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1.
BMJ Open ; 10(9): e040644, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928868

RESUMO

OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Infecções por Coronavirus , Estrogênios/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipoglicemiantes/farmacologia , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral , Anti-Inflamatórios não Esteroides/farmacologia , Betacoronavirus/metabolismo , Regulação para Baixo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Insulina/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Peptidil Dipeptidase A/metabolismo , Tiazolidinedionas/farmacologia , Reino Unido , Regulação para Cima
3.
PLoS One ; 15(8): e0231806, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817622

RESUMO

The cAMP-dependent protein kinase (PKA) signaling pathway is the primary means by which the heart regulates moment-to-moment changes in contractility and metabolism. We have previously found that PKA signaling is dysfunctional in the diabetic heart, yet the underlying mechanisms are not fully understood. The objective of this study was to determine if decreased insulin signaling contributes to a dysfunctional PKA response. To do so, we isolated adult cardiomyocytes (ACMs) from wild type and Akita type 1 diabetic mice. ACMs were cultured in the presence or absence of insulin and PKA signaling was visualized by immunofluorescence microscopy using an antibody that recognizes proteins specifically phosphorylated by PKA. We found significant decreases in proteins phosphorylated by PKA in wild type ACMs cultured in the absence of insulin. PKA substrate phosphorylation was decreased in Akita ACMs, as compared to wild type, and unresponsive to the effects of insulin. The decrease in PKA signaling was observed regardless of whether the kinase was stimulated with a beta-agonist, a cell-permeable cAMP analog, or with phosphodiesterase inhibitors. PKA content was unaffected, suggesting that the decrease in PKA signaling may be occurring by the loss of specific PKA substrates. Phospho-specific antibodies were used to discern which potential substrates may be sensitive to the loss of insulin. Contractile proteins were phosphorylated similarly in wild type and Akita ACMs regardless of insulin. However, phosphorylation of the glycolytic regulator, PFK-2, was significantly decreased in an insulin-dependent manner in wild type ACMs and in an insulin-independent manner in Akita ACMs. These results demonstrate a defect in PKA activation in the diabetic heart, mediated in part by deficient insulin signaling, that results in an abnormal activation of a primary metabolic regulator.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Insulina/metabolismo , Insulina/farmacologia , Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/fisiologia , Inibidores de Fosfodiesterase/farmacologia , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos
4.
Medicine (Baltimore) ; 99(34): e21821, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846824

RESUMO

BACKGROUND: Traditional Chinese medicine Tongxinluo (TXL) has been widely used to treat coronary artery disease in China, since it could reduce myocardial infarct size and ischemia/reperfusion injury in both non-diabetic and diabetic conditions. It has been shown that TXL could regulate peroxisome proliferator activated receptor-α (PPAR-α), a positive modulator of angiopoietin-like 4 (Angptl4), in diabetic rats. Endothelial junction substructure components, such as VE-cadherin, are involved in the protection of reperfusion injury. Thus, we hypothesized cell-intrinsic and endothelial-specific Angptl4 mediated the protection of TXL on endothelial barrier under high glucose condition against ischemia/reperfusion-injury via PPAR-α pathway. METHODS: Incubated with high glucose medium, the human cardiac microvascular endothelial cells (HCMECs) were then exposed to oxygen-glucose-serum deprivation (2 hours) and restoration (2 hours) stimulation, with or without TXL, insulin, or rhAngptl4 pretreatment. RESULTS: TXL, insulin, and rhAngptl4 had similar protective effects on the endothelial barrier. TXL treatment reversed the endothelial barrier breakdown in HCMECs significantly as identified by decreasing endothelial permeability, upregulating the expression of JAM-A, VE-cadherin, and integrin-α5 and increasing the membrane location of VE-cadherin and integrin-α5, and these effects of TXL were as effective as insulin and rhAngptl4. However, Angptl4 knock-down with small interfering RNA (siRNA) interference and PPAR-α inhibitor MK886 partially abrogated these beneficial effects of TXL. Western blotting also revealed that similar with insulin, TXL upregulated the expression of Angptl4 in HCMECs, which could be inhibited by Angptl4 siRNA or MK886 exposure. TXL treatment increased PPAR-α activity, which could be diminished by MK886 but not by Angptl4 siRNA. CONCLUSION: These data suggest cell-intrinsic and endothelial-specific Angptl4 mediates the protection of TXL against endothelial barrier breakdown during oxygen-glucose-serum deprivation and restoration under high glucose condition partly via the PPAR-α/Angptl4 pathway.


