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1.
Life Sci ; 256: 118003, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32589998

RESUMO

INTRODUCTION AND AIMS: Polycystic ovary syndrome (PCOS) is a widespread endocrine disorder affecting females. Mechanisms underlying PCOS complicated pathology remain largely unknown, making current treatment only symptomatic. Increasing reports suggest impaired PI3K/AKT/mTOR pathway and tumor necrosis factor-α (TNF-α) levels are involved in cellular proliferation and metabolism-related disorders. However, rare data explored their role in PCOS. Hence, this study investigated TNF-α and pancreatic PI3K/AKT/mTOR levels in PCOS animal model and evaluated their effects on developed pancreatic deficits. Secondly; we explored the impact of nanocurcumin as powerful anti-inflammatory supplement against these developed pancreatic pathologies. METHODS: PCOS was induced in rats using letrozole. Nanocurcumin was formulated to increase solubility and bioavailability of curcumin. Transmission electron microscopy (TEM), zeta potential and Infra-red spectroscopy (FT-IR) were used for characterization. Nanocurcumin was orally ingested for 15 days. FINDINGS: PCOS group exhibited significant disturbance in sex hormones, oxidative stress markers, and TNF-α levels as determined by immunoassay. Western blotting revealed significant reduction of PI3K/AKT/mTOR levels leading to impaired insulin sensitivity, decreased ß cells function and mass as confirmed by HOMA assessments and immunohistochemistry. Nanocurcumin significantly improved oxidative markers, glucose indices and TNF-α levels. It reinstated PI3K/AKT/mTOR levels, alleviated insulin resistance, and retained islets integrity consequently restoring normal sex hormonal levels. SIGNIFICANCE: To the best of our knowledge, the study is the first to report pancreatic role of PI3K/AKT/mTOR and TNF-α in PCOS and the first to demonstrate nanocurcumin promising potential against PCOS-related pancreatic molecular and histological pathologies that can indeed offer better control of the disease.


Assuntos
Curcumina/farmacologia , Resistência à Insulina , Nanopartículas , Pâncreas/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Animais , Curcumina/administração & dosagem , Modelos Animais de Doenças , Feminino , Pâncreas/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
Toxicol Appl Pharmacol ; 399: 115035, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32422327

RESUMO

BACKGROUND AND AIMS: Cholecystokinin (CCK) may potentially be used to treat obesity. However, it is well-known to induce acute pancreatitis and pancreas neoplasia in rodents, but not in primates. Here we report the nonclinical safety profile of a long-acting CCK-1 receptor (CCK-1R) agonist, NN9056, in rats and monkeys to support a First-in-Man clinical trial with NN9056. METHODS: Thirteen-week toxicological studies were conducted in rats and non-human primates followed by histopathological evaluation of affected tissues. NN9056 was characterised in vitro, and CCK-1R expression was assessed by in situ hybridization in cynomolgus monkey and human pancreas tissues. RESULTS: Affinity and potency of NN9056 was comparable to native sulphated CCK-8 (CCK-8) across species on the CCK-1R while it had no effect on the CCK-2 receptor (CCK-2R). In situ hybridization demonstrated abundant expression of CCK-1Rs in the exocrine pancreas of the rat. In contrast, it was only discreetly expressed on pancreatic acinar cells in the periphery of scattered lobules in monkeys. A similar expression pattern was observed in human pancreas. 13-weeks daily dosing with NN9056 produced the expected pancreatic pathological findings in rats. In monkeys, NN9056 increased pancreas weight and induced histopathological changes despite the low expression level of CCK-1Rs. CONCLUSION: Surprisingly, chronic CCK-1R activation constitutes a risk for pancreatitis and trophic actions on the exocrine pancreas in monkeys. Since similar CCK-1R expression patterns were found in pancreas of monkeys and humans this risk is likely translatable to humans and clinical development of NN9056 was therefore halted.


