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1.
Brain Behav Immun ; 122: 325-338, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39134184

RESUMO

Prostaglandins (PGs) play a crucial role in sleep regulation, yet the broader physiological context that leads to the activation of the prostaglandin-mediated sleep-promoting system remains elusive. In this study, we explored sleep-inducing mechanisms potentially involving PGs, including microbial, immune and thermal stimuli as well as homeostatic sleep responses induced by short-term sleep deprivation using cyclooxygenase-2 knockout (COX-2 KO) mice and their wild-type littermates (WT). Systemic administration of 0.4 µg lipopolysaccharide (LPS) induced increased non-rapid-eye movement sleep (NREMS) and fever in WT animals, these effects were completely absent in COX-2 KO mice. This finding underscores the essential role of COX-2-dependent prostaglandins in mediating sleep and febrile responses to LPS. In contrast, the sleep and fever responses induced by tumor necrosis factor α, a proinflammatory cytokine which activates COX-2, were preserved in COX-2 KO animals, indicating that these effects are independent of COX-2-related signaling. Additionally, we examined the impact of ambient temperature on sleep. The sleep-promoting effects of moderate warm ambient temperature were suppressed in COX-2 KO animals, resulting in significantly reduced NREMS at ambient temperatures of 30 °C and 35 °C compared to WT mice. However, rapid-eye-movement sleep responses to moderately cold or warm temperatures did not differ between the two genotypes. Furthermore, 6 h of sleep deprivation induced rebound increases in sleep with no significant differences observed between COX-2 KO and WT mice. This suggests that while COX-2-derived prostaglandins are crucial for the somnogenic effects of increased ambient temperature, the homeostatic responses to sleep loss are COX-2-independent. Overall, the results highlight the critical role of COX-2-derived prostaglandins as mediators of the sleep-wake and thermoregulatory responses to various physiological challenges, including microbial, immune, and thermal stimuli. These findings emphasize the interconnected regulation of body temperature and sleep, with peripheral mechanisms emerging as key players in these integrative processes.


Assuntos
Ciclo-Oxigenase 2 , Febre , Lipopolissacarídeos , Camundongos Knockout , Privação do Sono , Sono , Animais , Ciclo-Oxigenase 2/metabolismo , Camundongos , Lipopolissacarídeos/farmacologia , Sono/fisiologia , Masculino , Privação do Sono/metabolismo , Privação do Sono/fisiopatologia , Febre/metabolismo , Camundongos Endogâmicos C57BL , Prostaglandinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Homeostase/fisiologia
2.
Theriogenology ; 227: 151-156, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39089078

RESUMO

Prostaglandins have many roles in the equine reproductive tract, including but not limited to luteolysis, luteal support, ovulation, transport through the uterine tube, uterine contraction, embryonic mobility, inflammation, and fibrosis. Altered secretion of inflammatory proteins are likely to disrupt the balance of endometrial function and could impair fertility. Our overall goal was to measure the expression of several prostaglandin- and inflammation-related genes in mares with different degrees of endometrial histological changes. Our hypothesis was that mares with neutrophilic and lymphocytic plasmocytic inflammation, fibrosis, or different biopsy grades would have altered concentrations of prostaglandin E2 (PGE2) and F2α (PGF2α), as well as altered expression of inflammation- and prostaglandin-related genes, compared to mares with minimal to no histological changes on biopsy evaluation. Forty-five endometrial biopsies from estrous mares were assessed by a reproductive pathologist for the degree of neutrophilic inflammation, lymphocytic and plasmocytic inflammation, and fibrosis, and a biopsy grade was assigned based on the Kenney-Doig system. A low-volume uterine lavage was collected from a subset of twenty-six mares prior to biopsy collection and was used to measure PGE2 and PGF2α concentrations via ELISA. Total RNA was extracted from biopsies and mRNA expression was evaluated for twenty-five genes of interest. A restricted maximum likelihood linear model was used to compare differences of mRNA expression, with a statistical significance set at P < 0.05. There was no difference in the abundance of PGE2 or PGF2α between any of the variables tested. Mares with endometrial biopsy grade I had lower expression of NF-kB, PTGS1 and HPGD compared to grade IIA or IIB (P < 0.05). Mares with neutrophilic inflammation had decreased expression of NF-kB, PTGS1, PTGER4, CBR1, mPGES2 and PTGIS compared to mares without inflammation. Mares with mild or minimal endometrial fibrosis had increased expression of mPGES2 and PTGIS, compared to mares with moderate endometrial fibrosis. In conclusion, several genes were identified to be differentially expressed in mares with histological changes compared to mares with no to minimal histological changes. The presence of inflammation and fibrosis may alter the concentration of prostaglandins in endometrial tissue, which could impair many of the uterine reproductive and immune functions during estrus, affecting early embryo survival.


