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1.
iScience ; 26(12): 108409, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38058311

RESUMO

Given the importance of the kinin B1 receptor in insulin and leptin hormonal regulation, which in turn is crucial in maternal adaptations to ensure nutrient supply to the fetus, we investigated the role of this receptor in maternal metabolism and fetoplacental development. Wild-type and kinin B1 receptor-deficient (B1KO) female mice were mated with male mice of the opposite genotype. Consequently, the entire litter was heterozygous for kinin B1 receptor, ensuring that there would be no influence of offspring genotype on the maternal phenotype. Maternal kinin B1 receptor blockade reduces adiponectin secretion by adipose tissue ex vivo, consistent with lower adiponectin levels in pregnant B1KO mice. Furthermore, fasting insulinemia also increased, which was associated with placental insulin resistance, reduced placental glycogen accumulation, and heavier offspring. Therefore, we propose the combination of chronic hyperinsulinemia and reduced adiponectin secretion in B1KO female mice create a maternal obesogenic environment that results in heavier pups.

2.
NPJ Aging ; 9(1): 7, 2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-37012386

RESUMO

The gut microbiota impacts systemic levels of multiple metabolites including NAD+ precursors through diverse pathways. Nicotinamide riboside (NR) is an NAD+ precursor capable of regulating mammalian cellular metabolism. Some bacterial families express the NR-specific transporter, PnuC. We hypothesized that dietary NR supplementation would modify the gut microbiota across intestinal sections. We determined the effects of 12 weeks of NR supplementation on the microbiota composition of intestinal segments of high-fat diet-fed (HFD) rats. We also explored the effects of 12 weeks of NR supplementation on the gut microbiota in humans and mice. In rats, NR reduced fat mass and tended to decrease body weight. Interestingly, NR increased fat and energy absorption but only in HFD-fed rats. Moreover, 16S rRNA gene sequencing analysis of intestinal and fecal samples revealed an increased abundance of species within Erysipelotrichaceae and Ruminococcaceae families in response to NR. PnuC-positive bacterial strains within these families showed an increased growth rate when supplemented with NR. The abundance of species within the Lachnospiraceae family decreased in response to HFD irrespective of NR. Alpha and beta diversity and bacterial composition of the human fecal microbiota were unaltered by NR, but in mice, the fecal abundance of species within Lachnospiraceae increased while abundances of Parasutterella and Bacteroides dorei species decreased in response to NR. In conclusion, oral NR altered the gut microbiota in rats and mice, but not in humans. In addition, NR attenuated body fat mass gain in rats, and increased fat and energy absorption in the HFD context.

3.
Lancet Microbe ; 2(10): e527-e535, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34258603

RESUMO

BACKGROUND: Mutations accrued by SARS-CoV-2 lineage P.1-first detected in Brazil in early January, 2021-include amino acid changes in the receptor-binding domain of the viral spike protein that also are reported in other variants of concern, including B.1.1.7 and B.1.351. We aimed to investigate whether isolates of wild-type P.1 lineage SARS-CoV-2 can escape from neutralising antibodies generated by a polyclonal immune response. METHODS: We did an immunological study to assess the neutralising effects of antibodies on lineage P.1 and lineage B isolates of SARS-CoV-2, using plasma samples from patients previously infected with or vaccinated against SARS-CoV-2. Two specimens (P.1/28 and P.1/30) containing SARS-CoV-2 lineage P.1 (as confirmed by viral genome sequencing) were obtained from nasopharyngeal and bronchoalveolar lavage samples collected from patients in Manaus, Brazil, and compared against an isolate of SARS-CoV-2 lineage B (SARS.CoV2/SP02.2020) recovered from a patient in Brazil in February, 2020. Isolates were incubated with plasma samples from 21 blood donors who had previously had COVID-19 and from a total of 53 recipients of the chemically inactivated SARS-CoV-2 vaccine CoronaVac: 18 individuals after receipt of a single dose and an additional 20 individuals (38 in total) after receipt of two doses (collected 17-38 days after the most recent dose); and 15 individuals who received two doses during the phase 3 trial of the vaccine (collected 134-230 days after the second dose). Antibody neutralisation of P.1/28, P.1/30, and B isolates by plasma samples were compared in terms of median virus neutralisation titre (VNT50, defined as the reciprocal value of the sample dilution that showed 50% protection against cytopathic effects). FINDINGS: In terms of VNT50, plasma from individuals previously infected with SARS-CoV-2 had an 8·6 times lower neutralising capacity against the P.1 isolates (median VNT50 30 [IQR <20-45] for P.1/28 and 30 [<20-40] for P.1/30) than against the lineage B isolate (260 [160-400]), with a binominal model showing significant reductions in lineage P.1 isolates compared with the lineage B isolate (p≤0·0001). Efficient neutralisation of P.1 isolates was not seen with plasma samples collected from individuals vaccinated with a first dose of CoronaVac 20-23 days earlier (VNT50s below the limit of detection [<20] for most plasma samples), a second dose 17-38 days earlier (median VNT50 24 [IQR <20-25] for P.1/28 and 28 [<20-25] for P.1/30), or a second dose 134-260 days earlier (all VNT50s below limit of detection). Median VNT50s against the lineage B isolate were 20 (IQR 20-30) after a first dose of CoronaVac 20-23 days earlier, 75 (<20-263) after a second dose 17-38 days earlier, and 20 (<20-30) after a second dose 134-260 days earlier. In plasma collected 17-38 days after a second dose of CoronaVac, neutralising capacity against both P.1 isolates was significantly decreased (p=0·0051 for P.1/28 and p=0·0336 for P.1/30) compared with that against the lineage B isolate. All data were corroborated by results obtained through plaque reduction neutralisation tests. INTERPRETATION: SARS-CoV-2 lineage P.1 might escape neutralisation by antibodies generated in response to polyclonal stimulation against previously circulating variants of SARS-CoV-2. Continuous genomic surveillance of SARS-CoV-2 combined with antibody neutralisation assays could help to guide national immunisation programmes. FUNDING: São Paulo Research Foundation, Brazilian Ministry of Science, Technology and Innovation and Funding Authority for Studies, Medical Research Council, National Council for Scientific and Technological Development, National Institutes of Health. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Neutralizantes , Anticorpos Antivirais , Brasil/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , SARS-CoV-2/genética , Estados Unidos , Vacinação
4.
Nutrients ; 14(1)2021 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-35010977

