RESUMO
Post-transplant diabetes mellitus is a frequent complication of solid organ transplantation that generally requires treatment with lifestyle interventions and antidiabetic medication. A number of demonstrated and potential pharmacokinetic drug-drug interactions (DDIs) exist between commonly used immunosuppressants and antidiabetic drugs, which are comprehensively summarized in this review. Cyclosporine (CsA) itself inhibits the cytochrome P450 (CYP) 3A4 enzyme and a variety of drug transporters. As a result, it increases exposure to repaglinide and sitagliptin, will likely increase the exposure to nateglinide, glyburide, saxagliptin, vildagliptin and alogliptin, and could theoretically increase the exposure to gliquidone and several sodium-glucose transporter (SGLT)-2 inhibitors. Currently available data, although limited, suggest that these increases are modest and, particularly with regard to gliptins and SGLT-2 inhibitors, unlikely to result in hypoglycemia. The interaction with repaglinide is more pronounced but does not preclude concomitant use if repaglinide dose is gradually titrated. Mycophenolate mofetil and azathioprine do not engage in DDIs with any antidiabetic drug. Although calcineurin inhibitors (CNIs) and mammalian target of rapamycin inhibitors (mTORi) are intrinsically prone to DDIs, their disposition is not influenced by metformin, pioglitazone, sulfonylureas (except possibly glyburide) or insulin. An effect of gliptins on the disposition of CNIs and mTORi is unlikely, but has not been definitively ruled out. Based on their disposition profiles, glyburide and canagliflozin could affect CNI and mTORi disposition although this requires further study. Finally, delayed gastric emptying as a result of glucagon-like peptide-1 agonists seems to have a limited, but not necessarily negligible effect on CNI disposition.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Interações Medicamentosas , Hipoglicemiantes/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim/efeitos adversos , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Hipoglicemiantes/farmacologia , Transplante de Rim/métodos , Masculino , Prognóstico , Medição de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Targeting excessive production of reactive oxygen species (ROS) could be an effective therapeutic strategy to prevent oxidative stress-associated gastrointestinal inflammation. NADPH oxidase (NOX) and mitochondrial complexes (I and II) are the major sources of ROS production contributing to TNF-α/cycloheximide (CHX)-induced apoptosis in the mouse intestinal epithelial cell line, MODE-K. In the current study, the influence of a polyphenolic compound (resveratrol) and a water-soluble carbon monoxide (CO)-releasing molecule (CORM-A1) on the different sources of TNF-α/CHX-induced ROS production in MODE-K cells was assessed. This was compared with H2O2-, rotenone- or antimycin-A-induced ROS-generating systems. Intracellular total ROS, mitochondrial-derived ROS and mitochondrial superoxide anion (O2(-)) production levels were assessed. Additionally, the influence on TNF-α/CHX-induced changes in mitochondrial membrane potential (Ψm) and mitochondrial function was studied. In basal conditions, CORM-A1 did not affect intracellular total or mitochondrial ROS levels, while resveratrol increased intracellular total ROS but reduced mitochondrial ROS production. TNF-α/CHX- and H2O2-mediated increase in intracellular total ROS production was reduced by both resveratrol and CORM-A1, whereas only resveratrol attenuated the increase in mitochondrial ROS triggered by TNF-α/CHX. CORM-A1 decreased antimycin-A-induced mitochondrial O2(-) production without any influence on TNF-α/CHX- and rotenone-induced mitochondrial O2(-) levels, while resveratrol abolished all three effects. Finally, resveratrol greatly reduced and abolished TNF-α/CHX-induced mitochondrial depolarization and mitochondrial dysfunction, while CORM-A1 only mildly affected these parameters. These data indicate that the cytoprotective effect of resveratrol is predominantly due to mitigation of mitochondrial ROS, while CORM-A1 acts solely on NOX-derived ROS to protect MODE-K cells from TNF-α/CHX-induced cell death. This might explain the more pronounced cytoprotective effect of resveratrol.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Boranos/farmacologia , Carbonatos/farmacologia , Cicloeximida/toxicidade , Células Epiteliais/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estilbenos/farmacologia , Fator de Necrose Tumoral alfa/toxicidade , Animais , Linhagem Celular , Citoproteção , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NADPH Oxidases/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Resveratrol , Superóxidos/metabolismoRESUMO
Neutrophils are essential for the innate immune response against bacterial pathogens and play a key role during the early phases of infection, including mastitis and endometritis in cows. When directly challenged with bacteria, neutrophils undergo phagocytosis induced cell death (PICD). The molecular mechanisms of this cell death modality are poorly understood, especially for bovine neutrophils. Therefore, this study aimed to determine the mechanisms and hallmarks of PICD in bovine neutrophils after in vitro challenge with Escherichia coli (E. coli). Our data show that various apoptotic hallmarks such as blebbing, chromatin condensation and executioner caspase (C)-3/-7 activity are only observed during constitutive bovine neutrophil apoptosis. In contrast, bovine neutrophil PICD is characterized by production of reactive oxygen species (ROS), pro-inflammatory C-1 activation, nuclear factor (NF)-κB activation, and interleukin (IL)-1ß and IL-6 secretion. Nevertheless, under both conditions these phagocytes undergo cell death with the exposure of phosphatidylserine (PS). Although PS exposure is generally attributed to the anti-inflammatory features of executioner caspase-dependent apoptosis, it surprisingly preceded plasma membrane rupture during bovine neutrophil PICD. Moreover, C-1 inhibition strongly affected IL-1ß production but not the PICD kinetics. This indicates that the secretion of the latter pro-inflammatory cytokine is a bystander effect rather than a regulator of PICD in bovine neutrophils, in marked contrast to the IL-1ß-dependent pyroptosis reported for macrophages.
