , Ligantes , Hormônio Adrenocorticotrópico/genética , Síndrome , Mutação
12.
Cell Biochem Funct ; 42(3): e4012, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38584583

RESUMO

Osteoarthritis (OA) is characterised by the deterioration of cartilage in the joints and pain. We hypothesise that semaphorin-3A (sema-3A), a chemorepellent for sensory nerves, plays a role in joint degradation and pain. We used the mechanical joint loading (MJL) model of OA to investigate sema-3A expression in the joint and examine its association with the development of OA and pain. We also analyse its effect on chondrocyte differentiation using the ATDC5 cell line. We demonstrate that sema-3A is present in most tissues in the healthy joint and its expression increases in highly innervated tissues, such as cruciate ligaments, synovial lining and subchondral bone, in loaded compared to nonloaded control joints. In contrast, sema-3A expression in cartilage was decreased in the severe OA induced by the application of high loads. There was a significant increase in circulating sema-3A, 6 weeks after MJL compared to the nonloaded mice. mRNA for sema-3A and its receptor Plexin A1 were upregulated in the dorsal root ganglia of mice submitted to MJL. These increases were supressed by zoledronate, an inhibitor of bone pain. Sema-3A was expressed at all stages of Chondrocyte maturation and, when added exogenously, stimulated expression of markers of chondrocyte differentiation. This indicates that sema-3A could affect joint tissues distinctively during the development of OA. In highly innervated joint tissues, sema-3A could control innervation and/or induce pain-associated neuronal changes. In cartilage, sema-3A could favour its degeneration by modifying chondrocyte differentiation.


Assuntos
Osso e Ossos , Semaforina-3A , Camundongos , Animais , Semaforina-3A/genética , Semaforina-3A/metabolismo , Osso e Ossos/metabolismo , Diferenciação Celular , Linhagem Celular , Dor
13.
PeerJ ; 12: e17185, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38584937

RESUMO

Background: Cardiovascular diseases are the leading cause of death worldwide, significantly impacting public health. Atherosclerotic cardiovascular diseases account for the majority of these deaths, with atherosclerosis marking the initial and most critical phase of their pathophysiological progression. There is a complex relationship between atherosclerosis, the gut microbiome's composition and function, and the potential mediating role of exercise. The adaptability of the gut microbiome and the feasibility of exercise interventions present novel opportunities for therapeutic and preventative approaches. Methodology: We conducted a comprehensive literature review using professional databases such as PubMed and Web of Science. This review focuses on the application of meta-omics techniques, particularly metagenomics and metabolomics, in studying the effects of exercise interventions on the gut microbiome and atherosclerosis. Results: Meta-omics technologies offer unparalleled capabilities to explore the intricate connections between exercise, the microbiome, the metabolome, and cardiometabolic health. This review highlights the advancements in metagenomics and metabolomics, their applications in research, and examines how exercise influences the gut microbiome. We delve into the mechanisms connecting these elements from a metabolic perspective. Metagenomics provides insight into changes in microbial strains post-exercise, while metabolomics sheds light on the shifts in metabolites. Together, these approaches offer a comprehensive understanding of how exercise impacts atherosclerosis through specific mechanisms. Conclusions: Exercise significantly influences atherosclerosis, with the gut microbiome serving as a critical intermediary. Meta-omics technology holds substantial promise for investigating the gut microbiome; however, its methodologies require further refinement. Additionally, there is a pressing need for more extensive cohort studies to enhance our comprehension of the connection among these element.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/genética , Doenças Cardiovasculares/metabolismo , Metabolômica/métodos , Metaboloma
15.
Front Immunol ; 15: 1367048, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38585259

RESUMO

Objective: In the defense against microorganisms like Candida albicans, macrophages recruit LC3(Microtubule-associated protein 1A/1B-light chain 3) to the periplasm, engaging in the elimination process through the formation of a single-membrane phagosome known as LC3-associated phagocytosis (LAP). Building on this, we propose the hypothesis that glucocorticoids may hinder macrophage phagocytosis of Candida glabrata by suppressing LAP, and rapamycin could potentially reverse this inhibitory effect. Methods: RAW264.7 cells were employed for investigating the immune response to Candida glabrata infection. Various reagents, including dexamethasone, rapamycin, and specific antibodies, were utilized in experimental setups. Assays, such as fluorescence microscopy, flow cytometry, ELISA (Enzyme-Linked Immunosorbent Assay), Western blot, and confocal microscopy, were conducted to assess phagocytosis, cytokine levels, protein expression, viability, and autophagy dynamics. Results: Glucocorticoids significantly inhibited macrophage autophagy, impairing the cells' ability to combat Candida glabrata. Conversely, rapamycin exhibited a dual role, initially inhibiting and subsequently promoting phagocytosis of Candida glabrata by macrophages. Glucocorticoids hinder macrophage autophagy in Candida glabrata infection by suppressing the MTOR pathway(mammalian target of rapamycin pathway), while the activation of MTOR pathway by Candida glabrata diminishes over time. Conclusion: Our study elucidates the intricate interplay between glucocorticoids, rapamycin, and macrophage autophagy during Candida glabrata infection. Understanding the implications of these interactions not only sheds light on the host immune response dynamics but also unveils potential therapeutic avenues for managing fungal infections.