Assuntos
Proteína 4 Semelhante a Angiopoietina/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/efeitos dos fármacos , Endotélio/efeitos dos fármacos , Endotélio/fisiopatologia , PPAR alfa/metabolismo , Proteína 4 Semelhante a Angiopoietina/genética , Proteína 4 Semelhante a Angiopoietina/farmacologia , Caderinas/metabolismo , Permeabilidade Capilar , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Vasos Coronários/citologia , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Glucose/farmacologia , Humanos , Indóis/farmacologia , Insulina/farmacologia , Integrina alfa5/metabolismo , Inibidores de Lipoxigenase/farmacologia , Microvasos/citologia , Oxigênio/metabolismo , Oxigênio/farmacologia , Receptores de Superfície Celular/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais
5.
Acta Cir Bras ; 35(7): e202000704, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32813772

RESUMO

Purpose Given the high prevalence of diabetes (D), several animal models have been analyzed. In the literature, most of the animal models have studied severe D. However, in clinical practice, most patients have moderate disease. Therefore, the present study aimed to describe a moderate D condition. Methods We analyzed 20 Wistar rats, age eight-weeks, weight between 200g-250g. All animals received an intravenous injection of Streptozotocin (55mg/kg weight). On the 15th day after D induction, the animals were divided into two groups: Group I - animals receiving a single daily dose of fast-acting insulin (FAIG) NPH (1UI,SC) for partial glycemic control, and Group II - animals receiving slow-acting insulin(SAIG) twice a week. We measured glycemia, weight, and adverse events every week during two months. Results Of the total of animals analyzed in the study, three animals died in the FAIG and two animals died in the SAIG. Regarding the glycemic level, results were 339.5 ± 125.4mg/dL (95CI 302.3402 to 376.6842) in the FAIG, and 367.8 ± 66.1mg/dL (95IC 333.7607 to 401.8978) in the SAIG. There was no difference between groups as to weight during the study. Conclusion The use of slow-acting-insulin is not inferior to the use of fast-acting-insulin in the management of partially insulin-controlled moderate diabetes in rats.


Assuntos
Diabetes Mellitus , Insulina/farmacologia , Animais , Glicemia , Hemoglobina A Glicada , Hipoglicemiantes , Ratos , Ratos Wistar
6.
Lancet Neurol ; 19(9): 758-766, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32730766

RESUMO

Insulin is a peptide secreted by the pancreas and plays an important role in the regulation of glucose metabolism in peripheral tissues. Although the role of insulin in the periphery is well understood, less is known about its multifactorial role in the brain. However, emerging evidence from human and animal studies indicate that insulin influences cerebral bioenergetics, enhances synaptic viability and dendritic spine formation, and increases turnover of neurotransmitters, such as dopamine. Insulin also has a role in proteostasis, influencing clearance of the amyloid ß peptide and phosphorylation of tau, which are hallmarks of Alzheimer's disease. Insulin also modulates vascular function through effects on vasoreactivity, lipid metabolism, and inflammation. Through these multiple pathways, insulin dysregulation could contribute to neurodegeneration. Thus, new approaches to restore cerebral insulin function that could offer therapeutic benefit to adults with Alzheimer's disease, vascular cognitive impairment, or related disorders are being investigated.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Encéfalo/metabolismo , Resistência à Insulina/fisiologia , Comportamento de Redução do Risco , Animais , Encéfalo/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Insulina/farmacologia , Insulina/uso terapêutico
8.
Gene ; 754: 144903, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32540374

