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1.
Ceska Gynekol ; 86(5): 349-354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34736335

RESUMO

OBJECTIVE: In this paper, we summarize the role of the endocannabinoid system in relation to pregnancy and childbirth and its potential for dia-gnosis of preterm birth. METHODS: Review of articles in peer-reviewed journals using the PubMed database. RESULTS: Endocannabinoid system plays a significant role in embryo development, transport and implantation as well as in placentation. It consists of numerous endogenous ligands; however, in relation to pregnancy there are mainly two studied representatives: anandamide and 2-arachidonoylglycerol. There is increasing evidence, in addition to early pregnancy events, that anandamide plays a regulatory role in pregnancy maintenance and the timing of labour. The activity of anandamide depends on its metabolic pathway and the enzymatic activity that ensures its conversion. Ultimately, changes in anandamide concentration lead to increased production of prostaglandins or prostamides, with inverse effects on pregnancy. The abuse of exogenous cannabinoids in pregnancy has substantial impact on the unborn child in many ways and may result in detrimental effects including preterm birth. CONCLUSION: Measuring anandamide concentration and the prostaglandin to prostamide ratio could be a useful tool in assessing the risk of preterm birth.


Assuntos
Endocanabinoides , Nascimento Prematuro , Adulto , Implantação do Embrião , Feminino , Humanos , Recém-Nascido , Gravidez , Prostaglandinas
2.
J Immunol ; 207(10): 2561-2569, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34635585

RESUMO

PGs are important proinflammatory lipid mediators, the significance of which is highlighted by the widespread and efficacious use of nonsteroidal anti-inflammatory drugs in the treatment of inflammation. 4-Octyl itaconate (4-OI), a derivative of the Krebs cycle-derived metabolite itaconate, has recently garnered much interest as an anti-inflammatory agent. In this article, we show that 4-OI limits PG production in murine macrophages stimulated with the TLR1/2 ligand Pam3CSK4. This decrease in PG secretion is due to a robust suppression of cyclooxygenase 2 (COX2) expression by 4-OI, with both mRNA and protein levels decreased. Dimethyl fumarate, a fumarate derivative used in the treatment of multiple sclerosis, with properties similar to itaconate, replicated the phenotype observed with 4-OI. We also demonstrate that the decrease in COX2 expression and inhibition of downstream PG production occurs in an NRF2-independent manner. Our findings provide a new insight into the potential of 4-OI as an anti-inflammatory agent and also identifies a novel anti-inflammatory function of dimethyl fumarate.


Assuntos
Anti-Inflamatórios/farmacologia , Fumarato de Dimetilo/farmacologia , Macrófagos/efeitos dos fármacos , Prostaglandinas/metabolismo , Succinatos/farmacologia , Animais , Ciclo-Oxigenase 2/biossíntese , Humanos , Macrófagos/metabolismo , Camundongos
3.
J Immunol ; 207(10): 2551-2560, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34635586

RESUMO

The protozoan parasite Trypanosoma brucei is the causative agent of the neglected tropical disease human African trypanosomiasis, otherwise known as sleeping sickness. Trypanosomes have evolved many immune-evasion mechanisms to facilitate their own survival, as well as prolonging host survival to ensure completion of the parasitic life cycle. A key feature of the bloodstream form of T. brucei is the secretion of aromatic keto acids, which are metabolized from tryptophan. In this study, we describe an immunomodulatory role for one of these keto acids, indole-3-pyruvate (I3P). We demonstrate that I3P inhibits the production of PGs in activated macrophages. We also show that, despite the reduction in downstream PGs, I3P augments the expression of cyclooxygenase (COX2). This increase in COX2 expression is mediated in part via inhibition of PGs relieving a negative-feedback loop on COX2. Activation of the aryl hydrocarbon receptor also participates in this effect. However, the increase in COX2 expression is of little functionality, as we also provide evidence to suggest that I3P targets COX activity. This study therefore details an evasion strategy by which a trypanosome-secreted metabolite potently inhibits macrophage-derived PGs, which might promote host and trypanosome survival.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Indóis/metabolismo , Macrófagos/imunologia , Prostaglandinas/metabolismo , Tripanossomíase Africana/imunologia , Animais , Humanos , Evasão da Resposta Imune/imunologia , Indóis/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Prostaglandinas/imunologia , Trypanosoma brucei brucei/imunologia , Trypanosoma brucei brucei/metabolismo , Tripanossomíase Africana/metabolismo
4.
FASEB J ; 35(11): e21949, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34591339