Assuntos
Pâncreas Exócrino/efeitos dos fármacos , Pâncreas Exócrino/patologia , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Receptores da Colecistocinina/agonistas , Células Acinares/efeitos dos fármacos , Células Acinares/patologia , Animais , Células COS , Chlorocebus aethiops , Colecistocinina/metabolismo , Humanos , Macaca fascicularis , Primatas , Ratos
3.
Adv Clin Exp Med ; 29(5): 587-595, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32459401

RESUMO

BACKGROUND: Disturbances in pancreatic microcirculation, beginning with vasoconstriction, are crucial in early pancreatitis and progression to necrotizing pancreatitis. Thus, vascular-targeted treatment aiming to restore a sufficient level of microcirculation through vasodilation would possibly reduce the severity of pancreatitis. Lidocaine is an anti-arrhythmic and local anesthetic drug, which also acts as a vasodilator at higher concentrations. OBJECTIVES: To evaluate the efficacy of intra-arterial infusion of lidocaine into the celiac trunk in treatment of cerulein-induced acute pancreatitis. MATERIAL AND METHODS: Wistar rats (n = 20) were randomly divided into 2 equal groups: the control group (NaCl group, n = 10) and the study group (lidocaine group, n = 10). All subjects underwent surgical intervention with intra-arterial infusion of 0.9% NaCl (control group) or 1% lidocaine hydrochloride (study group) into the celiac trunk. Blood samples were collected 5 times at regular intervals from each rat for amylase and lipase measurements. Histopathological analysis of the pancreas was performed. RESULTS: A total number of 16 rats (control group n = 7, study group n = 9) were included. In the postoperative course, the study group (lidocaine group) revealed lower values of serum amylase and lipase levels compared to the control group (NaCl group), except the values at the 1st treatment point, which appeared 1 h after intraoperative drug injection. Significantly lower treatment endpoint levels of pancreatic enzymes were seen in the lidocaine group. Moreover, no differences were observed between the 1st and the last treatment point in the control group; however, these differences were significant for both enzymes in the study group. Histopathology revealed reduced pancreatitis severity in the study group compared to the controls. CONCLUSIONS: Intra-arterial lidocaine infusion into the celiac trunk decreases pancreatitis severity. What is more, this study demonstrates the relevance of early vasodilation in the therapy of acute pancreatitis.


Assuntos
Ceruletídeo/efeitos adversos , Lidocaína/administração & dosagem , Pancreatite/tratamento farmacológico , Doença Aguda , Animais , Ceruletídeo/uso terapêutico , Infusões Intra-Arteriais , Lidocaína/uso terapêutico , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/patologia , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do Tratamento
4.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188360, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32234337

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor prognosis and high mortality. Molecular aberrations associated with PDAC pathogenesis and progression have been extensively investigated. Nevertheless, these findings have not been translated into clinical practice. Lack of therapeutics for PDAC treatment is another challenge. Recent application of molecularly targeted and immunoregulatory therapies appears to be disappointing. Thus, discovery of new targets and therapeutics is urgently needed to combat this malignant disease. The RON receptor tyrosine kinase is a tumorigenic determinant in PDAC malignancy, which provides the rationale to target RON for PDAC treatment. In this review, we summarize the latest evidence of RON in PDAC pathogenesis and the development of anti-RON antibody-drug conjugates for potential PDAC therapy. The finding that anti-RON antibody-drug conjugates show efficacy in preclinical animal models highlights the potential of this novel class of anti-cancer biotherapeutics in future clinical trials.


Assuntos
Anticorpos Monoclonais/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Imunoconjugados/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Humanos , Imunoconjugados/uso terapêutico , Terapia de Alvo Molecular/métodos , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Toxicol Lett ; 326: 106-113, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32142839