RESUMO

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among reproductive-age women. The circRNA-miRNA axis functions in various diseases progression have been partially revealed in the past two decades. However, little is known about the role of the circRNA-miRNA axis in PCOS progression. MicroRNA miR-760, which is characterized by tissue-specific, has been studied in several cancers. Firstly, we found that miR-760 expression was decreased in PCOS tissues insulin treated GCs, KGN and SVOG cells. Secondly, The CCK-8 and apoptosis experiment results suggested that downregulated miR-760 promoted cell proliferation ability and suppressed apoptosis activity in KGN and SVOG cells. Then, the bioinformatic analysis result indicated that circPUM1 was a potential sponge to miR-760. By performing AGO2-RIP, RNA pull-down, Luciferase reporter, and qRT-PCR experiments, we demonstrated that circPUM1 acted as a molecular sponge to miR-760, and decreased miR-760 expression. Moreover, it was found that the promotive effect of circPUM1 was mediated by regulating miR-760. Collectively, our findings suggest that circPUM1 promotes PCOS progression through sponging to miR-760. We may provide a promising therapeutic target for PCOS.


Assuntos
Regulação da Expressão Gênica , Células da Granulosa/patologia , MicroRNAs/genética , Síndrome do Ovário Policístico/patologia , RNA Circular/genética , Apoptose , Proliferação de Células , Células Cultivadas , Progressão da Doença , Feminino , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo
9.
Am J Physiol Heart Circ Physiol ; 319(1): H162-H170, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502373

RESUMO

Vasodilatory effects of insulin support the delivery of insulin and glucose to skeletal muscle. Concurrently, insulin exerts central effects that increase sympathetic nervous system activity (SNA), which is required for the acute maintenance of blood pressure (BP). Indeed, in a cohort of young healthy adults, herein we show that intravenous infusion of insulin increases muscle SNA while BP is maintained. We next tested the hypothesis that sympathoexcitation evoked by hyperinsulinemia restrains insulin-stimulated peripheral vasodilation and contributes to sustaining BP. To address this, a separate cohort of participants were subjected to 5-s pulses of neck suction (NS) to simulate carotid hypertension and elicit a reflex-mediated reduction in SNA. NS was conducted before and 60 min following intravenous infusion of insulin. Insulin infusion caused an increase in leg vascular conductance and cardiac output (CO; P < 0.050), with maintenance of BP (P = 0.540). As expected, following NS, decreases in BP were greater in the presence of hyperinsulinemia compared with control (P = 0.045). However, the effect of NS on leg vascular conductance did not differ between insulin and control conditions (P = 0.898). Instead, the greater decreases in BP following NS in the setting of insulin infusion paralleled with greater decreases in CO (P = 0.009). These findings support the idea that during hyperinsulinemia, SNA-mediated increase in CO, rather than restraint of leg vascular conductance, is the principal contributor to the maintenance of BP. Demonstration in isolated arteries that insulin suppresses α-adrenergic vasoconstriction suggests that the observed lack of restraint of leg vascular conductance may be attributed to sympatholytic actions of insulin.NEW & NOTEWORTHY We examined the role of sympathetic activation in restraining vasodilatory responses to hyperinsulinemia and sustaining blood pressure in healthy adults. Data are reported from two separate experimental protocols in humans and one experimental protocol in isolated arteries from mice. Contrary to our hypothesis, the present findings support the idea that during hyperinsulinemia, a sympathetically mediated increase in cardiac output, rather than restraint of peripheral vasodilation, is the principal contributor to the maintenance of systemic blood pressure.