RESUMO

Atopic dermatitis (AD) is the most common inflammatory skin disease in children. The serum level of thymus and activation-regulated chemokine (TARC) is a useful AD index to reflect disease severity; however, it requires blood collection from young children. In comparison, urine samples are easier to collect in a pediatric clinical setting. Here, we analyzed the lipids excreted in urine to identify a diagnostic biomarker for AD. We generated a murine dermatitis model by repeated topical application of 2,4-dinitrofluorobenzene (DNFB) or tape-stripping the dorsal skin. Lipid metabolites excreted in the urine were comprehensively analyzed using liquid chromatography-tandem mass spectrometry. To corroborate our findings, we also analyzed urine samples from patients with AD. DNFB application induced AD-like skin lesions, including epidermal thickening, infiltration of eosinophils and T cells, and an increase in Th2 cytokine levels. Assessment of lipids excreted in urine showed a dominance of prostaglandins (PGs), namely, a PGF2α metabolite (13,14-dihydro-15-keto-tetranor-PGF1α ), a PGE2 metabolite (13,14-dihydro-15-keto-tetranor-PGE2 ), and a PGD2 metabolite (13,14-dihydro-15-keto PGJ2 ). mRNA and protein expression of PGF2α , PGE2 , and PGD2 synthase was upregulated in DNFB-treated skin. The tape-stripping model also caused dermatitis but without Th2 inflammation; urine PGF2α and PGD2 metabolite levels remained unaffected. Finally, we confirmed that the urinary levels of the aforementioned PG metabolites, as well as PGI2 metabolite, 6,15-diketo-13,14-dihydro-PGF1α and arachidonic acid metabolite, 17-hydroxyeicosatetraenoic acid (17-HETE) increased in patients with AD. Our data highlights the unique urinary lipid profile in patients with AD, which may provide insight into novel urinary biomarkers for AD diagnosis.


Assuntos
Dermatite Atópica/diagnóstico , Dermatite Atópica/urina , Prostaglandinas/urina , Índice de Gravidade de Doença , Administração Cutânea , Animais , Biomarcadores/urina , Criança , Pré-Escolar , Cromatografia Líquida/métodos , Dermatite Atópica/induzido quimicamente , Dinitrofluorbenzeno/administração & dosagem , Dinitrofluorbenzeno/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pele/efeitos dos fármacos , Pele/metabolismo , Espectrometria de Massas em Tandem/métodos
5.
ACS Chem Biol ; 16(9): 1663-1670, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34478263