RESUMO

This study aimed to investigate the toxic effects of microcystin-LR (MC-LR), which is released from several bloom-forming cyanobacteria, on the glucose metabolism of pancreatic ß cells in vivo and in vitro. Male mice and the pancreatic MIN6 cells were respectively treated with varying concentrations of MC-LR. After 3- or 6- months of MC-LR exposure, increase in the body weight of mice was found to be inhibited, and the structure of their pancreatic tissues was damaged with impaired glucose tolerance and impaired insulin secretion. Further, these toxic effects became more pronounced with time and with increased dosages. Direct cytotoxic effects of MC-LR were observed in the MIN6 pancreatic ß-cells possibly due to their expression of the MC-LR specific transporter. MC-LR entered the MIN6 cells that significantly reduced the cell viability. Both in vivo and in vitro experiments demonstrated that MC-LR was able to induce apoptosis, possibly associated with mitochondrial damage. Above all, these findings implied that MC-LR may be transported into the pancreatic ß cells and cause subsequent cytotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cianobactérias/química , Glucose/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Microcistinas/toxicidade , Pâncreas/efeitos dos fármacos , Animais , Masculino , Camundongos
6.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188359, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32222610

RESUMO

Advanced cancer patients exhibit cachexia, a condition characterized by a significant reduction in the body weight predominantly from loss of skeletal muscle and adipose tissue. Cachexia is one of the major causes of morbidity and mortality in cancer patients. Decreased food intake and multi-organ energy imbalance in cancer patients worsen the cachexia syndrome. Cachectic cancer patients have a low tolerance for chemo- and radiation therapies and also have a reduced quality of life. The presence of tumors and the current treatment options for cancer further exacerbate the cachexia condition, which remains an unmet medical need. The onset of cachexia involves crosstalk between different organs leading to muscle wasting. Recent advancements in understanding the molecular mechanisms of skeletal muscle atrophy/hypertrophy and adipose tissue wasting/browning provide a platform for the development of new targeted therapies. Therefore, a better understanding of this multifactorial disorder will help to improve the quality of life of cachectic patients. In this review, we summarize the metabolic mediators of cachexia, their molecular functions, affected organs especially with respect to muscle atrophy and adipose browning and then discuss advanced therapeutic approaches to cancer cachexia.


Assuntos
Estimulantes do Apetite/uso terapêutico , Caquexia/patologia , Atrofia Muscular/patologia , Neoplasias/complicações , Apoio Nutricional/métodos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/efeitos da radiação , Antineoplásicos/efeitos adversos , Estimulantes do Apetite/farmacologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Osso e Ossos/efeitos da radiação , Caquexia/etiologia , Caquexia/metabolismo , Caquexia/terapia , Citocinas/metabolismo , Suplementos Nutricionais , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/efeitos da radiação , Glucocorticoides/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos da radiação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/efeitos da radiação , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/efeitos da radiação , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Neoplasias/terapia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Pâncreas/efeitos da radiação , Hormônio Paratireóideo/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Qualidade de Vida , Radioterapia/efeitos adversos , Ganho de Peso/efeitos dos fármacos
7.
Am J Physiol Gastrointest Liver Physiol ; 318(4): G694-G704, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32116022

RESUMO

Alcoholic pancreatitis is a multifactorial, progressive, inflammatory disorder of the pancreas. Alcohol initiates pancreatitis and promotes its progression in the context of genetic susceptibility and/or other environmental risk factors such as smoking. Genetic mutations can cause digestive enzyme misfolding, which induces endoplasmic reticulum (ER) stress and elicits pancreatitis. Here, we tested the hypothesis that alcohol synergizes with misfolding in promoting ER stress and thereby accelerates chronic pancreatitis progression. To this end, we fed an ethanol-containing diet to CPA1 N256K mice, which carry the human p.N256K CPA1 mutation and develop spontaneous chronic pancreatitis. Inexplicably, CPA1 N256K mice suffered generalized seizures after 2-3 wk of ethanol feeding, which resulted in high mortality and the early termination of the study. Analysis of CPA1 N256K mice euthanized after 3-3.5 wk of ethanol feeding revealed more severe chronic pancreatitis associated with significantly increased Hspa5 [ER chaperone immunoglobulin heavy chain-binding protein (BiP)] mRNA levels when compared with CPA1 N256K mice on a control liquid diet. In contrast, ethanol feeding of C57BL/6N mice for 4 wk increased Hspa5 levels to a lesser degree and caused no pancreatitis. We conclude that ethanol feeding synergizes with the misfolding CPA1 mutant in promoting ER stress and thereby accelerates progression of chronic pancreatitis in CPA1 N256K mice.NEW & NOTEWORTHY Alcoholic pancreatitis is a multifactorial, progressive, inflammatory disorder of the pancreas. This study demonstrates that alcohol synergizes with digestive enzyme misfolding in promoting endoplasmic reticulum stress and thereby accelerates progression of chronic pancreatitis.