Assuntos
Caspases/fisiologia , Escherichia coli/patogenicidade , Neutrófilos/imunologia , Fosfatidilserinas/fisiologia , Animais , Apoptose , Caspase 1/fisiologia , Caspase 3/fisiologia , Caspase 7/fisiologia , Bovinos , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , NF-kappa B/metabolismo , Ativação de Neutrófilo , Neutrófilos/fisiologia , Fagocitose , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Neutrophil extracellular traps (NETs) are extracellular chromatin structures that can trap and degrade microbes. They arise from neutrophils that have activated a cell death program called NET cell death, or NETosis. Activation of NETosis has been shown to involve NADPH oxidase activity, disintegration of the nuclear envelope and most granule membranes, decondensation of nuclear chromatin and formation of NETs. We report that in phorbol myristate acetate (PMA)-stimulated neutrophils, intracellular chromatin decondensation and NET formation follow autophagy and superoxide production, both of which are required to mediate PMA-induced NETosis and occur independently of each other. Neutrophils from patients with chronic granulomatous disease, which lack NADPH oxidase activity, still exhibit PMA-induced autophagy. Conversely, PMA-induced NADPH oxidase activity is not affected by pharmacological inhibition of autophagy. Interestingly, inhibition of either autophagy or NADPH oxidase prevents intracellular chromatin decondensation, which is essential for NETosis and NET formation, and results in cell death characterized by hallmarks of apoptosis. These results indicate that apoptosis might function as a backup program for NETosis when autophagy or NADPH oxidase activity is prevented.
Assuntos
Apoptose , Autofagia , Neutrófilos/metabolismo , Superóxidos/metabolismo , Montagem e Desmontagem da Cromatina , Doença Granulomatosa Crônica/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , NADH NADPH Oxirredutases/metabolismo , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Neutrófilos/citologia , Acetato de Tetradecanoilforbol/farmacologiaAssuntos
Aspergilose/prevenção & controle , Quimiotaxia de Leucócito/genética , Doença Granulomatosa Crônica/terapia , Neutrófilos/fisiologia , Antifúngicos/metabolismo , Aspergilose/etiologia , Aspergilose/genética , Aspergilose/metabolismo , Aspergillus nidulans , Quimiotaxia de Leucócito/imunologia , Criança , Terapia Genética/métodos , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/imunologia , Humanos , Masculino , Neutrófilos/metabolismoRESUMO
Neutrophil cell death plays a crucial role in neutrophil homeostasis and the resolution of inflammation. The superoxide-producing NADPH oxidase is involved in pathogen degradation and subsequent activation of cell death programs. Neutrophils from patients with chronic granulomatous disease, who have a deficient NADPH oxidase activity, have been demonstrated previously to have a prolonged lifespan, suggesting that a basal NADPH oxidase activity also regulates spontaneous neutrophil turnover. The NADPH oxidase inhibitor parabutoporin (PP) does delay spontaneous apoptosis, but this effect is completely independent of NADPH oxidase inhibition. Instead, the prosurvival effect of PP depends on activation of protein kinase B/Akt via lipid raft signaling. Disruption of lipid rafts abrogates the prosurvival effect without interfering with NADPH oxidase activity. Furthermore, we cannot detect a different rate of spontaneous apoptosis between normal and NADPH oxidase-deficient neutrophils, arguing against a role of NADPH oxidase in spontaneous neutrophil apoptosis.
Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Apoptose/efeitos dos fármacos , Microdomínios da Membrana/fisiologia , NADPH Oxidases/antagonistas & inibidores , Neutrófilos/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Venenos de Escorpião/farmacologia , Células Cultivadas , Humanos , Cinética , NADPH Oxidase 1RESUMO
We investigated parabutoporin (PP), an antimicrobial scorpion peptide, to understand its inhibition on NADPH oxidase in human PMN. We show that PP is a good substrate for all PKC-isotypes, implicated in the activation of NADPH oxidase, and acts as a potent competitive inhibitor of in vitro p47(phox)-phosphorylation by PKC-alpha, -betaI, -betaII and -delta, but not PKC-zeta. In PMN, PP also inhibits the PMA-stimulated phosphorylation of p47(phox) and its subsequent translocation. In contrast, PP affects the PKC-independent activation to a much lesser degree. This indicates that PP inhibits the activation of NADPH oxidase at submicromolar concentrations in a strongly PKC-dependent manner.