RESUMO

Many pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) and lipoteichoic acid, are potent immunostimulatory molecules and promote the expression of cyclooxygenase 2 (COX-2). While the production of COX-2, and ultimately prostaglandin E2, could be protective, persistent induction of COX-2 leads to inflamed environments that can result in septic shock and death. Bacterial derived cyclic dinucleotides (CDNs), c-di-GMP and c-di-AMP, are also PAMPs and have been shown to produce inflamed environments via the production of pro-inflammatory cytokines such as type I interferons. The well-characterized CDN immunostimulatory mechanism involves binding to stimulator of interferon genes (STING), which ultimately results in the phosphorylation of IRF3 or release of NF-κB to promote expression of type I IFN or pro-inflammatory cytokines. In this study, we sought to investigate if CDNs promote COX-2 expression. Using RAW macrophages as a model system, we reveal that c-di-GMP, but not c-di-AMP or the host-derived 2',3'-cGAMP, promotes COX-2 expression. Using analogues of CDNs, we show that the presence of two guanines and two 3',5'-phosphodiester linkages are requirements for the promotion of COX-2 expression by cyclic dinucleotides. Both c-di-GMP and LPS inductions of COX-2 expression in RAW macrophages are STING-independent and are regulated by Tpl2-MEK-ERK-CREB signaling; inhibitors of Tpl2, MEK, and ERK could attenuate COX-2 expression promoted by c-di-GMP. This work adds to the growing body of evidence that cyclic dinucleotides regulate pathways other than the STING-TBK1-IRF3 axis. Additionally, the differential COX-2 induction by c-di-GMP but not c-di-AMP or cGAMP suggests that the type and level of inflammation could be dictated by the nucleotide signature of the invading pathogen.


Assuntos
GMP Cíclico/análogos & derivados , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Macrófagos/metabolismo , Animais , Proteína Beclina-1/metabolismo , Linhagem Celular , GMP Cíclico/metabolismo , Fosfatos de Dinucleosídeos/metabolismo , Regulação da Expressão Gênica , Guanina/metabolismo , Imunidade Inata , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Camundongos , NF-kappa B/metabolismo , Oligonucleotídeos/metabolismo , Fosforilação , Prostaglandinas/metabolismo , Transdução de Sinais
6.
FASEB J ; 35(9): e21877, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34449098

RESUMO

Although commonly thought to produce prostacyclin (prostaglandin I2 ; PGI2 ) that evokes vasodilatation and protects vessels from the development of diseases, the endothelial cyclooxygenase (COX)-mediated metabolism has also been found to release substance(s) called endothelium-derived contracting factor(s) (EDCF) that causes endothelium-dependent contraction and implicates in endothelial dysfunction of disease conditions. Various mechanisms have been proposed for the process; however, the major endothelial COX metabolite PGI2 , which has been classically considered to activate the I prostanoid receptor (IP) that mediates vasodilatation and opposes the effects of thromboxane (Tx) A2 produced by COX in platelets, emerges as a major EDCF in health and disease conditions. Our recent studies from genetically altered mice further suggest that vasomotor reactions to PGI2 are collectively modulated by IP, the vasoconstrictor Tx-prostanoid receptor (TP; the prototype receptor of TxA2 ) and E prostanoid receptor-3 (EP3; a vasoconstrictor receptor of PGE2 ) although with differences in potency and efficacy; a contraction to PGI2 reflects activities of TP and/or EP3 outweighing that of the concurrently activated IP. Here, we discuss the history of endothelium-dependent contraction, evidences that support the above hypothesis, proposed mechanisms for the varied reactions to endothelial PGI2 synthesis as well as the relation of its dilator activity to the effect of another NO-independent vasodilator mechanism, the endothelium-derived hyperpolarizing factor. Also, we address the possible pathological and therapeutic implications as well as questions remaining to be resolved or limitations of our above findings obtained from genetically altered mouse models.


Assuntos
Endotélio Vascular/metabolismo , Epoprostenol/metabolismo , Vasoconstrição/fisiologia , Animais , Endotélio Vascular/efeitos dos fármacos , Humanos , Camundongos , Prostaglandinas/metabolismo , Receptores de Prostaglandina/metabolismo , Receptores de Tromboxanos/metabolismo , Tromboxanos/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/metabolismo
7.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360975