RESUMO

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.


Assuntos
Envelhecimento/fisiologia , NAD/metabolismo , Idoso , Animais , Regulação da Expressão Gênica , Humanos , NAD/genética , Especificidade da Espécie
5.
Am J Physiol Endocrinol Metab ; 319(6): E1053-E1060, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32985254

RESUMO

Obesity and insulin resistance (IR) are associated with endoplasmic reticulum (ER) stress and mitochondrial dysfunction in several tissues. Although for many years mitochondrial and ER function were studied separately, these organelles also connect to produce interdependent functions. Communication occurs at mitochondria-associated ER membranes (MAMs) and regulates lipid and calcium homeostasis, apoptosis, and the exchange of adenine nucleotides, among other things. Recent evidence suggests that MAMs contribute to organelle, cellular, and systemic metabolism. In obesity and IR models, metabolic tissues such as the liver, skeletal muscle, pancreas, and adipose tissue present alterations in MAM structure or function. The purpose of this mini review is to highlight the MAM disruptions that occur in each tissue during obesity and IR and its relationship with glucose homeostasis and IR. We also discuss the current controversy that surrounds MAMs' role in the development of IR.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/metabolismo , Glucose/metabolismo , Resistência à Insulina/fisiologia , Membranas Intracelulares/metabolismo , Mitocôndrias/metabolismo , Animais , Cálcio/metabolismo , Retículo Endoplasmático/ultraestrutura , Homeostase/fisiologia , Humanos , Insulina/metabolismo , Fígado/metabolismo , Obesidade/metabolismo , Transdução de Sinais/fisiologia
6.
Neuropharmacology ; 54(3): 597-604, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18164734

RESUMO

The peripheral injection of phorbol myristate acetate (PMA) into the mouse paw induces nociception mediated through activation of protein kinase C (PKC). In the present study, we examine the contribution of kinin B1 receptor to PMA-induced nociception. Nociception was assessed after intraplantar injection of PMA or the B1 receptor agonist des-Arg9-bradykinin in mice. Mechanisms of nociception were studied using the combination of knockout mice, selective drugs, and measurement of B1 receptor mRNA and protein levels. Peripheral injection of PMA (50 pmol/paw) induced a nociceptive behaviour that was abolished by selective B1 receptor antagonist des-Arg9-Leu8-bradykinin or by the B1 receptor gene deletion. Moreover, PMA treatment did not alter B1 receptor mRNA levels, but greatly increased B1 receptor protein levels in the mouse paw. The injection of des-Arg9-bradykinin did not cause nociception in naive mice, but produced marked nociception in animals previously treated with a low dose of PMA (0.5 nmol/paw). The co-treatment of PMA with selective PKC or protein synthesis inhibitors, but not with p38 mitogen activated protein kinase (MAPK) or transcription inhibitors significantly reduced des-Arg9-bradykinin-induced nociception. On the other hand, the co-administration of selective PKC or p38 MAPK inhibitors, but not of protein synthesis or transcription inhibitors, reduced des-Arg9-bradykinin-induced nociception when evaluated in PMA pre-injected animals. These results suggest that the B1 receptor exerts a critical role in the nociception caused by PKC activation in peripheral tissues. Since the PKC pathway is downstream of several pro-inflammatory mediators, B1 receptor stimulation appears to contribute to the acute inflammatory pain process.