Assuntos
Pressão Sanguínea , Débito Cardíaco , Hiperinsulinismo/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Vasodilatação , Adrenérgicos/farmacologia , Adulto , Animais , Artérias/efeitos dos fármacos , Artérias/fisiologia , Feminino , Humanos , Insulina/administração & dosagem , Insulina/farmacologia , Perna (Membro)/irrigação sanguínea , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fluxo Sanguíneo Regional
10.
Nat Struct Mol Biol ; 27(7): 615-624, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32483339

RESUMO

Human insulin and its current therapeutic analogs all show propensity, albeit varyingly, to self-associate into dimers and hexamers, which delays their onset of action and makes blood glucose management difficult for people with diabetes. Recently, we described a monomeric, insulin-like peptide in cone-snail venom with moderate human insulin-like bioactivity. Here, with insights from structural biology studies, we report the development of mini-Ins-a human des-octapeptide insulin analog-as a structurally minimal, full-potency insulin. Mini-Ins is monomeric and, despite the lack of the canonical B-chain C-terminal octapeptide, has similar receptor binding affinity to human insulin. Four mutations compensate for the lack of contacts normally made by the octapeptide. Mini-Ins also has similar in vitro insulin signaling and in vivo bioactivities to human insulin. The full bioactivity of mini-Ins demonstrates the dispensability of the PheB24-PheB25-TyrB26 aromatic triplet and opens a new direction for therapeutic insulin development.


Assuntos
Antígenos CD/química , Insulina/química , Venenos de Moluscos/química , Venenos de Moluscos/metabolismo , Receptor de Insulina/química , Substituição de Aminoácidos , Animais , Antígenos CD/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Insulina/análogos & derivados , Insulina/metabolismo , Insulina/farmacologia , Camundongos Endogâmicos C57BL , Modelos Moleculares , Simulação de Dinâmica Molecular , Venenos de Moluscos/genética , Venenos de Moluscos/farmacologia , Peptídeos/química , Peptídeos/genética , Peptídeos/metabolismo , Conformação Proteica , Ratos Sprague-Dawley , Receptor de Insulina/metabolismo , Relação Estrutura-Atividade , Tirosina
11.
Nat Commun ; 11(1): 2186, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32367034

RESUMO

Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/ß or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.


Assuntos
Cálcio/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Homeostase , Resistência à Insulina , Proteínas Musculares/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Cardiomiopatias Diabéticas/genética , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Insulina/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Musculares/genética , Mutação , Quinase de Cadeia Leve de Miosina/genética , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Transdução de Sinais/genética
12.
Mol Cell ; 79(1): 43-53.e4, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32464093

RESUMO

The physiological role of immune cells in the regulation of postprandial glucose metabolism has not been fully elucidated. We have found that adipose tissue macrophages produce interleukin-10 (IL-10) upon feeding, which suppresses hepatic glucose production in cooperation with insulin. Both elevated insulin and gut-microbiome-derived lipopolysaccharide in response to feeding are required for IL-10 production via the Akt/mammalian target of rapamycin (mTOR) pathway. Indeed, myeloid-specific knockout of the insulin receptor or bone marrow transplantation of mutant TLR4 marrow cells results in increased expression of gluconeogenic genes and impaired glucose tolerance. Furthermore, myeloid-specific Akt1 and Akt2 knockout results in similar phenotypes that are rescued by additional knockout of TSC2, an inhibitor of mTOR. In obesity, IL-10 production is impaired due to insulin resistance in macrophages, whereas adenovirus-mediated expression of IL-10 ameliorates postprandial hyperglycemia. Thus, the orchestrated response of the endogenous hormone and gut environment to feeding is a key regulator of postprandial glycemia.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Hiperglicemia/patologia , Insulina/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/análise , Gluconeogênese/genética , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina , Interleucina-10/fisiologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout , Período Pós-Prandial , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Proteína 2 do Complexo Esclerose Tuberosa/fisiologia
13.
Life Sci ; 255: 117856, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32473246