RESUMO

Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, ferroptosis and pyroptosis, is induced during the acute phase of liver IRI. The release of danger-associated molecular patterns (DAPMs) and mitochondrial dysfunction resulting from the disturbance of metabolic homeostasis initiates graft inflammation. The inflammation in the short term exacerbates hepatic damage, leading to graft dysfunction and a higher incidence of acute rejection. The subsequent changes in the graft immune environment due to hepatic IRI may result in chronic rejection, cancer recurrence and fibrogenesis in the long term. In this review, we mainly focus on new mechanisms of inflammation initiated by immune activation related to metabolic alteration in the short term during liver IRI. The latest mechanisms of cancer recurrence and fibrogenesis due to the long-term impact of inflammation in hepatic IRI is also discussed. Furthermore, the development of therapeutic strategies, including ischemia preconditioning, pharmacological inhibitors and machine perfusion, for both attenuating acute inflammatory injury and preventing late-phase disease recurrence, will be summarized in the context of clinical, translational and basic research.


Assuntos
Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/metabolismo , Disfunção Primária do Enxerto/metabolismo , Animais , Humanos , Precondicionamento Isquêmico/métodos , Fígado/irrigação sanguínea , Fígado/metabolismo , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/terapia , Disfunção Primária do Enxerto/tratamento farmacológico , Disfunção Primária do Enxerto/terapia , Prostaglandinas/uso terapêutico
8.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445711

RESUMO

Angioedema is a life-threatening emergency event that is associated with bradykinin and histamine-mediated cascades. Although bradykinin-mediated angioedema currently has specific therapeutic options, angioedema is sometimes intractable with current treatments, especially histamine-mediated angioedema, suggesting that some other mediators might contribute to the development of angioedema. Fatty acids are an essential fuel and cell component, and act as a mediator in physiological and pathological human diseases. Recent updates of studies revealed that these fatty acids are involved in vascular permeability and vasodilation, in addition to bradykinin and histamine-mediated reactions. This review summarizes each fatty acid's function and the specific receptor signaling responses in blood vessels, and focuses on the possible pathogenetic role of fatty acids in angioedema.


Assuntos
Angioedema/tratamento farmacológico , Angioedema/fisiopatologia , Ácidos Graxos/uso terapêutico , Angioedema/metabolismo , Bradicinina/metabolismo , Permeabilidade Capilar , Ácidos Graxos/metabolismo , Ácidos Graxos/fisiologia , Histamina/metabolismo , Humanos , Prostaglandinas/metabolismo , Prostaglandinas/fisiologia
9.
J Vet Med Sci ; 83(9): 1443-1447, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34334510

RESUMO

We determined a comprehensive immunohistochemistry of putative isoforms of enzymes for prostaglandin (PG) F2α and PGE2 biosynthesis and these PGs levels in placenta and fetal membrane of normal pregnant rats in vivo. Placenta and fetal membrane showed positive immunoreactions for phospholipase A2 group 4A, but not group 2A, and cyclooxygenase (COX)-1 rather than COX-2. They showed positive immunoreactions for at least one isoform of each of PGF synthase and PGE synthase with tissue-dependent variations. PGF2α and PGE2 levels in both tissues were highest on day 12 and declined and remained low thereafter. Obtained data would be the basic information on the primary PGs synthesis in rat placenta and fetal membrane in normal pregnancy.


Assuntos
Dinoprosta , Prostaglandinas F , Animais , Ciclo-Oxigenase 2 , Membranas Extraembrionárias , Feminino , Imuno-Histoquímica , Placenta , Gravidez , Prostaglandinas , Ratos
10.
Rev Med Interne ; 42(12): 825-831, 2021 Dec.
Artigo em Francês | MEDLINE | ID: mdl-34462153