Assuntos
Endométrio , Fibrose , Inflamação , Animais , Feminino , Cavalos , Endométrio/metabolismo , Endométrio/patologia , Fibrose/veterinária , Fibrose/genética , Biópsia/veterinária , Inflamação/veterinária , Inflamação/genética , Inflamação/metabolismo , Doenças dos Cavalos/genética , Doenças dos Cavalos/metabolismo , Doenças dos Cavalos/patologia , Regulação da Expressão Gênica , Prostaglandinas/metabolismo , Prostaglandinas/genética , Endometrite/veterinária , Endometrite/patologia , Endometrite/genética , Endometrite/metabolismo
3.
Prostaglandins Other Lipid Mediat ; 174: 106864, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38955261

RESUMO

The vasculature of the retina is exposed to systemic and local factors that have the capacity to induce several retinal vascular diseases, each of which may lead to vision loss. Prostaglandin signaling has arisen as a potential therapeutic target for several of these diseases due to the diverse manners in which these lipid mediators may affect retinal blood vessel function. Previous reports and clinical practices have investigated cyclooxygenase (COX) inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) to address retinal diseases with varying degrees of success; however, targeting individual prostanoids or their distinct receptors affords more signaling specificity and poses strong potential for therapeutic development. This review offers a comprehensive view of prostanoid signaling involved in five key retinal vascular diseases: retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, retinal occlusive diseases, and uveitis. Mechanistic and clinical studies of these lipid mediators provide an outlook for therapeutic development with the potential to reduce vision loss in each of these conditions.


Assuntos
Prostaglandinas , Doenças Retinianas , Transdução de Sinais , Humanos , Prostaglandinas/metabolismo , Doenças Retinianas/metabolismo , Doenças Retinianas/tratamento farmacológico , Animais , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia
4.
Alzheimers Res Ther ; 16(1): 171, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39080778

RESUMO

BACKGROUND: Isoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aß-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects. METHODS: Targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aß-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression. RESULTS: Increased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. None of the metabolites showed evidence of association with MCI to AD progression. CONCLUSIONS: Oxidative stress (8,12-iso-iPF2α VI) and inflammatory (PGF2α) biomarkers are correlated with biomarkers of AD pathology during the prodromal stage of AD and relation of PGF2α with tau pathology markers may be influenced by APOE genotype.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Disfunção Cognitiva , Estresse Oxidativo , Proteínas tau , Humanos , Disfunção Cognitiva/líquido cefalorraquidiano , Doença de Alzheimer/líquido cefalorraquidiano , Estresse Oxidativo/fisiologia , Biomarcadores/líquido cefalorraquidiano , Feminino , Masculino , Idoso , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Isoprostanos/líquido cefalorraquidiano , Progressão da Doença , Pessoa de Meia-Idade , Inflamação/líquido cefalorraquidiano , Metabolômica/métodos , Idoso de 80 Anos ou mais , Prostaglandinas/líquido cefalorraquidiano
5.
Circ Res ; 135(6): e133-e149, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39082135