RESUMO

BACKGROUND: Ferulic acid (FA) is a phenolic phytochemical known to protect against various diabetic complications. However, its role in diabetic neuropathy is still unclear. The present study investigated the potential protective effects of FA alone and its combination with insulin against streptozotocin (STZ)-induced diabetic neuropathy in rats. METHODS: STZ (55 mg/kg) was injected in adult Sprague-Dawley rats to induce diabetes. Diabetic rats were treated with FA (25, 50, and 100 mg/kg, p.o), insulin (10 IU/kg, s.c.) and the combination of FA (100 mg/kg, p.o.) with insulin (10 IU/kg, s.c.) for four weeks. Body weight, blood glucose, insulin, glycosylated hemoglobin, nerve conduction velocity and pain parameters were measured. Moreover, oxidative stress, inflammatory (TNF-α, IL-1ß, COX-2) and apoptotic markers (Bcl-2, Bax, caspase 3) were assessed in the sciatic nerve tissue. Na+-K+-ATPase activity and nerve growth factor (NGF) levels were also determined. RESULTS: FA attenuated STZ induced alteration in metabolic parameters, nociceptive threshold, motor nerve conduction velocity, NGF levels and Na+-K+-ATPase activity. In addition, FA boosted anti-oxidant defenses and suppressed oxidative stress, pro-inflammatory mediators and apoptotic markers. Furthermore, diabetic rats treated with insulin-FA (100 mg/kg) combination demonstrated more pronounced beneficial effects as compared to either agent alone. CONCLUSIONS: Collectively, our results suggest that FA either alone or in combination with insulin therapy could serve as an efficacious agent for treating diabetic neuropathy.


Assuntos
Ácidos Cumáricos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Animais , Antioxidantes/metabolismo , Glicemia/efeitos dos fármacos , Ácidos Cumáricos/administração & dosagem , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estreptozocina
14.
Nat Biomed Eng ; 4(5): 507-517, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32393892

RESUMO

Treatment of patients with diabetes with insulin and pramlintide (an amylin analogue) is more effective than treatment with insulin only. However, because mixtures of insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of people with diabetes needing rapid-acting insulin. Here, we show that the supramolecular modification of insulin and pramlintide with cucurbit[7]uril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances postprandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100 h at 37 °C under continuous agitation, whereas commercial formulations of insulin analogues aggregate after 10 h under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and insulin from 0.4 ± 0.2 to 0.7 ± 0.1 (mean ± s.d.) for the separate administration of the hormones. The co-administration of supramolecularly stabilized insulin and pramlintide better mimics the endogenous kinetics of co-secreted insulin and amylin, and holds promise as a dual-hormone replacement therapy.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Composição de Medicamentos , Glucagon/metabolismo , Insulina/uso terapêutico , Polipeptídeo Amiloide das Ilhotas Pancreáticas/uso terapêutico , Animais , Hidrocarbonetos Aromáticos com Pontes/química , Difusão , Vias de Administração de Medicamentos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Imidazóis/química , Insulina/administração & dosagem , Insulina/farmacocinética , Insulina/farmacologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/administração & dosagem , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacocinética , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Masculino , Polietilenoglicóis/química , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Suínos
15.
Int. j. morphol ; 38(2): 340-347, abr. 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1056445

RESUMO

Diabetes mellitus is a serious disease with a high incidence of occurrence in our community. Gum Arabic (GA) is a branched-chain polysaccharide which has strong antioxidant properties, and has been used to reduce the experimental toxicity. Yet, the effects of GA on testicular tissue in type I diabetic rats have not been enough investigated. This study was designed to investigate histological changes in testes of male Wistar rats and investigate the protective potential of GA against diabetes- induced testicular toxicity in rats. Fifty adult male Wistar rats were assigned into five groups (n = 10 of each): Group 1 (non-diabetic rats) served as control, Group 2 served as diabetic group injected with Alloxan, Group 3 diabetic group plus insulin, Group 4 diabetic group given 15 % GA in drinking water and Group 5 diabetic group plus insulin and GA for 4 weeks. Compared to control group, histopathological examinations of testicular tissue from the diabetic rats group, showed degeneration, necrosis and atrophy of seminiferous with presence of giant cells. Necrosis and hemorrhage in the renal tissue. On the other hand, treatment with GA ameliorated all the previous histological changes. Overall, oral administration of GA alone or with insulin daily for 4 weeks successfully ameliorated the testicular histological changes. These data demonstrated that GA significantly improved diabetes complication in rat testis. This study suggested that GA might have a protective effect against oxidative stress-induced impaired testicular functions in diabetic rats. The possible mechanisms of this action might be ascribed to their antioxidant and anti-inflammatory properties.