RESUMO

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue disease (CTD). Data on use of prostanoids in this particular subset of patients are lacking. We aimed to describe the characteristics of patients with PAH-CTD treated with prostanoids and the outcomes under treatment. METHODS: In this multicenter retrospective study, all patients treated with prostanoids since 2006 were included. Data on PAH and CTD were collected at the time of prostanoid introduction and under treatment. RESULTS: Twenty-one patients were included, of whom 20 (95%) had limited cutaneous systemic sclerosis. Nineteen patients were treated with oral monotherapy or combination before addition of prostanoid. Treprostinil was the most used molecule (57% of patients). At the time of prostanoid introduction, 90% of patients were considered at high risk for death. Among patients who had right heart catheterization during follow-up, there was no significant difference in haemodynamics. No extrarespiratory worsening of the CTD was reported. The 1-year survival under prostanoid was 62%. In univariate analysis, NYHA functional class was associated with survival under treatment. CONCLUSION: This study provides original data on use of prostanoids in a cohort consisting mainly of systemic sclerosis. It underlines the difficulty to achieve a standardized assessment in this subset of patients. Safety profile was comparable with data reported in idiopathic PAH.


Assuntos
Doenças do Tecido Conjuntivo , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/tratamento farmacológico , Doenças do Tecido Conjuntivo/epidemiologia , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/etiologia , Prostaglandinas , Estudos Retrospectivos
11.
Jpn J Ophthalmol ; 65(5): 591-597, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34283308

RESUMO

PURPOSE: To examine the effect of switching from a prostanoid FP receptor agonists to EP2 receptor agonist (omidenepag isopropyl) on the deepening of the upper eyelid sulcus (DUES) and intraocular pressure (IOP) in Japanese glaucoma patients over 3 months post treatment. STUDY DESIGN: Prospective observational study. METHODS: Patients with glaucoma who received FP receptor agonists treatment and had complained of DUES-related reduction in quality of life were included. Their FP receptor agonists was switched to omidenepag isopropyl without a drug holiday. At baseline and 1 and 3 months post-switch, photographs were taken and the changes in DUES were assessed by three independent observers. IOP and adverse events were also assessed. RESULTS: The study included 23 eyes of 23 patients (6 men, 17 women; average age, 60.6 years). After switching, DUES improved in 12 eyes at 1 month and in 16 eyes at 3 months; eyes in the remaining patients showed no worsening of the condition. The mean IOP before switching was 15.3 ± 3.3 mmHg (95% confidence interval 13.9-16.7 mmHg). Following the switch, the mean IOP values were 15.6 ± 3.3 mmHg (14.1-17.0 mmHg) at 1 month and 15.5 ± 3.3 mmHg (14.1-16.9 mmHg) at 3 months (P = 1.0 at 1 month, P = 1.0 at 3 months; both adjusted by Bonferroni correction). No adverse effects were observed. CONCLUSION: Omidenepag isopropyl improved DUES while maintaining IOP in over 70% of Japanese patients with glaucoma who exhibited DUES caused by FP receptor agonists; the improvement was observed within 3 months after switching from FP receptor agonists.


Assuntos
Glaucoma de Ângulo Aberto , Qualidade de Vida , Anti-Hipertensivos/uso terapêutico , Pálpebras , Feminino , Glaucoma de Ângulo Aberto/diagnóstico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas , Prostaglandinas , Receptores de Prostaglandina
14.
Cells ; 10(6)2021 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199169

RESUMO

The prostaglandins constitute a family of lipids of 20 carbon atoms that derive from polyunsaturated fatty acids such as arachidonic acid. Traditionally, prostaglandins have been linked to inflammation, female reproductive cycle, vasodilation, or bronchodilator/bronchoconstriction. Recent studies have highlighted the involvement of these lipids in cancer. In this review, existing information on the prostaglandins associated with different types of cancer and the advances related to the potential use of them in neoplasm therapies have been analyzed. We can conclude that the effect of prostaglandins depends on multiple factors, such as the target tissue, their plasma concentration, and the prostaglandin subtype, among others. Prostaglandin D2 (PGD2) seems to hinder tumor progression, while prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2α) seem to provide greater tumor progression and aggressiveness. However, more studies are needed to determine the role of prostaglandin I2 (PGI2) and prostaglandin J2 (PGJ2) in cancer due to the conflicting data obtained. On the other hand, the use of different NSAIDs (non-steroidal anti-inflammatory drugs), especially those selective of COX-2 (cyclooxygenase 2), could have a crucial role in the fight against different neoplasms, either as prophylaxis or as an adjuvant treatment. In addition, multiple targets, related to the action of prostaglandins on the intracellular signaling pathways that are involved in cancer, have been discovered. Thus, in depth research about the prostaglandins involved in different cancer and the different targets modulated by them, as well as their role in the tumor microenvironment and the immune response, is necessary to obtain better therapeutic tools to fight cancer.


