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1.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371877

RESUMO

Pathological mechanisms underlining diabetic bone defects include oxidative damage and insulin/IGF-1 imbalance. Morin is a bioflavonoid with antioxidant and anti-diabetic effects. This study evaluates morin's protective effects against altered bone histomorphometry in diabetic rats through assessing insulin/IGF-1 pathway as a potential mechanism. Diabetic animals were administered two morin doses (15 and 30 mg/kg) for 5 weeks. Different serum hepatic and renal functions tests were assessed. Bone density and histomorphometry in cortical and trabecular tissues were evaluated histologically. The expressions of insulin, c-peptide and IGF-1 were estimated. In addition, the enzymatic activities of the major antioxidant enzymes were determined. Diabetic-associated alterations in serum glucose, aminotransferases, urea and creatinine were attenuated by morin. Diabetic bone cortical and trabecular histomorphometry were impaired with increased fibrosis, osteoclastic functions, osteoid formation and reduced mineralization, which was reversed by morin; particularly the 30 mg/kg dose. Insulin/IGF-1 levels were diminished in diabetic animals, while morin treatment enhanced their levels significantly. Diabetes also triggered systemic oxidative stress noticeably. The higher dose (30 mg/kg) of morin corrected the endogenous antioxidant enzymatic activities in diabetic rats. Findings indicate the potential value of morin supplementation against hyperglycemia-induced skeletal impairments. Activation of insulin/IGF-1 signaling could be the underlining mechanism behind these effects.


Assuntos
Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Fêmur/efeitos dos fármacos , Flavonoides/farmacologia , Hipoglicemiantes/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/sangue , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/patologia , Fêmur/metabolismo , Fêmur/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais , Estreptozocina
2.
Photochem Photobiol Sci ; 20(6): 781-790, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34053000

RESUMO

Anterior Cingulate Cortex (ACC) has a crucial contribution to higher order pain processing. Photobiomodulation (PBM) has being used as integrative medicine for pain treatment and for a variety of nervous system disorders. This study evaluated the effects of PBM in the ACC of diabetic rats. Type 1 diabetes was induced by a single dose of streptozotocin (85 mg/Kg). A total of ten sessions of PBM (pulsed gallium-arsenide laser, 904 nm, 9500 Hz, 6.23 J/cm2) was applied to the rat peripheral nervous system. Glial fibrillary acidic protein (GFAP), mu-opioid receptor (MOR), glutamate receptor 1 (GluR1), and glutamic acid decarboxylase (GAD65/67) protein level expression were analyzed in the ACC of diabetic rats treated with PBM. Our data revealed that PBM decreased 79.5% of GFAP protein levels in the ACC of STZ rats. Moreover, STZ + PBM rats had protein levels of MOR increased 14.7% in the ACC. Interestingly, STZ + PBM rats had a decrease in 70.7% of GluR1 protein level in the ACC. Additionally, PBM decreased 45.5% of GAD65/67 protein levels in the ACC of STZ rats.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Giro do Cíngulo/metabolismo , Lasers , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Modelos Animais de Doenças , Processos Fotoquímicos , Ratos , Estreptozocina
4.
J Cancer Res Clin Oncol ; 147(6): 1623-1630, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33837821

RESUMO

PURPOSE: Immune checkpoint inhibitors (ICI) are highly effective in several cancer entities, but also invoke a variety of immune-related adverse events (irAE). These are mostly reversible, but can be life-threatening or even fatal. Currently, the pathogenesis is not fully understood, but crucial for effective treatment. Prediction and early detection of irAE could be facilitated and treatment optimized if relevant biomarkers and effector mechanisms were better characterized. METHODS: This study included a total of 45 irAE in patients with metastatic melanoma who were treated with ICI. All patients underwent a complete work-up with exclusion of other causes. Longitudinal blood samples were analyzed for a panel of soluble markers and compared to baseline and to patients who did not experience any irAE. Measurements included LDH, interleukin (IL)-6, IL-1ß, IL-17, C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha as well as tumor markers S100 and melanoma inhibitory activity (MIA). RESULTS: During the early onset of irAE increases in serum IL-6 (from mean 24.4 pg/ml at baseline to 51.0 pg/ml; p = 0.003) and CRP (from mean 7.0 mg/l at baseline to 17.7 mg/l; p = 0.001) and a decrease in MIA (from mean 5.4 pg/ml at baseline to 4.8 pg/ml; p = 0.035) were detected. No changes in IL-17 were noted. These effects were observed for irAE of different organ systems. CONCLUSION: Increases of a combination of IL-6 and CRP serum levels can be used for the early detection of irAE and tailored management. Interestingly, changes in MIA serum levels also correlate with irAE onset.