RESUMO

BACKGROUND: Prostaglandin I2 synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I2 production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I2 synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown. METHODS: Experiments were performed with wild-type, Pgis knockout (Pgis-/-) and Pgis/thromboxane-prostanoid receptor gene (Tp) double knockout (Pgis-/-Tp-/-) mice and Pgis-/- mice transplanted with unfractionated wild-type or Cox-1-/- bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored. RESULTS: PGF2α, PGE2, and a trace amount of PGD2, but not thromboxane A2 (TxA2), were produced in response to acetylcholine in Pgis-/- or PGIS-inhibited arteries. PGIS deficiency resulted in exacerbation or occurrence of EDC ex vivo and in vivo. Endothelium-dependent hyperpolarization was unchanged, but phosphorylation levels of eNOS (endothelial nitric oxide synthase) at Ser1177 and Thr495 were altered and NO production and the NO-dependent relaxation evoked by acetylcholine were remarkably reduced in Pgis-/- aortas. Pgis-/- mice developed high blood pressure and vascular remodeling at 16 to 17 weeks and subsequently cardiac hypertrophy at 24 to 26 weeks. Meanwhile, blood pressure and cardiac parameters remained normal at 8 to 10 weeks. Additional ablation of TP (TxA2 receptor) not only restrained EDC and the downregulation of NO signaling in Pgis-/- mice but also ameliorated the cardiovascular abnormalities. Stimulation of Pgis-/- vessels with acetylcholine in the presence of platelets led to increased TxA2 generation. COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in Pgis-/- mice though it largely suppressed the increase of plasma TxB2 (TxA2 metabolite) level. CONCLUSIONS: Our study demonstrates that the non-TxA2 prostanoids/TP axis plays an essential role in mediating the augmentation of EDC and cardiovascular disorders when PGIS is deficient, suggesting TP as a promising therapeutic target in diseases associated with PGIS insufficiency.


Assuntos
Endotélio Vascular , Oxirredutases Intramoleculares , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prostaglandinas , Vasoconstrição , Animais , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/deficiência , Oxirredutases Intramoleculares/metabolismo , Camundongos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Prostaglandinas/metabolismo , Humanos , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/deficiência , Tromboxano A2/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/etiologia , Masculino , Receptores de Tromboxanos/metabolismo , Receptores de Tromboxanos/genética , Vasodilatação , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Remodelação Vascular , Transdução de Sinais , Ciclo-Oxigenase 1/deficiência , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo
6.
J Infect Chemother ; 30(10): 959-970, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38977072

RESUMO

Respiratory viral infections, including respiratory syncytial virus (RSV), parainfluenza viruses and type A and B influenza viruses, can have severe outcomes. Bacterial infections frequently follow viral infections, and influenza or other viral epidemics periodically have higher mortalities from secondary bacterial pneumonias. Most secondary bacterial infections can cause lung immunosuppression by fatty acid mediators which activate cellular receptors to manipulate neutrophils, macrophages, natural killer cells, dendritic cells and other lung immune cells. Bacterial infections induce synthesis of inflammatory mediators including prostaglandins and leukotrienes, then eventually also special pro-resolving mediators, including lipoxins, resolvins, protectins and maresins, which normally resolve inflammation and immunosuppression. Concurrent viral and secondary bacterial infections are more dangerous, because viral infections can cause inflammation and immunosuppression before the secondary bacterial infections worsen inflammation and immunosuppression. Plausibly, the higher mortalities of secondary bacterial pneumonias are caused by the overwhelming inflammation and immunosuppression, which the special pro-resolving mediators might not resolve.


Assuntos
Pneumonia Bacteriana , Humanos , Pneumonia Bacteriana/mortalidade , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/imunologia , Mediadores da Inflamação/metabolismo , Coinfecção/microbiologia , Coinfecção/mortalidade , Coinfecção/imunologia , Coinfecção/virologia , Pulmão/microbiologia , Pulmão/virologia , Pulmão/patologia , Ácidos Docosa-Hexaenoicos , Tolerância Imunológica , Prostaglandinas/metabolismo , Lipoxinas/metabolismo , Inflamação , Leucotrienos/metabolismo
7.
Zhonghua Yan Ke Za Zhi ; 60(6): 547-558, 2024 Jun 11.
Artigo em Chinês | MEDLINE | ID: mdl-38825955