Assuntos
Dor/metabolismo , Proteína Quinase C/metabolismo , Receptor B1 da Bradicinina/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Carcinógenos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Knockout , Dor/induzido quimicamente , Dor/tratamento farmacológico , Medição da Dor , RNA Mensageiro/metabolismo , Receptor B1 da Bradicinina/deficiência , Acetato de Tetradecanoilforbol/efeitos adversos , Fatores de Tempo
7.
Regul Pept ; 136(1-3): 92-7, 2006 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-16822558

RESUMO

We investigated the expression and localization of B1 receptor in tissues of rats submitted to a renin-dependent model of hypertension (2K-1C), and analyzed the influence of endogenous Ang II in modulating the in vivo expression of these receptors. B1 mRNA levels in the heart, kidney and thoracic aorta were quantified by real time PCR, B1 receptor protein expression was assessed by immunohistochemistry, plasma Ang II levels were analyzed by radioimmunoassay and the effects of AT1 receptor blockade were determined after losartan treatment. 2K-1C rats presented a marked increase in Ang II levels when compared to sham-operated rats. In parallel, cardiac- (but not renal and aortic) B1 mRNA levels were 15-fold higher in 2K-1C than in sham rats. In 2K-1C, B1 expression was detected in the endothelium of small cardiac arteries and in cardiomyocytes. Losartan completely reverted the increased B1 mRNA levels and significantly decreased the protein expression observed in 2K-1C rats, despite reducing, but not normalizing blood pressure. We conclude that in the 2K-1C rat, induction of cardiac B1 receptor might be tightly linked to AT1 receptor activation. These data suggest the existence of a new site of interaction between kinins and angiotensins, and might provide important contributions for a better understanding of the pathophysiology of hypertension.


Assuntos
Angiotensina II/metabolismo , Regulação da Expressão Gênica , Cininas/biossíntese , Angiotensina II/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Hipertensão/patologia , Rim/metabolismo , Losartan/farmacologia , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
8.
Microbes Infect ; 8(1): 206-20, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16203170

RESUMO

Kinins, the vasoactive peptides proteolytically liberated from kininogens, were recently recognized as signals alerting the innate immune system. Here we demonstrate that Leishmania donovani and Leishmania chagasi, two etiological agents of visceral leishmaniasis (VL), activate the kinin system. Intravital microscopy in the hamster cheek pouch showed that topically applied promastigotes induced macromolecular leakage (FITC-dextran) through postcapillary venules. Peaking at 15 min, the parasite-induced leakage was drastically enhanced by captopril (Cap), an inhibitor of angiotensin-converting enzyme (ACE), a kinin-degrading metallopeptidase. The enhanced microvascular responses were cancelled by HOE-140, an antagonist of the B2 bradykinin receptor (B2R), or by pre-treatment of promastigotes with the irreversible cysteine proteinase inhibitor N-methylpiperazine-urea-Phe-homoPhe-vinylsulfone-benzene (N-Pip-hF-VSPh). In agreement with the above-mentioned data, the promastigotes vigorously induced edema in the paw of Cap-treated J129 mice, but not Cap-B2R-/- mice. Analysis of parasite-induced breakdown of high molecular weight kininogens (HK), combined with active site-affinity-labeling with biotin-N-Pip-hF-VSPh, identified 35-40 kDa proteins as kinin-releasing cysteine peptidases. We then checked if macrophage infectivity was influenced by interplay between these kinin-releasing parasite proteases, kininogens, and kinin-degrading peptidases (i.e. ACE). Our studies revealed that full-fledged B2R engagement resulted in vigorous increase of L. chagasi uptake by resident macrophages. Evidence that inflammatory macrophages treated with HOE-140 became highly susceptible to amastigote outgrowth, assessed 72 h after initial macrophage interaction, further suggests that the kinin/B2R activation pathway may critically modulate inflammation and innate immunity in visceral leishmaniasis.