Assuntos
Carboxipeptidases A/metabolismo , Etanol/toxicidade , Pâncreas/efeitos dos fármacos , Pancreatite Alcoólica/genética , Animais , Peso Corporal , Carboxipeptidases A/genética , Ingestão de Alimentos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Etanol/administração & dosagem , Predisposição Genética para Doença , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pancreatite Alcoólica/patologia
8.
Biol Pharm Bull ; 43(3): 509-515, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115510

RESUMO

Acute pancreatitis (AP) is one kind of acute surgical abdominal disease in the world. It causes intestinal damage with subsequent bacterial migration, endotoxemia and secondary pancreatic infections. In this investigation, we determined that edaravone (EDA) reduces pancreatic and intestinal injury after AP in mice. This was demonstrated by a reduction in histological score, apoptosis, interleukin (IL)-6, IL-1ß and tumor necrosis factor (TNF)-α, along with obstructing activation of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NFκB). Our study results suggested that EDA exerts its protective effects against pancreatic and intestinal injury after AP via regulation of the TLR4/NFκB pathway. Our findings provide the basis for EDA to treat AP-induced pancreatic and intestinal injury, even might develop as a potential therapy for other inflammatory diseases.


Assuntos
Edaravone/farmacologia , Intestinos/patologia , NF-kappa B/metabolismo , Pâncreas/patologia , Pancreatite/tratamento farmacológico , Pancreatite/metabolismo , Animais , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pancreatite/patologia , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
J Agric Food Chem ; 68(10): 2973-3005, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32105058

RESUMO

Leaf teas are widely used as a purported treatment for dysregulated glucose homeostasis. The objective of this study was to systematically evaluate the clinical and cellular-metabolic evidence, published between January 2013 and May 2019, and indexed on PubMed, ScienceDirect, and Web of Science, supporting the use of leaf teas for this purpose. Fourteen randomized controlled trials (RCTs) (13 on Camellia sinensis teas) were included, with mixed results, and providing scant mechanistic information. In contrast, 74 animal and cell culture studies focusing on the pancreas, liver, muscle, and adipose tissue yielded mostly positive results and highlighted enhanced insulin signaling as a recurring target associated with the effects of teas on glucose metabolism. We conclude that more studies, including RCTs and pre-clinical studies examining teas from a wider variety of species beyond C. sinensis, are required to establish a stronger evidence base on the use of leaf teas to normalize glucose metabolism.


Assuntos
Camellia sinensis/química , Glucose/metabolismo , Extratos Vegetais/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Humanos , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculos/efeitos dos fármacos , Músculos/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Extratos Vegetais/química , Folhas de Planta/química , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Life Sci ; 247: 117458, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32092333