Assuntos
Autoimunidade/efeitos dos fármacos , Biomarcadores Tumorais/sangue , Inibidores de Checkpoint Imunológico/efeitos adversos , Inflamação/sangue , Adulto , Autoimunidade/genética , Autoimunidade/imunologia , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/imunologia , Doenças do Sistema Endócrino/sangue , Doenças do Sistema Endócrino/induzido quimicamente , Doenças do Sistema Endócrino/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Alemanha , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Masculino , Melanoma/sangue , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Metástase Neoplásica , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Uveais/sangue , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/genética , Neoplasias Uveais/patologia
5.
J Med Case Rep ; 15(1): 214, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33892782

RESUMO

BACKGROUND: Immune checkpoint inhibitors have recently become widely used for the management of advanced cancer patients. During the development of immune checkpoint inhibitors (ICPIs), it was quickly recognized that they are associated with autoimmune or autoinflammatory side effects. These toxicities are known as immune-related adverse events (irAEs): common endocrine irAEs include hypophysitis and thyroid dysfunction, and uncommon irAEs include type 1 diabetes mellitus (T1DM). CASE PRESENTATION: A 62-year-old Japanese man with metastatic renal cell carcinoma was treated with sunitinib followed by the 10th cycle of treatment with the ICPI nivolumab. He had already had thyroiditis and hypophysitis due to these anti-cancer drugs. On admission, he showed an extremely elevated plasma glucose level (601 mg/dl) and a low C-peptide level, and was diagnosed with acute T1DM. The patient was treated with intravenous fluid infusion and continuous insulin infusion. On the second day, he was switched to multiple daily injections of insulin therapy. Since these treatments, his blood glucose levels have been stable and he has been treated with an additional 10 ICPI treatments for renal cell carcinoma for over a year. CONCLUSIONS: Treatment with ICPIs is expected to increase in the future. There may be cases in which their use for cancer treatment is inevitable despite the side effects. As long as treatment with ICPI continues, multiple side effects can be expected in some cases. It is important to carefully observe the side effects that occur during ICPI treatment and to provide appropriate treatment for each side effect.


Assuntos
Carcinoma de Células Renais , Diabetes Mellitus Tipo 1 , Hipofisite , Neoplasias Renais , Carcinoma de Células Renais/tratamento farmacológico , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Hipofisite/induzido quimicamente , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos
6.
Environ Res ; 197: 111152, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33844969

RESUMO

AIMS/HYPOTHESIS: Women with type 1 diabetes have increased risk for poor obstetric outcomes. Prenatal air pollution exposure is also associated with adverse outcomes for women and infants. We examined whether women with type 1 diabetes are more vulnerable than other women to pollution-associated risks during pregnancy. METHODS: In singleton deliveries from the Consortium on Safe Labor (2002-2008), obstetric and neonatal outcomes were compared for women with type 1 diabetes (n = 507) and women without autoimmune disease (n = 204,384). Preconception, trimester, and whole pregnancy average air pollutant exposure (ozone (O3), carbon monoxide (CO), particulate matter >10 µm (PM10), PM > 2.5 µm (PM2.5), sulfur dioxide (SO2), nitrogen oxides (NOx)) were estimated using modified Community Multiscale Air Quality models. Poisson regression models with diabetes*pollutant interaction terms estimated relative risks and 95% confidence intervals for adverse outcomes, adjusted for maternal characteristics and geographic region. RESULTS: For whole pregnancy exposure to SO2, women with type 1 diabetes had 15% increased risk (RR:1.15 95%CI:1.01,1.31) and women without autoimmune disease had 5% increased risk (RR:1.05 95%CI:1.05,1.06) for small for gestational age birth (pinteraction = 0.09). Additionally, whole pregnancy O3 exposure was associated with 10% increased risk (RR:1.10 95%CI:1.02,1.17) among women with type 1 diabetes and 2% increased risk (RR:1.02 95%CI:1.00,1.04) among women without autoimmune disease for perinatal mortality (pinteraction = 0.08). Similar patterns were observed between PM2.5 exposure and spontaneous preterm birth. CONCLUSIONS: Pregnant women with type 1 diabetes may be at greater risk for adverse outcomes when exposed to air pollution than women without autoimmune disease.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Diabetes Mellitus Tipo 1 , Nascimento Prematuro , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Exposição Materna/efeitos adversos , Dióxido de Nitrogênio/análise , Dióxido de Nitrogênio/toxicidade , Material Particulado/análise , Material Particulado/toxicidade , Gravidez
7.
Environ Res ; 197: 111075, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33798519