RESUMO

With the increasing prevalence of myopia among adolescents, the pathogenesis of this condition has garnered significant attention. Studies have discovered the expression of various hormone receptors in ocular tissues of both animals and humans. Additionally, changes in hormone levels accompany the development of myopia, although the exact relationships remain inconclusive. This article reviews the potential influences and mechanisms of action of endogenous hormones such as melatonin, serotonin, insulin, glucagon, sex hormones, vitamin D, and prostaglandins in ocular tissues including the retina, choroid, and sclera. It elaborates on the relationship between fluctuations in these hormone levels and the progression of myopia, aiming to provide guidance for exploring targets for myopia prevention and control.


Assuntos
Melatonina , Miopia , Humanos , Miopia/metabolismo , Melatonina/metabolismo , Vitamina D/metabolismo , Serotonina/metabolismo , Insulina/metabolismo , Glucagon/metabolismo , Animais , Hormônios Esteroides Gonadais/metabolismo , Prostaglandinas/metabolismo , Hormônios/metabolismo , Retina/metabolismo
8.
J Cell Biol ; 223(9)2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-38856684

RESUMO

Sonic Hedgehog (SHH) is a driver of embryonic patterning that, when corrupted, triggers developmental disorders and cancers. SHH effector responses are organized through primary cilia (PC) that grow and retract with the cell cycle and in response to extracellular cues. Disruption of PC homeostasis corrupts SHH regulation, placing significant pressure on the pathway to maintain ciliary fitness. Mechanisms by which ciliary robustness is ensured in SHH-stimulated cells are not yet known. Herein, we reveal a crosstalk circuit induced by SHH activation of Phospholipase A2α that drives ciliary E-type prostanoid receptor 4 (EP4) signaling to ensure PC function and stabilize ciliary length. We demonstrate that blockade of SHH-EP4 crosstalk destabilizes PC cyclic AMP (cAMP) equilibrium, slows ciliary transport, reduces ciliary length, and attenuates SHH pathway induction. Accordingly, Ep4-/- mice display shortened neuroepithelial PC and altered SHH-dependent neuronal cell fate specification. Thus, SHH initiates coordination between distinct ciliary receptors to maintain PC function and length homeostasis for robust downstream signaling.


Assuntos
Cílios , Proteínas Hedgehog , Prostaglandinas , Transdução de Sinais , Animais , Camundongos , Cílios/metabolismo , AMP Cíclico/metabolismo , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Camundongos Knockout , Prostaglandinas/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Receptores de Prostaglandina E Subtipo EP4/genética
9.
Clin Immunol ; 265: 110298, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38909972

RESUMO

Prostaglandins (PGs) play a crucial and multifaceted role in various physiological processes such as intercellular signaling, inflammation regulation, neurotransmission, vasodilation, vasoconstriction, and reproductive functions. The diversity and biological significance of these effects are contingent upon the specific types or subtypes of PGs, with each PG playing a crucial role in distinct physiological and pathological processes. Particularly within the immune system, PGs are essential in modulating the function of immune cells and the magnitude and orientation of immune responses. Hence, a comprehensive comprehension of the functions PG signaling pathways in immunosuppressive regulation holds substantial clinical relevance for disease prevention and treatment strategies. The manuscript provides a review of recent developments in PG signaling in immunosuppressive regulation. Furthermore, the potential clinical applications of PGs in immunosuppression are also discussed. While research into the immunosuppressive effects of PGs required further exploration, targeted therapies against their immunosuppressive pathways might open new avenues for disease prevention and treatment.