RESUMO

AIMS: The use of natural agents with anti-diabetic effect in combination therapy adds further positive clinical implications in the management of diabetes mellitus. Interestingly, quercetin is one of the most potent naturally occurring antioxidant which possesses various pharmacological actions including anti-diabetic effect. Thus, this research was conducted to assess the efficiency of a new combination from gliclazide and quercetin on glycemic control as well as pancreatic islets and beta cells in STZ-experimental model of diabetes. MAIN METHODS: Diabetes has been induced by a single intraperitoneal injection of streptozotocin (STZ; 45 mg/kg) in adult male Wistar rats. For 3 consecutive weeks, diabetic rats were given orally either gliclazide (10 mg/kg), quercetin (50 mg/kg), or their combination. At the end of the experiment, histological, immunohistochemical and morphometrical examination of pancreatic tissues was performed. Furthermore, the changes in glucose metabolism, lipid profile, oxidative and inflammatory status were evaluated. KEY FINDINGS: Treatment with gliclazide alone decreased serum glucose, total cholesterol, triglycerides, malondialdehyde, tumor necrosis factor-alpha and nuclear factor kappa-Beta while increased serum C-peptide, superoxide dismutase, reduced glutathione and adiponectin levels. Combined administration of quercetin with gliclazide markedly augmented serum superoxide dismutase and reduced glutathione more than gliclazide alone and normalized all the above-mentioned parameters. Besides, this combination therapy restored immunostaining intensity, number of pancreatic islets and beta cells along with its area and perimeter. SIGNIFICANCE: Based on the aforementioned results, this combination could be considered a promising one in diabetes mellitus management.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Gliclazida/uso terapêutico , Hipoglicemiantes/uso terapêutico , Quercetina/uso terapêutico , Estreptozocina/metabolismo , Animais , Glicemia/metabolismo , Peptídeo C/metabolismo , Colesterol/metabolismo , Quimioterapia Combinada/métodos , Glutationa/metabolismo , Inflamação/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Electron. j. biotechnol ; 43: 41-47, Jan. 2020. graf, ilus
Artigo em Inglês | LILACS | ID: biblio-1087517

RESUMO

Background: The harmful effects of type 2 diabetes mellitus and its complications have become a major global public health problem. In this study, the effects of Momordica charantia saponins (MCS) on lipid metabolism, oxidative stress, and insulin signaling pathway in type 2 diabetic rats were investigated. Results: MCS could attenuate the tendency of weight loss of the model rats. It could also improve glucose tolerance; reduce fasting blood glucose, nonesterified fatty acid, triglyceride, and total cholesterol; and increase the insulin content and insulin sensitivity index of the rats. The activity of superoxide dismutase and catalase increased, and the content of malondialdehyde decreased in the liver and pancreas tissues of rats in MCS-treated groups significantly. In addition, the expression of p-IRS-1 (Y612) and p-Akt (S473) increased, and the expression of p-IRS-1 (S307) decreased in the liver tissues and pancreas tissues of rats in MCS-treated groups significantly. Conclusion: MCS has an antidiabetic effect, which may be related to its improving the lipid metabolism disorder, reducing oxidative stress level, and regulating the insulin signaling pathway.


Assuntos
Animais , Masculino , Ratos , Saponinas/uso terapêutico , Momordica charantia/química , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Pâncreas/efeitos dos fármacos , Saponinas/farmacologia , Glicemia/efeitos dos fármacos , Peso Corporal , Resistência à Insulina , Ratos Wistar , Estresse Oxidativo/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Lipídeos , Fígado/efeitos dos fármacos
12.
Pharm Res ; 37(2): 21, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897616

RESUMO

PURPOSE: Pancreatic cancer (PC) is predicted to become the second leading cause of cancer associated deaths by 2020. Earlier, we confirmed the development and efficacy of our novel Loratadine Self-Microemulsifying-Drug-Delivery-System - Sulforaphane (LOR SMEDDS -SFN) nanoformulation in PC chemoprevention. In this report, we extend our studies to evaluate the PC chemoprevention efficacy of LOR SMEDDS - SFN. METHODS: The nanoformulation was subjected to in vitro colony formation assays, in vivo oral pharmacokinetics and stability studies. RESULTS: The colony formation assay using Panc-1 PC cells demonstrated a survival fraction of 0.74 with LOR-SFN (p < 0.001) which further reduced to 0.35 with LOR SMEDDS-SFN treatment (p < 0.0001) confirming the synergistic chemoprevention efficacy of the nanoformulation. Further, the oral pharmacokinetic studies of LOR SMEDDS-SFN showed 4-fold and 9-fold increase in Cmax (503.2 ± 5.8 ng/mL) and oral bioavailability (20,274.8 ± 3711.0 ng·h/mL) for LOR compared to LOR-SFN combination respectively assuring the enhanced performance by the SMEDDS. Additionally, the formulation exhibited statistically non-significant alteration in globule size, zeta potential, drug content and in vitro drug release during stability studies confirming its stability and pharmaceutical acceptability. CONCLUSION: Our studies have demonstrated a potential of LOR SMEDDS-SFN nanoformulation as an effective PC chemoprevention strategy.