RESUMO

OBJECTIVE: We investigated the effects of chronic exposures to particulate and traffic-related air pollution on allostatic load (AL) score, a marker of cumulative biological risk, among youth with type 1 diabetes. RESEARCH DESIGN AND METHODS: Participants were drawn from five clinical sites of the SEARCH for Diabetes in Youth (SEARCH) study (n = 2338). Baseline questionnaires, anthropometric measures, and a fasting blood test were taken at a clinic visit between 2001 and 2005. AL was operationalized using 10 biomarkers reflecting cardiovascular, metabolic, and inflammatory risk. Annual residential exposures to PM2.5 and proximity to heavily-trafficked major roadways were estimated for each participant. Poisson regression models adjusted for sociodemographic and lifestyle factors were conducted for each exposure. RESULTS: No significant associations were observed between exposures to PM2.5 or proximity to traffic and AL score, however analyses were suggestive of effect modification by race for residential distance to heavily-trafficked major roadways (p = 0.02). In stratified analyses, residing <100, 100-<200 and 200-<400 m compared to 400 m or more from heavily-trafficked major roadways was associated with 11%, 26% and 14% increases in AL score, respectively (95% CIs: -4, 29; 9, 45; -1, 30) for non-white participants compared to 6%, -2%, and -2% changes (95% CIs: -2, 15; -10, 7; -8, 6) for white participants. CONCLUSIONS: Among this population of youth with type 1 diabetes, we did not observe consistent relationships between chronic exposures to particulate and traffic-related air pollution and changes in AL score, however associations for traffic-related pollution exposures may differ by race/ethnicity and warrant further examination.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Alostase , Diabetes Mellitus Tipo 1 , Poluição Relacionada com o Tráfego , Adolescente , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/epidemiologia , Exposição Ambiental/análise , Humanos , Material Particulado/análise , Material Particulado/toxicidade , Emissões de Veículos/análise , Emissões de Veículos/toxicidade
8.
Eur J Pharmacol ; 901: 174061, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33766618

RESUMO

It has been previously demonstrated by our group that genetic inhibition of thioredoxin-interacting-protein (TXNIP) preserved retinal neuronal function in chemically-induced retinopathy. Moreover, elevated intracellular levels of TXNIP and calcium ions play important roles in hyperglycemia-induced oxidative stress and inflammation. Current study aimed to appraise the potential therapeutic benefits of pharmacological inhibition of TXNIP using verapamil in diabetic retinopathy. Diabetic retinopathy was assessed in type-1 diabetes rat model induced by a single intravenous injection of streptozotocin (45 mg/kg), with or without daily treatment with verapamil (10 mg/kg, oral) for 4 months. Verapamil treatment commenced 48 h post-streptozotocin insult and continued for 16 weeks. Untreated diabetic rats exhibited higher expression of toll-like-receptor-4 (TLR4), TXNIP, nucleotide-binding domain-like receptor protein-3 (NLRP3), caspase-1, cytochrome-c, and ssDNA as assessed immunohistochemically in both retinal and pancreatic tissues 16 weeks post-diabetes induction. This was associated with a reduced thioredoxin reductase (Trx-R) activity, increased release of TNF-α and IL-1ß into vitreous fluid along with retinal ganglion cell (RGC) loss, pancreatic islets shrinkage, and enhanced CD34 expression. The treatment with verapamil enhanced Trx-R activity, significantly inhibited TLR4 mediated NLRP3-inflammasome assembly with subsequent diminishing of inflammatory markers (TNF-α and IL-1ß) release into the vitreous, suppression of pathological angiogenesis, and preservation of RGC count and pancreatic islets diameter. Current study showed that using the calcium channel blocker, verapamil, interferes with the pathogenesis of diabetic retinopathy and pancreatic islets damage at multiple levels mainly through the inhibition of TLR4, TXNIP and NLRP3-inflammasome, suggesting its promising role as an anti-diabetic and a neuroprotective agent.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Retinopatia Diabética/tratamento farmacológico , Inflamassomos/efeitos dos fármacos , Pancreatopatias/tratamento farmacológico , Verapamil/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ratos , Ratos Wistar , Células Ganglionares da Retina/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Perda de Peso/efeitos dos fármacos
10.
Biochem Biophys Res Commun ; 546: 185-191, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33601314