Assuntos
Terapia de Imunossupressão , Prostaglandinas , Transdução de Sinais , Humanos , Prostaglandinas/imunologia , Prostaglandinas/metabolismo , Animais , Transdução de Sinais/imunologia , Tolerância Imunológica
10.
Reprod Domest Anim ; 59(6): e14651, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38923132

RESUMO

The efficiency of combining oestrous induction via a light program (16 h of light and 8 h of darkness for 60 days, ending on Day 0 - D0) with cloprostenol administration, followed by the male effect or not, was tested in acyclic Saanen goats during the non-breeding season (June/2019 to January/2020). Initially, all animals (males and females) were submitted to the described light program; 60 days after its ending (D60), the females were divided into two groups, with (G1; n = 67) or without (G2; n = 61) a male effect from D60 to D75 after the light program. At D75, both groups received two cloprostenol doses (120 µg; intramuscular) 7.5 days apart (D75 and D82.5). Artificial insemination was performed at a specific time according to the oestrous onset (approximately 68.4 ± 1.2 h between the second cloprostenol dose and IA). Ultrasound scans were performed at different intervals to evaluate follicular dynamics and confirm pregnancy. At the first cloprostenol dose (D75), the proportion of does with at least a corpus luteum (CL), which indicates resumed cyclicity, was greater in G1 than in G2 (85.2% vs. 48.8%; p < .05), although no difference was found at the second dose (p > .05). The adjusted pregnancy rates (number of pregnant goats/oestrous goats) differed between G1 and G2 (21.7% vs. 42.0%; p < .05). G1 also showed a higher frequency of functional CL (based on blood flow and morphology) compared to G2 (96.9% vs. 66.7%; p < .05) at D116. A male effect using photo-stimulated bucks after the first cloprostenol dose increased the number of does presenting CL after buck removal, and no impairment in the pregnancy rates of multiparous does was found.


Assuntos
Cloprostenol , Sincronização do Estro , Cabras , Inseminação Artificial , Estações do Ano , Animais , Cabras/fisiologia , Feminino , Masculino , Cloprostenol/farmacologia , Cloprostenol/administração & dosagem , Gravidez , Inseminação Artificial/veterinária , Prostaglandinas , Fotoperíodo , Reprodução/fisiologia , Reprodução/efeitos dos fármacos
11.
Arch Dermatol Res ; 316(6): 312, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38822924

RESUMO

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with high rates of metastasis and mortality. In vitro studies suggest that selinexor (KPT-330), an inhibitor of exportin 1, may be a targeted therapeutic option for MCC. This selective inhibitor prevents the transport of oncogenic mRNA out of the nucleus. Of note, 80% of MCC tumors are integrated with Merkel cell polyomavirus (MCPyV), and virally encoded tumor-antigens, small T (sT) and large T (LT) mRNAs may require an exportin transporter to relocate to the cytoplasm and modulate host tumor-suppressing pathways. To explore selinexor as a targeted therapy for MCC, we examine its ability to inhibit LT and sT antigen expression in vitro and its impact on the prostaglandin synthesis pathway. Protein expression was determined through immunoblotting and quantified by densitometric analysis. Statistical significance was determined with t-test. Treatment of MCPyV-infected cell lines with selinexor resulted in a significant dose-dependent downregulation of key mediators of the prostaglandin synthesis pathway. Given the role of prostaglandin synthesis pathway in MCC, our findings suggest that selinexor, alone or in combination with immunotherapy, could be a promising treatment for MCPyV-infected MCC patients who are resistant to chemotherapy and immunotherapy.


Assuntos
Carcinoma de Célula de Merkel , Hidrazinas , Neoplasias Cutâneas , Triazóis , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Humanos , Carcinoma de Célula de Merkel/virologia , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/patologia , Triazóis/farmacologia , Triazóis/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/patologia , Linhagem Celular Tumoral , Prostaglandinas/metabolismo , Poliomavírus das Células de Merkel , Proteína Exportina 1 , Carioferinas/metabolismo , Carioferinas/antagonistas & inibidores , Antígenos Virais de Tumores , Receptores Citoplasmáticos e Nucleares/metabolismo
12.
J Lipid Res ; 65(7): 100583, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38909689