La diabetes mellitus es una enfermedad grave con una alta incidencia en nuestra comunidad. La goma arábiga (GA) es un polisacárido con propiedades antioxidantes importantes, y se ha utilizado para reducir la toxicidad experimental. Sin embargo, los efectos de GA sobre el tejido testicular en ratas diabéticas tipo I no se ha investigado lo suficiente. El estudio fue diseñado para pesquisar los cambios histológicos en los testículos de ratas Wistar macho e investigar el potencial protector de GA contra la toxicidad testicular inducida por la diabetes en ratas. Fueron asignadas cincuenta ratas Wistar macho adultas en cinco grupos (n = 10 de cada una): el grupo 1 (ratas no diabéticas) sirvió como control, el grupo 2 sirvió como grupo diabético inyectado con Alloxan, grupo diabético del grupo 3 más insulina. El grupo 4 diabético recibió 15 % de GA en agua potable, y el grupo diabético 5 más insulina y GA durante 4 semanas. Al comparar con el grupo control, los exámenes histopatológicos del tejido testicular del grupo de ratas diabéticas mostraron degeneración, necrosis y atrofia de los túbulos seminíferos con presencia de células gigantes, necrosis y hemorragia en el tejido renal. Por otra parte, el tratamiento con GA mejoró todos los cambios histológicos previos. En general, la administración oral de GA solamente, o con insulina diariamente durante 4 semanas mejoró los cambios histológicos testiculares. Estos datos demostraron que GA mejoró significativamente los efectos de la diabetes en testículos de rata. Este estudio sugiere que GA podría tener un efecto protector contra las funciones testiculares deterioradas, inducidas por el estrés oxidativo en ratas diabéticas. Los posibles mecanismos de esta acción podrían atribuirse a sus propiedades antioxidantes y antiinflamatorias.


Assuntos
Animais , Masculino , Ratos , Testículo/efeitos dos fármacos , Goma Arábica/farmacologia , Insulina/farmacologia , Ratos Wistar , Diabetes Mellitus Experimental/tratamento farmacológico , Goma Arábica/administração & dosagem
16.
Viruses ; 12(4)2020 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-32260595

RESUMO

Porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV) have been reported to use aminopeptidase N (APN) as a cellular receptor. Recently, the role of APN as a receptor for PEDV has been questioned. In our study, the role of APN in PEDV and TGEV infections was studied in primary porcine enterocytes. After seven days of cultivation, 89% of enterocytes presented microvilli and showed a two- to five-fold higher susceptibility to PEDV and TGEV. A significant increase of PEDV and TGEV infection was correlated with a higher expression of APN, which was indicative that APN plays an important role in porcine coronavirus infections. However, PEDV and TGEV infected both APN positive and negative enterocytes. PEDV and TGEV Miller showed a higher infectivity in APN positive cells than in APN negative cells. In contrast, TGEV Purdue replicated better in APN negative cells. These results show that an additional receptor exists, different from APN for porcine coronaviruses. Subsequently, treatment of enterocytes with neuraminidase (NA) had no effect on infection efficiency of TGEV, implying that terminal cellular sialic acids (SAs) are no receptor determinants for TGEV. Treatment of TGEV with NA significantly enhanced the infection which shows that TGEV is masked by SAs.