RESUMO

Type 1 diabetes mellitus (T1DM) is characterized by hyperglycemia manifesting as insufficient insulin. Toll-like receptor-4 (TLR4) has been implicated in diabetic osteoporosis. We established streptozotocin (STZ)-induced diabetic mouse model and examined the relevant osteoporosis factors in different experimental groups, the WT-CON group, WT-STZ group, KO-CON group and KO-STZ group, respectively. No obvious protection of TLR4 deletion was shown in mice with diabetes. There was no obvious difference in the body weight or blood glucose concentration between WT-STZ group and KO-STZ group. However, TLR4 deletion reduced the receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation. Furthermore, TLR4 knockout attenuated STZ-induced diabetic osteoporosis via inhibiting osteoblasts and pre-inflammation factors mediated by the NF-κB pathway. TLR4 deletion ameliorated STZ-induced diabetic osteoporosis in mice, and TLR4 may be used as a potential therapeutic target for the treatment of diabetic osteoporosis.


Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Osteoporose/induzido quimicamente , Osteoporose/genética , Estreptozocina , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/genética , Animais , Osso Esponjoso/citologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/patologia , Diferenciação Celular/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Masculino , Camundongos , Terapia de Alvo Molecular , Fator 88 de Diferenciação Mieloide/metabolismo , Osteoclastos/citologia , Osteoclastos/patologia , Osteoporose/complicações , Osteoporose/patologia , Ligante RANK/metabolismo , Tíbia/citologia , Tíbia/diagnóstico por imagem , Tíbia/patologia , Microtomografia por Raio-X
11.
Int J Mol Sci ; 22(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546300

RESUMO

Type 1 diabetes mellitus is an autoimmune disease characterized by increased production of pro-inflammatory cytokines secreted by infiltrating macrophages and T cells that destroy pancreatic ß cells in a free radical-dependent manner that causes decrease or absence of insulin secretion and consequent hyperglycemia. Hence, suppression of pro-inflammatory cytokines and oxidative stress may ameliorate or decrease the severity of diabetes mellitus. To investigate the effect and mechanism(s) of action of RVD1, an anti-inflammatory metabolite derived from docosahexaenoic acid (DHA), on STZ-induced type 1 DM in male Wistar rats, type 1 diabetes was induced by single intraperitoneal (i.p) streptozotocin (STZ-65 mg/kg) injection. RVD1 (60 ng/mL, given intraperitoneally) was administered from day 1 along with STZ for five consecutive days. Plasma glucose, IL-6, TNF-α, BDNF (brain-derived neurotrophic factor that has anti-diabetic actions), LXA4 (lipoxin A4), and RVD1 levels and BDNF concentrations in the pancreas, liver, and brain tissues were measured. Apoptotic (Bcl2/Bax), inflammatory (COX-1/COX-2/Nf-κb/iNOS/PPAR-γ) genes and downstream insulin signaling proteins (Gsk-3ß/Foxo1) were measured in the pancreatic tissue along with concentrations of various antioxidants and lipid peroxides. RVD1 decreased severity of STZ-induced type 1 DM by restoring altered plasma levels of TNF-α, IL-6, and BDNF (p < 0.001); expression of pancreatic COX-1/COX-2/PPAR-γ genes and downstream insulin signaling proteins (Gsk-3ß/Foxo1) and the concentrations of antioxidants and lipid peroxides to near normal. RVD1 treatment restored expression of Bcl2/Pdx genes, plasma LXA4 (p < 0.001) and RVD1 levels and increased brain, pancreatic, intestine, and liver BDNF levels to near normal. The results of the present study suggest that RVD1 can prevent STZ-induced type 1 diabetes by its anti-apoptotic, anti-inflammatory, and antioxidant actions and by activating the Pdx gene that is needed for pancreatic ß cell proliferation.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação , Estresse Oxidativo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Ácidos Docosa-Hexaenoicos/uso terapêutico , Regulação da Expressão Gênica , Células Secretoras de Insulina , Masculino , Ratos , Ratos Wistar , Estreptozocina/toxicidade
12.
Int J Med Sci ; 18(2): 474-481, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33390816