Assuntos
Loratadina/farmacologia , Loratadina/farmacocinética , Pâncreas/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/prevenção & controle , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimioprevenção/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Emulsões/farmacocinética , Emulsões/farmacologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Solubilidade/efeitos dos fármacos
13.
J Pharmacol Exp Ther ; 372(3): 256-263, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900320

RESUMO

Excess intramyocellular lipid (IMCL) deposition in skeletal muscle is closely associated with insulin resistance. Pharmacological inhibition of acetyl-CoA carboxylase (ACC) 2 offers a promising approach to treat insulin resistance through stimulation of mitochondrial fatty acid oxidation (FAO) and reduction of IMCL deposition. Previously reported experimental ACC2 inhibitors exhibited plasma glucose-lowering effects in diabetic rodents. However, their antidiabetic action may be potentially biased by off-target effects on triglyceride metabolism or by neurologic side effects. In this study, we investigated a safety profile, target dependency of its action, and antidiabetic efficacy of compound 2e, a novel olefin derivative potent ACC2 selective inhibitor. Four-day administration of suprapharmacological dose of compound 2e did not exhibit any obvious side effects in Sprague-Dawley rats. In db/db mice, single administration of compound 2e led to significantly elevated FAO and reduced IMCL deposition in skeletal muscle. In ACC2 knockout mice, treatment with pharmacological doses of compound 2e did not reduce plasma triglyceride levels, whereas A-908292, a previously reported ACC2 inhibitor, caused a significant triglyceride reduction, showing that compound 2e was devoid of off-target triglyceride-lowering activity. Chronic treatment of db/db mice with compound 2e improved hyperglycemia but did not decrease plasma triglyceride levels. Additionally, compound 2e showed significant improvements of whole-body insulin resistance in the clamp study and insulin tolerance test. Collectively, compound 2e demonstrated a good safety profile and significant antidiabetic effects through inhibition of ACC2-dependent pathways. These findings provide further evidence that selective inhibition of ACC2 is an attractive strategy against insulin resistance and type 2 diabetes. SIGNIFICANCE STATEMENT: This study shows that pharmacological inhibition of acetyl-CoA carboxylase (ACC) 2 leads to significant improvements in whole-body glucose homeostasis, independently of off-target metabolic pathways and toxicity, which were observed in previously reported ACC2 inhibitors. These findings support the concept that ACC2-selective inhibitors will be a novel remedy for treatment of type 2 diabetes.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Acetil-CoA Carboxilase/genética , Animais , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipoglicemiantes/toxicidade , Insulina/metabolismo , Camundongos Knockout , Músculo Esquelético/enzimologia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Ratos Sprague-Dawley , Testes de Toxicidade , Triglicerídeos/sangue
14.
Toxicol Appl Pharmacol ; 390: 114899, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31981641

RESUMO

High-fat diet (HFD)-induced obesity is implicated in diabetic nephropathy (DN). EX-527, a selective Sirtuin 1 (SIRT1) inhibitor, has multiple biological functions; however, its protective effect against DN is yet to be properly understood. This study was aimed to explore the protective effect of EX-527 against DN in HFD-induced diabetic Zucker (ZDF) rats. After 21 weeks of continually feeding HFD to the rats, the apparent characteristics of progressive DN were observed, which included an increase in kidney weight (~160%), hyperglycemia, oxidative stress, and inflammatory cytokines, and subsequent renal cell damage. However, the administration of EX-527 for 10 weeks significantly reduced the blood glucose concentration and kidney weight (~59%). Furthermore, EX-527 significantly reduced the serum concentration of transforming growth factor-ß1 (49%), interleukin (IL)-1ß (52%), and IL-6 in the HFD-fed rats. Overall, the antioxidant activities significantly increased, and oxidative damage to lipids or DNA was suppressed. Particularly, EX-527 significantly reduced blood urea nitrogen (81%), serum creatinine (71%), microalbumin (43%), and urinary excretion of protein-based biomarkers. Histopathological examination revealed expansion of the extracellular mesangial matrix and suppression of glomerulosclerosis following EX-527 administration. EX-527 downregulated the expression of α-SMA (~64%), TGF-ß (25%), vimentin, α-tubulin, fibronectin, and collagen-1 in the kidneys of the HFD-fed rats. Additionally, EX-527 substantially reduced claudin-1 and SIRT1 expression, but increased the expression of SIRT3 in the kidneys of the HFD-fed rats. EX-527 also inhibited the growth factor receptors, including EGFR, PDGFR-ß, and STAT3, which are responsible for the anti-fibrotic effect of SIRT-1. Therefore, the administration of EX-527 protects against HFD-induced DN.