Assuntos
Antígenos CD13/metabolismo , Gastroenterite Suína Transmissível/patologia , Vírus da Diarreia Epidêmica Suína/metabolismo , Receptores Virais/metabolismo , Ácidos Siálicos/metabolismo , Vírus da Gastroenterite Transmissível/metabolismo , Animais , Células Cultivadas , Chlorocebus aethiops , Infecções por Coronavirus/patologia , Infecções por Coronavirus/veterinária , Enterócitos/virologia , Hidrocortisona/farmacologia , Insulina/farmacologia , Mucosa Respiratória/virologia , Espermidina/farmacologia , Suínos , Células Vero , Ligação Viral , Replicação Viral/efeitos dos fármacos
17.
Artigo em Inglês | MEDLINE | ID: mdl-32348172

RESUMO

Reactive oxygen species such as hydrogen peroxide have been implicated in causing metabolic dysfunction such as insulin resistance. Heme groups, either by themselves or when incorporated into proteins, have been shown to scavenge peroxide and demonstrate protective effects in various cell types. Thus, we hypothesized that a metalloporphyrin similar in structure to heme, Fe(III)tetrakis(4-benzoic acid)porphyrin (FeTBAP), would be a peroxidase mimetic that could defend cells against oxidative stress. After demonstrating that FeTBAP has peroxidase activity with reduced nicotinamide adenine dinucleotide phosphate (NADPH) and NADH as reducing substrates, we determined that FeTBAP partially rescued C2C12 myotubes from peroxide-induced insulin resistance as measured by phosphorylation of AKT (S473) and insulin receptor substrate 1 (IRS-1, Y612). Furthermore, we found that FeTBAP stimulates insulin signaling in myotubes and mouse soleus skeletal muscle to about the same level as insulin for phosphorylation of AKT, IRS-1, and glycogen synthase kinase 3ß (S9). We found that FeTBAP lowers intracellular peroxide levels and protects against carbonyl formation in myotubes exposed to peroxide. Additionally, we found that FeTBAP stimulates glucose transport in myotubes and skeletal muscle to about the same level as insulin. We conclude that a peroxidase mimetic can blunt peroxide-induced insulin resistance and also stimulate insulin signaling and glucose transport, suggesting a possible role of peroxidase activity in regulation of insulin signaling.


Assuntos
Antioxidantes/farmacologia , Mimetismo Biológico , Peróxido de Hidrogênio/toxicidade , Resistência à Insulina , Insulina/farmacologia , Metaloporfirinas/farmacologia , Mioblastos Esqueléticos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peroxidases/farmacologia , Animais , Linhagem Celular , Glicogênio Sintase Quinase 3 beta/metabolismo , Peróxido de Hidrogênio/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Mioblastos Esqueléticos/metabolismo , Mioblastos Esqueléticos/patologia , Fosforilação , Carbonilação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
18.
Vascul Pharmacol ; 130: 106678, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32229255

RESUMO

BACKGROUND: Hyperglycemia plays a role in promoting insulin resistance in adipocytes, hepatocytes and myocytes. Its effects on insulin signaling in endothelial cells remain, however, incompletely understood. AIM: To investigate the proteomic and metabolomic profiles of human aortic endothelial cells (HAECs) exposed to insulin, normal glucose (NG), high glucose (HG) or its hyperosmolar control high mannitol (HM), and to examine whether and how HG or HM may promote insulin resistance. METHODS AND RESULTS: We exposed HAECs to HG and HM in shorter (3 h) and longer-term experiments (24 h), followed by insulin treatment for 45 min. Label-free proteomics and network analysis showed a downregulation of proteins linked to the PI3K-Akt/mTOR/eNOS signaling pathway in HAECs. Metabolomic profiling showed decreased levels of "odd-chain acylcarnitines" such as C3. At immunoblotting, HG or HM blunted insulin ability to activate the PI3K/AKT/eNOS pathway, which was reverted through a silencing of aquaporin 1 (AQP1) and Tonicity enhancer binding protein (TonEBP), while inducing p-P38 and pERK1/2. CONCLUSIONS: HG impairs the PI3K/AKT/eNOS pathway and shifts insulin signaling towards the activation of mitogenic and pro-inflammatory effectors, such as p38 and ERK1/2. These effects may explain the progression of insulin resistance as a result of endothelial glucotoxicity.