RESUMO

Diabetes induces dry skin that may cause infective diseases. In this study, we aimed to clarify the mechanism of diabetes-induced skin dryness in animal models. We also examined the difference in the mechanism of skin dryness in type 1 and type 2 diabetes. We examined skin dryness in type 1 diabetes model mice (streptozotocin [STZ] induction), non-obesity type 2 diabetes model mice (newborn STZ injection), and obesity type 2 diabetes model mice (KK-Ay/TaJcl). An increase in transepidermal water loss was observed in the type 1 diabetes model mice, and reduced skin hydration was observed in the type 2 diabetes model mice. In the type 1 diabetes model mice, an increase in advanced glycation end products and matrix metalloproteinase-9 led to a decline in collagen IV level, inducing skin dryness. In the obesity type 2 diabetes model mice, an increase in the release of histamine and hyaluronidase by mast cells resulted in a decline in the level of hyaluronic acid, inducing skin dryness. However, in the non-obesity type 2 diabetes model mice, the main factors of skin dryness could not be clearly identified. Nevertheless, inflammatory cytokine levels increased. We hypothesize that inflammatory cytokines disrupt the collagen of the skin. Diabetes caused skin dryness in each mouse model, and the mechanism of skin dryness differed by diabetes type.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Dermatopatias/etiologia , Pele/patologia , Animais , Colágeno Tipo IV/análise , Colágeno Tipo IV/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 2/induzido quimicamente , Modelos Animais de Doenças , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Masculino , Metaloproteinase 9 da Matriz , Camundongos , Transdução de Sinais/imunologia , Pele/química , Pele/imunologia , Dermatopatias/patologia , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade
13.
Clin Sci (Lond) ; 135(1): 19-34, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33399849

RESUMO

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by insulin-producing pancreatic ß-cell destruction and hyperglycemia. While monocytes and NOD-like receptor family-pyrin domain containing 3 (NLRP3) are associated with T1D onset and development, the specific receptors and factors involved in NLRP3 inflammasome activation remain unknown. Herein, we evaluated the inflammatory state of resident peritoneal macrophages (PMs) from genetically modified non-obese diabetic (NOD), NLRP3-KO, wild-type (WT) mice and in peripheral blood mononuclear cells (PBMCs) from human T1D patients. We also assessed the effect of docosahexaenoic acid (DHA) on the inflammatory status. Macrophages from STZ-induced T1D mice exhibited increased inflammatory cytokine/chemokine levels, nitric oxide (NO) secretion, NLRP3 and iNOS protein levels, and augmented glycolytic activity compared to control animals. In PMs from NOD and STZ-induced T1D mice, DHA reduced NO production and attenuated the inflammatory state. Furthermore, iNOS and IL-1ß protein expression levels and NO production were lower in the PMs from diabetic NLRP3-KO mice than from WT mice. We also observed increased IL-1ß secretion in PBMCs from T1D patients and immortalized murine macrophages treated with advanced glycation end products and palmitic acid. The present study demonstrated that the resident PMs are in a proinflammatory state characterized by increased NLRP3/iNOS pathway-mediated NO production, up-regulated proinflammatory cytokine/chemokine receptor expression and altered glycolytic activity. Notably, ex vivo treatment with DHA reverted the diabetes-induced changes and attenuated the macrophage inflammatory state. It is plausible that DHA supplementation could be employed as adjuvant therapy for treating individuals with T1D.