Assuntos
Carbazóis/farmacologia , Nefropatias Diabéticas/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , Animais , Biomarcadores/sangue , Glicemia , Citocinas/genética , Citocinas/metabolismo , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/etiologia , Regulação da Expressão Gênica , Produtos Finais de Glicação Avançada , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Ratos , Ratos Zucker
15.
J Nat Med ; 74(1): 34-40, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31256310

RESUMO

Four new cucurbitane-type triterpenes were isolated from the fruit of Momordica charantia L. The structures of the new compounds were identified based on HR-ESI-MS and 1D- and 2D-NMR spectroscopic methods. The cytotoxicity of the isolated compounds was evaluated using three human cancer cell lines, HeLa, Caco2, and U87. Compound 3 exhibited significant cytotoxic activity against HeLa cells with an IC50 value of 11.18 µM. Additionally, the cytoprotective activity of these compounds was determined in vitro against H2O2-induced pancreatic injury. The results revealed that all the compounds obtained possess cytoprotective effects against H2O2-induced injury in MIN6 ß-cells at a concentration of 10 µM.


Assuntos
Glicosídeos/química , Peróxido de Hidrogênio/efeitos adversos , Momordica charantia/química , Pâncreas/efeitos dos fármacos , Triterpenos/química , Humanos
16.
Planta Med ; 86(2): 113-120, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31801161

RESUMO

As a kind of traditional Chinese medicine extract, curcumin has been proven to be effective in inhibiting inflammation and apoptosis in pancreatic islet ß cells in the streptozotocin-induced diabetes mellitus rat model, although the underlying mechanism has not yet been clarified. To examine the effect of curcumin on inflammation and apoptosis in pancreatic islet ß cells, we established a type 2 diabetes rat model by feeding the animals a high-fat diet and intraperitoneally injecting streptozotocin. The curcumin was administered by intraperitoneal injection. The rat body weight, fasting blood glucose, intraperitoneal glucose tolerance tests, and insulin tolerance tests were recorded and analyzed. Hematoxylin and eosin staining was used for morphological analysis, and a TUNEL assay was performed to detect the apoptotic cells. The expression levels of proteins related to oxidative stress, inflammation and apoptosis were detected by Western blotting and ELISA. Curcumin administration significantly decreased fasting blood glucose and promoted recovery of pancreas function in type 2 diabetes rats. In curcumin-treated rats, the pancreatic tissue destruction and apoptosis index were reduced. The expression of IL-1ß, IL-6, TNF-α, caspase-3, Bax, and malondialdehyde were significantly reduced, and Bcl-2, superoxide dismutase 2, and glutathione peroxidase were significantly increased. Curcumin inhibited the expression of phosphorylated JNK and NF-κB proteins to block the RAGE/JNK/NF-κB signaling pathway. In conclusion, these results indicate that curcumin blocks the phosphorylation of JNK and NF-κB protein to inhibit this signaling pathway, thereby further inhibiting inflammation and apoptosis in pancreatic islet ß cells. Curcumin has potential value for the treatment of diabetes.