Assuntos
Permeabilidade Capilar/fisiologia , Cisteína Endopeptidases/metabolismo , Cininas/metabolismo , Leishmania donovani/enzimologia , Leishmania infantum/enzimologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Animais , Cricetinae , Deleção de Genes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Peptidil Dipeptidase A/metabolismo , Receptores da Bradicinina/genética , Receptores da Bradicinina/metabolismo , Fatores de Tempo
9.
J Neurosci ; 25(9): 2405-12, 2005 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-15745967

RESUMO

Injury to peripheral nerves often results in a persistent neuropathic pain condition that is characterized by spontaneous pain, allodynia, and hyperalgesia. Nerve injury is accompanied by a local inflammatory reaction in which nerve-associated and immune cells release several pronociceptive mediators. Kinin B1 receptors are rarely expressed in nontraumatized tissues, but they can be expressed after tissue injury. Because B1 receptors mediate chronic inflammatory painful processes, we studied their participation in neuropathic pain using receptor gene-deleted mice. In the absence of neuropathy, we found no difference in the paw-withdrawal responses to thermal or mechanical stimulation between B1 receptor knock-out mice and 129/J wild-type mice. Partial ligation of the sciatic nerve in the wild-type mouse produced a profound and long-lasting decrease in thermal and mechanical thresholds in the paw ipsilateral to nerve lesion. Threshold changed neither in the sham-operated animals nor in the paw contralateral to lesion. Ablation of the gene for the B1 receptor resulted in a significant reduction in early stages of mechanical allodynia and thermal hyperalgesia. Furthermore, systemic treatment with the B1 selective receptor antagonist des-Arg9-[Leu8]-bradykinin reduced the established mechanical allodynia observed 7-28 d after nerve lesion in wild-type mice. Partial sciatic nerve ligation induced an upregulation in B1 receptor mRNA in ipsilateral paw, sciatic nerve, and spinal cord of wild-type mice. Together, kinin B1 receptor activation seems to be essential to neuropathic pain development, suggesting that an oral-selective B1 receptor antagonist might have therapeutic potential in the management of chronic pain.


Assuntos
Neuralgia/etiologia , Receptor B1 da Bradicinina/deficiência , Receptor B1 da Bradicinina/fisiologia , Neuropatia Ciática/complicações , Animais , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Bradicinina/uso terapêutico , Antagonistas de Receptor B1 da Bradicinina , Feminino , Lateralidade Funcional , Expressão Gênica/fisiologia , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Knockout/fisiologia , Neuralgia/terapia , Medição da Dor/métodos , RNA Mensageiro/metabolismo , Receptor B1 da Bradicinina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Pele/metabolismo , Pele/patologia , Temperatura Cutânea/genética , Fatores de Tempo
10.
Circ Res ; 94(10): 1375-82, 2004 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-15087417

RESUMO

The bradykinin B1 receptor (B1R) is normally absent under physiological conditions, but is highly inducible during inflammatory conditions or following tissue damage. The present study attempted to determine some of the mechanisms underlying B1R upregulation following tissue injury in rat portal vein. Damage induced by tissue isolation and in vitro incubation caused a significant and time-dependent increase in des-Arg9-bradykinin (des-Arg9-BK) responsiveness that paralleled the B1R mRNA expression, as confirmed by real-time quantitative PCR. In vitro incubation of rat portal vein also induced the activation of some members of the mitogen activated protein kinase (MAPK) family, namely, extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 MAPK, an effect accompanied by degradation of the inhibitory protein IkappaBalpha and translocation of nuclear transcription factor-kappaB (NF-kappaB) to the nucleus. The blockade of p38 MAPK, JNK or NF-kappaB, but not ERK pathways with selective inhibitors, resulted in a significant reduction of the upregulated contractile response caused by the selective B1R agonist des-Arg9-BK, and largely prevented the induction of B1R mRNA expression in the rat portal vein. Together, these results demonstrate that in vitro tissue damage induces activation of several intracellular signaling pathways that have a key role in the control of B1R expression. B1R could exert a pivotal role in the development of the cardiovascular response associated with vascular damage.


Assuntos
Bradicinina/análogos & derivados , Proteínas Quinases Ativadas por Mitógeno/fisiologia , NF-kappa B/fisiologia , Veia Porta/metabolismo , Receptor B1 da Bradicinina/biossíntese , Animais , Bradicinina/farmacologia , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica , Técnicas In Vitro , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Veia Porta/anatomia & histologia , Veia Porta/enzimologia , RNA Mensageiro/metabolismo , Ratos , Receptor B1 da Bradicinina/genética , Transdução de Sinais , Regulação para Cima
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