Assuntos
Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/tratamento farmacológico , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Adulto , Animais , Células Cultivadas , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/enzimologia , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Macrófagos Peritoneais/enzimologia , Macrófagos Peritoneais/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Gravidez , Transdução de Sinais , Estreptozocina
14.
J Oncol Pharm Pract ; 27(3): 716-721, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32723064

RESUMO

INTRODUCTION: Immune-checkpoint inhibitors have become an increasingly popular form of systemic therapy for cancer treatment. Their use has proven to be so effective that certain regimens have gained approval as first-line therapy for various solid tumor types. The most common and well-studied forms of immunotherapy include agents that target cytotoxic T-lymphocyte antigen-4, programmed death-1, and programmed death ligand-1. These therapies act by blocking signaling between immune cells and cancer cells which subsequently augment T cell-mediated destruction of tumor cells. CASE REPORT: Here, we report a case of a 77-year-old black male with no history of or risk factors for diabetes mellitus who presented with acute onset of diabetic ketoacidosis after beginning immunotherapy with nivolumab for metastatic high-grade neuroendocrine tumor of the lung. He was admitted and treated for diabetic ketoacidosis but required prolonged use of an insulin infusion with frequent need of intravenous dextrose due to labile blood sugars. The patient was eventually discharged and discontinued further immunotherapy with nivolumab. DISCUSSION: Due to the unique mechanisms by which immune-checkpoint inhibitors cause immune-mediated destruction of tumor cells, clinicians may be challenged with their associated autoimmune complications referred to as immune-related adverse events. In particular, the incidence of endocrine dysfunction following immune-checkpoint inhibitor therapy is approximately 12%, with the development of insulin-dependent diabetes mellitus being a rare complication. Increasing awareness of immune-related adverse events is essential for the early recognition and effective management of patients who present with life-threatening complications related to immune-checkpoint inhibitor therapy.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Diabetes Mellitus Tipo 1/induzido quimicamente , Imunoterapia/efeitos adversos , Cetose/induzido quimicamente , Nivolumabe/efeitos adversos , Idoso , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Humanos , Imunoterapia/tendências , Cetose/sangue , Cetose/diagnóstico , Masculino
15.
Free Radic Biol Med ; 162: 129-140, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33278511

RESUMO

The aim of this work was to study the early events that occur in heart mitochondria and to analyse the temporal evolution of cardiac mitochondrial dysfunction in a type 1 diabetes model. Male Wistar rats were injected with Streptozotocin (STZ, single dose, 60 mg × kg-1, i.p.) and hyperglycemic state was confirmed 72 h later. The animals were sacrificed 10 or 14 days after STZ-injection. Heart mitochondrial state 3 O2 consumption sustained by malate-glutamate (21%) or by succinate (16%), and complexes I-III (27%), II-III (24%) and IV (22%) activities were lower in STZ group, when animals were sacrificed at day 14, i.e. ~11 days of hyperglycemia. In contrast, after 10 days of STZ-injection (~7 days of hyperglycemia), only the state 3 O2 consumption sustained by malate-glutamate (23%) and its corresponding respiratory control (30%) were lower in diabetic rats, in accordance with complex I-III activity reduction (17%). Therefore, this time (~7 days of hyperglycemia) has been considered as an "early stage" of cardiac mitochondrial dysfunction. At this point, mitochondrial production rates of H2O2 (117%), NO (30%) and ONOO- (~225%), and mtNOS expression (29%) were higher; and mitochondrial SOD activity (15%) and [GSH + GSSG] (28%) were lower in diabetic rats. Linear correlations between the modified mitochondrial parameters and glycemias were observed. PGC-1α expression was similar between groups, suggesting that mitochondrial biogenesis was not triggered in this initial phase of mitochondrial dysfunction. Consequently, complex I, H2O2 and NO could be considered early subcellular signals of cardiac mitochondrial dysfunction, with NO and H2O2 being located upstream de novo synthesis of mitochondria.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Animais , Diabetes Mellitus Tipo 1/induzido quimicamente , Peróxido de Hidrogênio , Masculino , Mitocôndrias Cardíacas , Ratos , Ratos Wistar
16.
Biomed Pharmacother ; 133: 110977, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33249280