RESUMO

Dramatic postmortem prostanoid (PG) enzymatic synthesis in the brain causes a significant artifact during PG analysis. Thus, enzyme deactivation is required for an accurate in situ endogenous PG quantification. To date, the only method for preventing postmortem brain PG increase with tissue structure preservation is fixation by head-focused microwave irradiation (MW), which is considered the gold standard method, allowing for rapid in situ heat-denaturation of enzymes. However, MW requires costly equipment that suffers in reproducibility, causing tissue loss and metabolite degradation if overheated. Our recent study indicates that PGs are not synthesized in the ischemic brain unless metabolically active tissue is exposed to atmospheric O2. Based on this finding, we proposed a simple and reproducible alternative method to prevent postmortem PG increase by slow enzyme denaturation before craniotomy. To test this approach, mice were decapitated directly into boiling saline. Brain temperature reached 100°C after ∼140 s during boiling, though 3 min boiling was required to completely prevent postmortem PG synthesis, but not free arachidonic acid release. To validate this fixation method, brain basal and lipopolysaccharide (LPS)-induced PG were analyzed in unfixed, MW, and boiled tissues. Basal and LPS-induced PG levels were not different between MW and boiled brains. However, unfixed tissue showed a significant postmortem increase in PG at basal conditions, with lesser differences upon LPS treatment compared to fixed tissue. These data indicate for the first time that boiling effectively prevents postmortem PG alterations, allowing for a reproducible, inexpensive, and conventionally accessible tissue fixation method for PG analysis.


Assuntos
Encéfalo , Prostaglandinas , Animais , Camundongos , Prostaglandinas/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Mudanças Depois da Morte , Masculino , Camundongos Endogâmicos C57BL , Lipopolissacarídeos/farmacologia , Micro-Ondas
13.
Mar Drugs ; 22(5)2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38786610

RESUMO

Octocoral of the genus Clavularia is a kind of marine invertebrate possessing abundant cytotoxic secondary metabolites, such as prostanoids and dolabellanes. In our continuous natural product study of C. spp., two previously undescribed prostanoids [clavulone I-15-one (1) and 12-O-deacetylclavulone I (2)] and eleven known analogs (3-13) were identified. The structures of these new compounds were elucidated based on analysis of their 1D and 2D NMR, HRESIMS, and IR data. Additionally, all tested prostanoids (1 and 3-13) showed potent cytotoxic activities against the human oral cancer cell line (Ca9-22). The major compound 3 showed cytotoxic activity against the Ca9-22 cells with the IC50 value of 2.11 ± 0.03 µg/mL, which echoes the cytotoxic effect of the coral extract. In addition, in silico tools were used to predict the possible effects of isolated compounds on human tumor cell lines and nitric oxide production, as well as the pharmacological potentials.


Assuntos
Antozoários , Antineoplásicos , Prostaglandinas , Humanos , Antozoários/química , Animais , Linhagem Celular Tumoral , Prostaglandinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Óxido Nítrico/metabolismo , Concentração Inibidora 50 , Organismos Aquáticos , Estrutura Molecular
14.
Sci Signal ; 17(835): eadq1964, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38713766

RESUMO

Prostaglandins in the tumor microenvironment block IL-2-induced expansion of killer T cells.


Assuntos
Interleucina-2 , Microambiente Tumoral , Interleucina-2/imunologia , Interleucina-2/metabolismo , Humanos , Microambiente Tumoral/imunologia , Animais , Neoplasias/imunologia , Neoplasias/metabolismo , Prostaglandinas/metabolismo
15.
Am J Physiol Regul Integr Comp Physiol ; 327(1): R97-R108, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38780425