Assuntos
Quimioterapia Adjuvante , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Prostaglandinas/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos
15.
Nat Commun ; 12(1): 3296, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075043

RESUMO

Zinc, an abundant transition metal, serves as a signalling molecule in several biological systems. Zinc transporters are genetically associated with cardiovascular diseases but the function of zinc in vascular tone regulation is unknown. We found that elevating cytoplasmic zinc using ionophores relaxed rat and human isolated blood vessels and caused hyperpolarization of smooth muscle membrane. Furthermore, zinc ionophores lowered blood pressure in anaesthetized rats and increased blood flow without affecting heart rate. Conversely, intracellular zinc chelation induced contraction of selected vessels from rats and humans and depolarized vascular smooth muscle membrane potential. We demonstrate three mechanisms for zinc-induced vasorelaxation: (1) activation of transient receptor potential ankyrin 1 to increase calcitonin gene-related peptide signalling from perivascular sensory nerves; (2) enhancement of cyclooxygenase-sensitive vasodilatory prostanoid signalling in the endothelium; and (3) inhibition of voltage-gated calcium channels in the smooth muscle. These data introduce zinc as a new target for vascular therapeutics.


Assuntos
Endotélio Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Células Receptoras Sensoriais/metabolismo , Vasodilatação/fisiologia , Zinco/metabolismo , Idoso , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Canais de Cálcio Tipo N/metabolismo , Quelantes/farmacologia , Citoplasma/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/inervação , Etilenodiaminas/farmacologia , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/efeitos dos fármacos , Técnicas de Patch-Clamp , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/metabolismo , Ratos , Canal de Cátion TRPA1/genética , Canal de Cátion TRPA1/metabolismo , Vasodilatação/efeitos dos fármacos
16.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069086

RESUMO

Hydrogen sulfide (H2S) is an endogenously produced molecule with anti-inflammatory and cytoprotective properties. We aimed to investigate for the first time if a novel, esterase-sensitive H2S-prodrug, BW-HS-101 with the ability to release H2S in a controllable manner, prevents gastric mucosa against acetylsalicylic acid-induced gastropathy on microscopic and molecular levels. Wistar rats were pretreated intragastrically with vehicle, BW-HS-101 (0.5-50 µmol/kg) or its analogue without the ability to release H2S, BW-iHS-101 prior to ASA administration (125 mg/kg, intragastrically). BW-HS-101 was administered alone or in combination with nitroarginine (L-NNA, 20 mg/kg, intraperitoneally) or zinc protoporphyrin IX (10 mg/kg, intraperitoneally). Gastroprotective effects of BW-HS-101 were additionally evaluated against necrotic damage induced by intragastrical administration of 75% ethanol. Gastric mucosal damage was assessed microscopically, and gastric blood flow was determined by laser flowmetry. Gastric mucosal DNA oxidation and PGE2 concentration were assessed by ELISA. Serum and/or gastric protein concentrations of IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-13, VEGF, GM-CSF, IFN-γ, TNF-α, and EGF were determined by a microbeads/fluorescent-based multiplex assay. Changes in gastric mucosal iNOS, HMOX-1, SOCS3, IL1-R1, IL1-R2, TNF-R2, COX-1, and COX-2 mRNA were assessed by real-time PCR. BW-HS-101 or BW-iHS-101 applied at a dose of 50 µmol/kg protected gastric mucosa against ASA-induced gastric damage and prevented a decrease in the gastric blood flow level. H2S prodrug decreased DNA oxidation, systemic and gastric mucosal inflammation with accompanied upregulation of SOCS3, and EGF and HMOX-1 expression. Pharmacological inhibition of nitric oxide (NO) synthase but not carbon monoxide (CO)/heme oxygenase (HMOX) activity by L-NNA or ZnPP, respectively, reversed the gastroprotective effect of BW-HS-101. BW-HS-101 also protected against ethanol-induced gastric injury formation. We conclude that BW-HS-101, due to its ability to release H2S in a controllable manner, prevents gastric mucosa against drugs-induced gastropathy, inflammation and DNA oxidation, and upregulate gastric microcirculation. Gastroprotective effects of this H2S prodrug involves endogenous NO but not CO activity and could be mediated by cytoprotective and anti-inflammatory SOCS3 and EGF pathways.