RESUMO

Puerarin is an isoflavonoid extracted from Pueraria lobate with extensive pharmacological effects in traditional Chinese medicine. The evidence implicates that puerarin mitigates hyperglycemia and various relevant complications. Here, the effect of puerarin on skeletal muscle wasting induced by type 1 diabetes (T1D) was explored. Streptozotocin (STZ)-induced T1D male Sprague Dawley (SD) rats were used in this study. Muscle strength, weight and size were measured. L6 rat skeletal muscle cells were applied for in vitro study. Our results showed that eight-week oral puerarin administration (100 mg/kg) increased muscle strengths and weights accompanied by enhanced skeletal muscle cross-sectional areas in diabetic rats. Simultaneously, puerarin also reduced expressions of several muscle wasting marker genes including F-box only protein 32 (Atrogin-1) and muscle-specific RING-finger 1 (Murf-1) in diabetic group both in vitro and in vivo. Transformation from type I fibers (slow muscle) to type II fibers (fast muscle) were also observed under puerarin administration in diabetic rats. Puerarin promoted Akt/mTOR while inhibited LC3/p62 signaling pathway in skeletal muscle cells. In conclusion, our study showed that puerarin mitigated skeletal muscle wasting in T1D rats and closely related with Akt/mTOR activation and autophagy inhibition. Whether this effect in murine applies to humans remains to be determined.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Isoflavonas/farmacologia , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Lenta/efeitos dos fármacos , Atrofia Muscular/prevenção & controle , Animais , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Masculino , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Rápida/patologia , Fibras Musculares de Contração Lenta/metabolismo , Fibras Musculares de Contração Lenta/patologia , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Força Muscular/efeitos dos fármacos , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Estreptozocina , Serina-Treonina Quinases TOR/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
17.
J Mater Chem B ; 9(3): 648-657, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33306077

RESUMO

Diabetes and its complications have become crucial public health challenges worldwide. In this study, we aim to develop a dissolving and glucose-responsive insulin-releasing microneedle (MN) patch system, for minimally invasive and glucose-responsive insulin delivery for type 1 diabetes therapy. The MNs were composed of dissolving and biodegradable gelatin and starch materials, which encapsulated glucose-responsive insulin-releasing gold nanocluster (AuNC) nanocarriers. The fabricated MNs had a complete and uniform structure, consisting of an array of 11 × 11 conical needles, with a needle height of 756 µm, a bottom diameter of 356 µm, a tip diameter of 10 µm, and a tip-to-tip distance of 591 µm. The encapsulated AuNC nanocarriers as additives in the MNs enhanced the mechanical strength of the MNs, and facilitated the penetration of the MNs into the skins of mice. Moreover, the AuNC nanocarrier drugs in the MNs enabled MN patches with a glucose-responsive insulin releasing behavior. With one transdermal application of MN patches on the dorsal skin of mice, the MN patches effectively regulated the BG levels of mice in normoglycemic ranges for 1 to 2 days, and effectively alleviated the diabetic symptoms in type 1 diabetic mice. This dissolving and glucose-responsive insulin-releasing MN patch system realized a closed-loop administration of insulin with minimal invasion, providing great potential applications for type 1 diabetes therapy.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Administração Cutânea , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Portadores de Fármacos/química , Ouro/química , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Insulina/administração & dosagem , Nanopartículas Metálicas/química , Camundongos , Camundongos Endogâmicos C57BL , Agulhas , Tamanho da Partícula , Estreptozocina , Propriedades de Superfície
18.
Artigo em Inglês | MEDLINE | ID: mdl-33377427

RESUMO

Type 1 diabetes (T1D) is an autoimmune disorder caused by the destruction of insulin-secreting ß-cells.T1D is on the rise around the world. Exposure to polycyclic aromatic hydrocarbons (PAHs) including 2-aminoanthracene (2AA) is considered a contributor to TID increase. The contribution of the ingestion of 2AA toward T1D vulnerability is examined. 2AA is found in a variety of household products. Juvenile male Sprague Dawley rats ingested various amounts of 2AA contaminated diet for 12 weeks. Results showed marginal reduction in body weight gain for the 100 mg/kg treated animals. Glucose tolerance test (GTT) indicated no changes at six weeks. However, at week 12, both treated groups had higher levels of blood glucose than the control group. Serum insulin concentration was elevated in the 50 mg/kg group while reduced in the 100 mg/kg animals. Serum lactate dehydrogenase activity was elevated in treated groups. Evaluation of pancreatic inflammatory cytokines revealed overexpression of IL-1B, IL-6, and IL-7. Apoptotic genes in the pancreas of exposed rats were overly expressed. Histopathology and insulin immunohistochemistry data showed the presence of mesenteric vessels surrounded by lymphocyte and enlarged size of islet cells respectively in the high dose group. These results suggest 2AA ingestion may enhance T1D development.