Assuntos
Candida glabrata , Candidíase , Animais , Camundongos , Candida glabrata/fisiologia , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Sirolimo/farmacologia , Camundongos Endogâmicos BALB C , Autofagia , Macrófagos , Serina-Treonina Quinases TOR/metabolismo , Mamíferos
16.
Front Immunol ; 15: 1379967, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38585264

RESUMO

Heme degradation by the heme oxygenase (HMOX) family of enzymes is critical for maintaining homeostasis and limiting heme-induced tissue damage. Macrophages express HMOX1 and 2 and are critical sites of heme degradation in healthy and diseased states. Here we review the functions of the macrophage heme oxygenase system and its clinical relevance in discrete groups of pathologies where heme has been demonstrated to play a driving role. HMOX1 function in macrophages is essential for limiting oxidative tissue damage in both acute and chronic hemolytic disorders. By degrading pro-inflammatory heme and releasing anti-inflammatory molecules such as carbon monoxide, HMOX1 fine-tunes the acute inflammatory response with consequences for disorders of hyperinflammation such as sepsis. We then discuss divergent beneficial and pathological roles for HMOX1 in disorders such as atherosclerosis and metabolic syndrome, where activation of the HMOX system sits at the crossroads of chronic low-grade inflammation and oxidative stress. Finally, we highlight the emerging role for HMOX1 in regulating macrophage cell death via the iron- and oxidation-dependent form of cell death, ferroptosis. In summary, the importance of heme clearance by macrophages is an active area of investigation with relevance for therapeutic intervention in a diverse array of human diseases.


Assuntos
Heme Oxigenase (Desciclizante) , Heme , Humanos , Heme Oxigenase (Desciclizante)/metabolismo , Heme/metabolismo , Relevância Clínica , Macrófagos/metabolismo , Ferro/metabolismo , Inflamação/metabolismo
17.
Front Immunol ; 15: 1369238, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38585273

RESUMO

Introduction: Exosome-enriched small extracellular vesicles (sEVs) are nanosized organelles known to participate in long distance communication between cells, including in the skin. Atopic dermatitis (AD) is a chronic inflammatory skin disease for which filaggrin (FLG) gene mutations are the strongest genetic risk factor. Filaggrin insufficiency affects multiple cellular function, but it is unclear if sEV-mediated cellular communication originating from the affected keratinocytes is also altered, and if this influences peptide and lipid antigen presentation to T cells in the skin. Methods: Available mRNA and protein expression datasets from filaggrin-insufficient keratinocytes (shFLG), organotypic models and AD skin were used for gene ontology analysis with FunRich tool. sEVs secreted by shFLG and control shC cells were isolated from conditioned media by differential centrifugation. Mass spectrometry was carried out for lipidomic and proteomic profiling of the cells and sEVs. T cell responses to protein, peptide, CD1a lipid antigens, as well as phospholipase A2-digested or intact sEVs were measured by ELISpot and ELISA. Results: Data analysis revealed extensive remodeling of the sEV compartment in filaggrin insufficient keratinocytes, 3D models and the AD skin. Lipidomic profiles of shFLGsEV showed a reduction in the long chain (LCFAs) and polyunsaturated fatty acids (PUFAs; permissive CD1a ligands) and increased content of the bulky headgroup sphingolipids (non-permissive ligands). This resulted in a reduction of CD1a-mediated interferon-γ T cell responses to the lipids liberated from shFLG-generated sEVs in comparison to those induced by sEVs from control cells, and an increase in interleukin 13 secretion. The altered sEV lipidome reflected a generalized alteration in the cellular lipidome in filaggrin-insufficient cells and the skin of AD patients, resulting from a downregulation of key enzymes implicated in fatty acid elongation and desaturation, i.e., enzymes of the ACSL, ELOVL and FADS family. Discussion: We determined that sEVs constitute a source of antigens suitable for CD1a-mediated presentation to T cells. Lipids enclosed within the sEVs secreted on the background of filaggrin insufficiency contribute to allergic inflammation by reducing type 1 responses and inducing a type 2 bias from CD1a-restricted T cells, thus likely perpetuating allergic inflammation in the skin.