Assuntos
Mucosa Gástrica/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacocinética , Substâncias Protetoras/farmacologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , DNA/metabolismo , Liberação Controlada de Fármacos , Etanol/toxicidade , Mucosa Gástrica/irrigação sanguínea , Mucosa Gástrica/patologia , Gastrite/induzido quimicamente , Gastrite/tratamento farmacológico , Gastrite/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Óxido Nítrico/metabolismo , Nitroarginina/administração & dosagem , Nitroarginina/farmacologia , Pró-Fármacos/farmacocinética , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/metabolismo , Substâncias Protetoras/administração & dosagem , Protoporfirinas/administração & dosagem , Protoporfirinas/farmacologia , Ratos Wistar
17.
FASEB J ; 35(7): e21718, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34105801

RESUMO

Acetaminophen, aspirin, and ibuprofen are mild analgesics commonly used by pregnant women, the sole current recommendation being to avoid ibuprofen from the fifth month of gestation. The nephrotoxicity of these three analgesics is well documented in adults, as is their interference with prostaglandins biosynthesis. Here we investigated the effect of these analgesics on human first trimester kidneys ex vivo. We first evaluated prostaglandins biosynthesis functionality by performing a wide screening of prostaglandin expression patterns in first trimester human kidneys. We demonstrated that prostaglandins biosynthesis machinery is functional during early nephrogenesis. Human fetal kidney explants aged 7-12 developmental weeks were exposed ex vivo to ibuprofen, aspirin or acetaminophen for 7 days, and analyzed by histology, immunohistochemistry, and flow cytometry. This study has revealed that these analgesics induced a spectrum of abnormalities within early developing structures, ranging from cell death to a decline in differentiating glomeruli density. These results warrant caution for the use of these medicines during the first trimester of pregnancy.


Assuntos
Analgésicos/efeitos adversos , Feto/efeitos dos fármacos , Glomérulos Renais/efeitos dos fármacos , Organogênese/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Feminino , Feto/metabolismo , Humanos , Glomérulos Renais/metabolismo , Gravidez , Primeiro Trimestre da Gravidez/efeitos dos fármacos , Prostaglandinas/metabolismo
18.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070207