Assuntos
Antracenos/toxicidade , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Exposição Dietética/análise , Poluentes Ambientais/toxicidade , Animais , Apoptose/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Interleucinas/genética , Masculino , Ratos , Ratos Sprague-Dawley , Risco
19.
Diab Vasc Dis Res ; 17(6): 1479164120970895, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33231124

RESUMO

BACKGROUND: The current study aimed to explore the role of SENP3 in endothelial cell dysfunction in a high-glucose setting. METHODS: The gene and protein expressions of SENP3 in high-glucose cultured HAECs were examined using quantitative PCR and western blotting. The effects of SENP3 on HAEC viability, apoptosis, migration, and endothelial-monocyte adhesion were evaluated in vitro by knockdown. Moreover, a mouse streptozotocin-induced type I diabetes model was established for SENP3 expression assessment. In addition, the effects of SENP3 on ROS-related signaling pathways were investigated in high-glucose cultured HAECs. RESULTS: Significantly increased levels of SENP3 mRNA and protein were found in high-glucose cultured HAECs in a time-dependent manner. SENP3 knockdown reversed high glucose-induced HAEC viability, apoptosis, and migration reduction. SENP3 knockdown attenuated the high glucose-induced intercellular adhesion of THP-1 monocytic cells and HAECs via downregulation of ICAM-1 and VCAM-1 expression. Increased levels of SENP3, ICAM-1, and VCAM-1 expression were observed in the aorta tissue of mice with type I diabetes. Downregulation of SENP3 expression was observed in HAECs cultured with high glucose levels using the free radical scavenger N-acetyl-L-cysteine or NOX4 siRNA. CONCLUSIONS: SENP3 was involved in high glucose-induced endothelial dysfunction, and ROS-dependent signaling served as the mechanism.


Assuntos
Cisteína Endopeptidases/metabolismo , Células Endoteliais/efeitos dos fármacos , Glucose/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Técnicas de Cocultura , Cisteína Endopeptidases/genética , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Transdução de Sinais , Estreptozocina , Células THP-1
20.
Sci Rep ; 10(1): 19358, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168874

RESUMO

5-HT inhibits cardiac sympathetic neurotransmission in normoglycaemic rats, via 5-HT1B, 5-HT1D and 5-HT5A receptor activation. Since type 1 diabetes impairs the cardiac sympathetic innervation leading to cardiopathies, this study aimed to investigate whether the serotonergic influence on cardiac noradrenergic control is altered in type 1 diabetic rats. Diabetes was induced in male Wistar rats by streptozotocin (50 mg/kg, i.p.). Four weeks later, the rats were anaesthetized, pithed and prepared for producing tachycardic responses by electrical preganglionic stimulation (C7-T1) of the cardioaccelerator sympathetic outflow or i.v. noradrenaline bolus injections. Immunohistochemistry was performed to study 5-HT1B, 5-HT1D and 5-HT5A receptor expression in the stellate ganglion from normoglycaemic and diabetic rats. In the diabetic group, i) i.v. continuous infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT1/5A agonist 5-carboxamidotryptamine (without modifying noradrenaline-induced tachycardia), but not by the agonists indorenate (5-HT1A), CP 93,129 (5-HT1B), PNU 142633 (5-HT1D), or LY344864 (5-HT1F); ii) SB 699551 (5-HT5A antagonist; i.v.) completely reversed 5-CT-induced cardiac sympatho-inhibition; and iii) 5-HT5A receptors were more expressed in the stellate ganglion compared to normoglycaemic rats. These results show the prominent role of the peripheral 5-HT5A receptors prejunctionally inhibiting the cardiac sympathetic drive in type 1 diabetic rats.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Receptores de Serotonina/fisiologia , Sistema Nervoso Simpático/fisiologia , 5-Metoxitriptamina/análogos & derivados , 5-Metoxitriptamina/farmacologia , Animais , Compostos de Bifenilo/farmacologia , Carbazóis/farmacologia , Cromanos/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Terapia por Estimulação Elétrica , Fluorbenzenos/farmacologia , Imuno-Histoquímica , Masculino , Norepinefrina/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Wistar , Receptor 5-HT1B de Serotonina/fisiologia , Receptor 5-HT1D de Serotonina/fisiologia , Serotonina/análogos & derivados , Serotonina/química , Serotonina/metabolismo
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