Assuntos
Dermatite Atópica , Vesículas Extracelulares , Humanos , Proteínas Filagrinas , Proteômica , Proteínas de Filamentos Intermediários/genética , Queratinócitos , Inflamação , Vesículas Extracelulares/metabolismo , Linfócitos T/metabolismo , Peptídeos/metabolismo , Lipídeos
18.
Front Immunol ; 15: 1362727, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38585277

RESUMO

Acute pancreatitis is a complex inflammatory disease resulting in extreme pain and can result in significant morbidity and mortality. It can be caused by several factors ranging from genetics, alcohol use, gall stones, and ductal obstruction caused by calcification or neutrophil extracellular traps. Acute pancreatitis is also characterized by immune cell infiltration of neutrophils and M1 macrophages. Toll-like receptor 4 (TLR4) is a pattern recognition receptor that has been noted to respond to endogenous ligands such as high mobility group box 1 (HMGB1) protein and or exogenous ligands such as lipopolysaccharide both of which can be present during the progression of acute pancreatitis. This receptor can be found on a variety of cell types from endothelial cells to resident and infiltrating immune cells leading to production of pro-inflammatory cytokines as well as immune cell activation and maturation resulting in the furthering of pancreatic damage during acute pancreatitis. In this review we will address the various mechanisms mediated by TLR4 in the advancement of acute pancreatitis and how targeting this receptor could lead to improved outcomes for patients suffering from this condition.


Assuntos
Pancreatite , Humanos , Pancreatite/metabolismo , Receptor 4 Toll-Like/metabolismo , Células Endoteliais/metabolismo , Doença Aguda , Pâncreas
19.
Int J Nanomedicine ; 19: 3123-3142, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38585474

RESUMO

Purpose: To study whether the absence of laminar shear stress (LSS) enables the uptake of very small superparamagnetic iron oxide nanoparticles (VSOP) in endothelial cells by altering the composition, size, and barrier function of the endothelial surface layer (ESL). Methods and Results: A quantitative particle exclusion assay with living human umbilical endothelial cells using spinning disc confocal microscopy revealed that the dimension of the ESL was reduced in cells cultivated in the absence of LSS. By combining gene expression analysis, flow cytometry, high pressure freezing/freeze substitution immuno-transmission electron microscopy, and confocal laser scanning microscopy, we investigated changes in ESL composition. We found that increased expression of the hyaluronan receptor CD44 by absence of shear stress did not affect the uptake rate of VSOPs. We identified collagen as a previously neglected component of ESL that contributes to its barrier function. Experiments with inhibitor halofuginone and small interfering RNA (siRNA) demonstrated that suppression of collagen expression facilitates VSOP uptake in endothelial cells grown under LSS. Conclusion: The absence of laminar shear stress disturbs the barrier function of the ESL, facilitating membrane accessibility and endocytic uptake of VSOP. Collagen, a previously neglected component of ESL, contributes to its barrier function.


Assuntos
Células Endoteliais , Nanopartículas Magnéticas de Óxido de Ferro , Humanos , Células Endoteliais/metabolismo , Endotélio , Perfilação da Expressão Gênica , Colágeno/metabolismo , Estresse Mecânico , Células Cultivadas
20.
Front Cell Infect Microbiol ; 14: 1322113, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38585654

RESUMO

Background: Dopamine, a frequently used therapeutic agent for critically ill patients, has been shown to be implicated in clinical infections recently, however, the precise mechanisms underlying this association remain elusive. Klebsiella quasivariicola, a novel strain belonging to the Klebsiella species, exhibits potential pathogenic attributes. The impact of dopamine on K. quasivariicola infection has aroused our interest. Objective: Considering the contribution of host immune factors during infection, this study aimed to investigate the intricate interactions between K. quasivariicola, dopamine, and macrophages were explored. Methods: RAW264.7 cells and C57/BL6 mice were infected with K. quasivariicola, and the bacterial growth within macrophage, the production of inflammatory cytokines and the pathological changes in mice lungs were detected, in the absence or presence of dopamine. Results: Dopamine inhibited the growth of K. quasivariicola in the medium, but promoted bacterial growth when co-cultured with macrophages. The expression of proinflammatory cytokines increased in RAW 264.7 cells infected with K. quasivariicola, and a significant rise was observed upon the addition of dopamine. The infection of K. quasivariicola in mice induced an inflammatory response and lung injury, which were exacerbated by the administration of dopamine. Conclusions: Our findings suggest that dopamine may be one of the potential risk factors associated with K. quasivariicola infection. This empirical insight provides solid references for clinical precision medicine. Furthermore, an in vitro model of microbes-drugs-host immune cells for inhibitor screening was proposed to more accurately replicate the complex in vivo environment. This fundamental work had contributed to the present understanding of the crosstalk between pathogen, dopamine and host immune cells.


Assuntos
Infecções por Klebsiella , Pulmão , Humanos , Camundongos , Animais , Pulmão/patologia , Dopamina , Klebsiella pneumoniae/metabolismo , Macrófagos/microbiologia , Citocinas/metabolismo , Klebsiella/metabolismo , Proliferação de Células , Infecções por Klebsiella/microbiologia , Camundongos Endogâmicos C57BL
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...