RESUMO

The transitional epithelial cells (urothelium) that line the lumen of the urinary bladder form a barrier between potentially harmful pathogens, toxins, and other bladder contents and the inner layers of the bladder wall. The urothelium, however, is not simply a passive barrier, as it can produce signaling factors, such as ATP, nitric oxide, prostaglandins, and other prostanoids, that can modulate bladder function. We investigated whether substances produced by the urothelium could directly modulate the contractility of the underlying urinary bladder smooth muscle. Force was measured in isolated strips of mouse urinary bladder with the urothelium intact or denuded. Bladder strips developed spontaneous tone and phasic contractions. In urothelium-intact strips, basal tone, as well as the frequency and amplitude of phasic contractions, were 25%, 32%, and 338% higher than in urothelium-denuded strips, respectively. Basal tone and phasic contractility in urothelium-intact bladder strips were abolished by the cyclooxygenase (COX) inhibitor indomethacin (10 µM) or the voltage-dependent Ca2+ channel blocker diltiazem (50 µM), whereas blocking neuronal sodium channels with tetrodotoxin (1 µM) had no effect. These results suggest that prostanoids produced in the urothelium enhance smooth muscle tone and phasic contractions by activating voltage-dependent Ca2+ channels in the underlying bladder smooth muscle. We went on to demonstrate that blocking COX inhibits the generation of transient pressure events in isolated pressurized bladders and greatly attenuates the afferent nerve activity during bladder filling, suggesting that urothelial prostanoids may also play a role in sensory nerve signaling.NEW & NOTEWORTHY This paper provides evidence for the role of urothelial-derived prostanoids in maintaining tone in the urinary bladder during bladder filling, not only underscoring the role of the urothelium as more than a barrier but also contributing to active regulation of the urinary bladder. Furthermore, cyclooxygenase products greatly augment sensory nerve activity generated by bladder afferents during bladder filling and thus may play a role in perception of bladder fullness.


Assuntos
Camundongos Endogâmicos C57BL , Contração Muscular , Músculo Liso , Prostaglandinas , Bexiga Urinária , Urotélio , Animais , Bexiga Urinária/inervação , Bexiga Urinária/fisiologia , Bexiga Urinária/efeitos dos fármacos , Urotélio/inervação , Urotélio/efeitos dos fármacos , Urotélio/metabolismo , Urotélio/fisiologia , Contração Muscular/efeitos dos fármacos , Prostaglandinas/metabolismo , Músculo Liso/efeitos dos fármacos , Músculo Liso/inervação , Músculo Liso/fisiologia , Músculo Liso/metabolismo , Camundongos , Masculino , Neurônios Aferentes/fisiologia , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Feminino
16.
Nat Commun ; 15(1): 4326, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773113

RESUMO

Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury.


Assuntos
Macrófagos , Pneumonia Pneumocócica , Streptococcus pneumoniae , Masculino , Camundongos , Dinoprostona/antagonistas & inibidores , Dinoprostona/metabolismo , Fibrose , Inflamação/imunologia , Inflamação/patologia , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Linfócitos/citologia , Linfócitos/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos Alveolares/citologia , Macrófagos Alveolares/imunologia , Camundongos Endogâmicos C57BL , Fagócitos/citologia , Fagócitos/imunologia , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/patologia , Prostaglandinas/biossíntese , Quinolinas/administração & dosagem , Streptococcus pneumoniae/fisiologia , Sulfonamidas/administração & dosagem , Linfócitos T/citologia , Linfócitos T/imunologia , Transcriptoma , Animais
17.
Prostaglandins Other Lipid Mediat ; 172: 106836, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38599513

RESUMO

Dravet syndrome is an intractable epilepsy with a high seizure burden that is resistant to current anti-seizure medications. There is evidence that neuroinflammation plays a role in epilepsy and seizures, however few studies have specifically examined neuroinflammation in Dravet syndrome under conditions of a higher seizure burden. Here we used an established genetic mouse model of Dravet syndrome (Scn1a+/- mice), to examine whether a higher seizure burden impacts the number and morphology of microglia in the hippocampus. Moreover, we examined whether a high seizure burden influences classical inflammatory mediators in this brain region. Scn1a+/- mice with a high seizure burden induced by thermal priming displayed a localised reduction in microglial cell density in the granule cell layer and subgranular zone of the dentate gyrus, regions important to postnatal neurogenesis. However, microglial cell number and morphology remained unchanged in other hippocampal subfields. The high seizure burden in Scn1a+/- mice did not affect hippocampal mRNA expression of classical inflammatory mediators such as interleukin 1ß and tumour necrosis factor α, but increased cyclooxygenase 2 (COX-2) expression. We then quantified hippocampal levels of prostanoids that arise from COX-2 mediated metabolism of fatty acids and found that Scn1a+/- mice with a high seizure burden displayed increased hippocampal concentrations of numerous prostaglandins, notably PGF2α, PGE2, PGD2, and 6-K-PGF1A, compared to Scn1a+/- mice with a low seizure burden. In conclusion, a high seizure burden increased hippocampal concentrations of various prostaglandin mediators in a mouse model of Dravet syndrome. Future studies could interrogate the prostaglandin pathways to further better understand their role in the pathophysiology of Dravet syndrome.