RESUMO

In domestic ruminants, endometrial receptivity is related to successful pregnancy and economic efficiency. Despite several molecules having been reported in the past regarding endometrial receptivity regulation, much regarding the mechanism of endometrial receptivity regulation remains unknown due to the complex nature of the trait. In this work, we demonstrated that the cysteine-rich transmembrane bone morphogenetic protein (BMP) regulator 1 (CRIM1) served as a novel regulator in the regulation of goat endometrial receptivity in vitro. Our results showed that hormones and IFN-τ increased the expression of CRIM1 in goat endometrial epithelial cells (EECs). Knockdown of CRIM1 via specific shRNA hindered cell proliferation, cell adhesion and prostaglandins (PGs) secretion and thus derailed normal endometrial receptivity. We further confirmed that receptivity defect phenotypes due to CRIM1 interference were restored by ATG7 overexpression in EECs while a loss of ATG7 further impaired receptivity phenotypes. Moreover, our results showed that changing the expression of ATG7 affected the reactive oxygen species (ROS) production. Moreover, mR-143-5p was shown to be a potential upstream factor of CRIM1-regulated endometrial receptivity in EECs. Overall, these results suggest that CRIM1, as the downstream target of miR-143-5p, has effects on ATG7-dependent autophagy, regulating cell proliferation, cell adhesion and PG secretion, and provides a new target for the diagnosis and treatment of early pregnancy failure and for improving the success rates of artificial reproduction.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas/fisiologia , Implantação do Embrião/genética , Endométrio/fisiologia , Cabras/fisiologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/deficiência , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/fisiologia , Receptores de Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Receptores de Proteínas Morfogenéticas Ósseas/genética , Adesão Celular , Proliferação de Células , Células Cultivadas , Implantação do Embrião/fisiologia , Endométrio/citologia , Endométrio/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Estradiol/farmacologia , Feminino , Técnicas de Silenciamento de Genes , Cabras/genética , Interferon Tipo I/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos , Gravidez , Proteínas da Gravidez/farmacologia , Progesterona/farmacologia , Prostaglandinas/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima
19.
Arch Oral Biol ; 129: 105201, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34174588

RESUMO

OBJECTIVE: The aim of this in vitro study was to investigate the expression of SARS-CoV-2 entry and processing genes in human gingival fibroblasts (HGnF) following treatment with Porphyromonas gingivalis-derived lipopolysaccharide (PgLPS) or inflammatory cytokines/mediators. DESIGN: We assessed the expression of SARS-CoV-2 entry and processing genes; angiotensin-converting enzyme 2 (ACE2), cellular serine proteases transmembrane serine protease 2 (TMPRSS2), Furin, and basigin (BSG) in HGnF by real-time PCR. To further asses the contribution of PgLPS and inflammatory cytokines/mediators to proliferation and SARS-CoV-2 entry and processing gene expression, HGnF were treated with PgLPS, IL1ß, TNFα, and PGE2. RESULTS: The expression for ACE2 in HGnF was significantly elevated after PgLPS or IL1ß, TNFα, PGE2 treatment. The expression of TMPRSS2 was increased by PgLPS, IL1ß, or PGE2 while BSG was elevated by PgLPS and IL1ß. The expression of BSG and FURIN decreased after TNFα treatment. CONCLUSION: SARS-CoV-2 entry and processing genes are expressed in human gingival fibroblasts and their expressions are altered by PgLPS, IL1ß, TNFα and PGE2 treatment.


Assuntos
COVID-19 , SARS-CoV-2 , Citocinas , Fibroblastos , Humanos , Lipopolissacarídeos/farmacologia , Porphyromonas gingivalis , Prostaglandinas , Prostaglandinas E
20.
Biomolecules ; 11(6)2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073892

RESUMO

Organ fibrosis is a common pathological result of various chronic diseases with multiple causes. Fibrosis is characterized by the excessive deposition of extracellular matrix and eventually leads to the destruction of the tissue structure and impaired organ function. Prostaglandins are produced by arachidonic acid through cyclooxygenases and various prostaglandin-specific synthases. Prostaglandins bind to homologous receptors on adjacent tissue cells in an autocrine or paracrine manner and participate in the regulation of a series of physiological or pathological processes, including fibrosis. This review summarizes the properties, synthesis, and degradation of various prostaglandins, as well as the roles of these prostaglandins and their receptors in fibrosis in multiple models to reveal the clinical significance of prostaglandins and their receptors in the treatment of fibrosis.


Assuntos
Comunicação Autócrina , Comunicação Parácrina , Prostaglandina-Endoperóxido Sintases , Prostaglandinas/metabolismo , Animais , Doença Crônica , Fibrose , Humanos
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