Assuntos
Células Endoteliais/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glucose/toxicidade , Hiperglicemia/metabolismo , Resistência à Insulina , Insulina/farmacologia , Aquaporina 1/genética , Aquaporina 1/metabolismo , Células Cultivadas , Células Endoteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Hiperglicemia/genética , Hiperglicemia/fisiopatologia , Manitol/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Concentração Osmolar , Pressão Osmótica/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
PLoS One ; 15(4): e0231212, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275682

RESUMO

Two major proteolytic systems, the proteasome and the autophagy pathway, are key components of the proteostasis network. The immunoproteasome, a proteasome subtype, and autophagy are upregulated under stress conditions, forming a coordinated unit designed to minimize the effect of cell stress. We investigated how genetic ablation of the LMP2 immunoproteasome subunit affects autophagy in retinal pigment epithelium (RPE) from WT and LMP2 knockout mice. We monitored autophagy regulation by measuring LC3, phosphorylation of AKT (S473), and phosphorylation of S6, a downstream readout of AKT (mTOR) pathway activation. We also evaluated transcription factor EB (TFEB) nuclear translocation, a transcription factor that controls expression of autophagy and lysosome genes. WT and LMP2 KO cells were monitored after treatment with EBSS to stimulate autophagy, insulin to stimulate AKT, or an AKT inhibitor (trehalose or MK-2206). Under basal conditions, we observed hyper-phosphorylation of AKT and S6, as well as lower nuclear-TFEB content in LMP2 KO RPE compared with WT. AKT inhibitors MK-2206 and trehalose significantly inhibited AKT phosphorylation and stimulated nuclear translocation of TFEB. Starvation and AKT inhibition upregulated autophagy, albeit to a lesser extent in LMP2 KO RPE. These data support the idea that AKT hyper-activation is an underlying cause of defective autophagy regulation in LMP2 KO RPE, revealing a unique link between two proteolytic systems and a previously unknown function in autophagy regulation by the immunoproteasome.


Assuntos
Autofagia , Complexo de Endopeptidases do Proteassoma/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Retina/citologia , Animais , Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Células Cultivadas , Cisteína Endopeptidases/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Humanos , Insulina/farmacologia , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Epitélio Pigmentado da Retina/citologia , Transdução de Sinais/efeitos dos fármacos
20.
Nat Commun ; 11(1): 1560, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32214091

RESUMO

Exercise training is a powerful means to combat metabolic diseases. Mice are extensively used to investigate the benefits of exercise, but mild cold stress induced by ambient housing temperatures may confound translation to humans. Thermoneutral housing is a strategy to make mice more metabolically similar to humans but its effects on exercise adaptations are unknown. Here we show that thermoneutral housing blunts exercise-induced improvements in insulin action in muscle and adipose tissue and reduces the effects of training on energy expenditure, body composition, and muscle and adipose tissue protein expressions. Thus, many reported effects of exercise training in mice are likely secondary to metabolic stress of ambient housing temperature, making it challenging to translate to humans. We conclude that adaptations to exercise training in mice critically depend upon housing temperature. Our findings underscore housing temperature as a critical parameter in the design and interpretation of murine exercise training studies.


Assuntos
Adaptação Fisiológica/fisiologia , Abrigo para Animais , Condicionamento Físico Animal/fisiologia , Tecido Adiposo/efeitos dos fármacos , Animais , Composição Corporal , Metabolismo Energético , Feminino , Microbioma Gastrointestinal , Insulina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Estresse Fisiológico , Temperatura
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