Assuntos
Modelos Animais de Doenças , Epilepsias Mioclônicas , Hipocampo , Canal de Sódio Disparado por Voltagem NAV1.1 , Prostaglandinas , Convulsões , Animais , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/metabolismo , Epilepsias Mioclônicas/patologia , Camundongos , Hipocampo/metabolismo , Hipocampo/patologia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Convulsões/metabolismo , Convulsões/genética , Convulsões/patologia , Prostaglandinas/metabolismo , Masculino , Microglia/metabolismo , Microglia/patologia
19.
Sci Adv ; 10(14): eadj7666, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38569041

RESUMO

Inflammation-associated fibroblasts (IAFs) are associated with progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial cells is unknown. Here, we developed an in vitro model whereby human colon fibroblasts are induced by specific cytokines and recapitulate key features of IAFs in vivo. When cocultured with patient-derived colon organoids (colonoids), IAFs induced rapid colonoid expansion and barrier disruption due to swelling and rupture of individual epithelial cells. Colonoids cocultured with IAFs also show increased DNA damage, mitotic errors, and proliferation arrest. These IAF-induced epithelial defects are mediated by a paracrine pathway involving prostaglandin E2 and its receptor EP4, leading to protein kinase A -dependent activation of the cystic fibrosis transmembrane conductance regulator. EP4-specific chemical inhibitors effectively prevented IAF-induced colonoid swelling and restored normal proliferation and genome stability. These findings reveal a mechanism by which IAFs could promote and perpetuate IBD and suggest a therapeutic avenue to mitigate inflammation-associated epithelial injury.


Assuntos
Doenças Inflamatórias Intestinais , Prostaglandinas , Humanos , Epitélio/metabolismo , Inflamação , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Fibroblastos/metabolismo
20.
Cell Tissue Res ; 396(2): 231-243, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38438567

RESUMO

C-C motif chemokine ligand 2 (CCL2) has been reported to be expressed in the bovine endometrium during pregnancy. However, the details of its functions involved in the implantation mechanism are still not clear. The purpose of this study is to analyze the functional properties of CCL2 in the bovine endometrium and embryos. The expression of CCR2 was not different between the luteal phase and implantation phase of their endometrial tissues, but was significantly high in IFNa treated bovine endometrial stromal (BES) cells in vitro. The expressions of PGES1, PGES2, AKR1C4, and AKR1C4 were high at the implantation stage compared with the luteal stage. On the other hand, PGES2 and AKR1B1 in BEE and PGES3 and AKR1A1 in BES were significantly increased by CCL2 treatment, respectively. The expressions of PCNA and IFNt were found significantly high in the bovine trophoblastic cells (BT) treated with CCL2 compared to the control. CCL2 significantly increased the attachment rate of BT vesicles to BEE in in vitro co-culture system. The expression of OPN and ICAM-1 increased in BEE, and ICAM-1 increased in BT by CCL2 treatment, respectively. The present results indicate that CCL2 has the potential to regulate the synthesis of PGs in the endometrium and the embryo growth. In addition, CCL2 has the possibility to regulate the process of bovine embryo attachment to the endometrium by modulation of binding molecules expression.


Assuntos
Quimiocina CCL2 , Implantação do Embrião , Endométrio , Prostaglandinas , Animais , Bovinos , Feminino , Gravidez , Quimiocina CCL2/metabolismo , Implantação do Embrião/genética , Endométrio/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interferon Tipo I , Proteínas da Gravidez , Prostaglandinas/metabolismo , Receptores CCR2/metabolismo , Células Estromais/metabolismo , Trofoblastos/metabolismo , Trofoblastos/citologia
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