Assuntos
Curcumina/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Pâncreas/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Curcumina/química , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Teste de Tolerância a Glucose , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estrutura Molecular , Pâncreas/patologia , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Sprague-Dawley , Estreptozocina
17.
Nat Prod Res ; 34(6): 759-765, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30445852

RESUMO

Silymarin is a mixture of flavonolignans extracted from the fruit of Silybum marianum (milk thistle). The latter is used as a medicinal plant to treat liver and gallbladder disorders. Recently, silymarin has been investigated for its effects against diabetes mellitus, and shown to reduce serum levels of glucose in model animals and in clinical trials. This effect can be explained mainly by the protective effect of silymarin against pancreatic beta-cells, but the involvement of other mechanisms is possible. We demonstrated the α-amylase inhibitory activity of silymarin and investigated the components responsible for this effect. Two major flavonolignans, silibinin and silychristin, did not show inhibition against α-amylase, but two novel silychristin derivatives conjugated with dehydrodiconiferyl alcohol were isolated as the mildly inhibiting components of silymarin. Further analyses indicated the presence of various silychristin derivatives in silymarin that may act synergistically to show α-amylase inhibitory activity.[Formula: see text].


Assuntos
Álcoois/química , Cardo-Mariano/química , alfa-Amilases Pancreáticas/antagonistas & inibidores , Silimarina/química , Álcoois/farmacologia , Animais , Antioxidantes/farmacologia , Pâncreas/efeitos dos fármacos , Pâncreas/enzimologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Silimarina/farmacologia
18.
Biomed Pharmacother ; 121: 109522, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31675539

RESUMO

Date palm fruit (Phoenix dactylifera L.) is an endemic functional food, with great nutritional and economic importance due to its phytochemical compositions. The microenvironment of pancreatic cancer consists of cellular and acellular components, including fibroblasts, myofibroblasts, pancreatic stellate cells (PSCs), immune cells, blood vessels, extracellular matrix (ECM) and soluble proteins, such as cytokines and growth factors. The ECM represents a physical barrier that protects the tumor cell from active therapeutic compounds. In this study, four different solvents; water, ethanol, acetone, and ethyl acetate have been used to extract natural products from date palm fruit using a maceration method. The prepared extracts were investigated for antifibrotic (expression of fibronectin-1 and alpha-smooth muscle actin) and antiproliferative activity in tumor necrosis factor (TNF) stimulated PSCs in vitro. Based on the pharmacological test results, the ethyl acetate extract was subsequently partitioned into nine fractions based on polarity using silica gel column chromatography. These nine collective fractions were further evaluated for their activity. Ethanol, ethyl acetate and acetone, but not water extract significantly reduced PSC proliferation (p < 0.05). Date fruit fractions reduced fibrosis, decreased PSC activity and reversed the PSCs' fibrotic phenotype. The findings suggest a new approach for targeting pancreatic cancer through the modulation of PSC activity, thereby possibly enhancing the effect of known anticancer drugs. Moreover, date palm fruit appears to have chemopreventive activity protecting from pancreatic and probably other types of cancer, and thereby might be useful candidate to the pharmaceutical and nutraceutical industries in the development of natural compound-based industrial anticancer product.


Assuntos
Antineoplásicos/farmacologia , Frutas/química , Neoplasias Pancreáticas/tratamento farmacológico , Phoeniceae/química , Extratos Vegetais/farmacologia , Antineoplásicos/química , Células Cultivadas , Matriz Extracelular/efeitos dos fármacos , Humanos , Pâncreas/efeitos dos fármacos , Células Estreladas do Pâncreas/efeitos dos fármacos , Extratos Vegetais/química , Microambiente Tumoral/efeitos dos fármacos
19.
Eur J Pharmacol ; 866: 172801, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31738935

RESUMO

Ginseng has been traditionally used to treat diabetes mellitus (DM) in China. Ginsenoside Rg1 is a major active ingredient in processed ginseng, which elicits proven biological and pharmacological effects. Although a correlation between nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and predisposition to type 1 diabetes mellitus (T1DM) has been identified, the mechanism underlying the potential function and activation of NLRP3 inflammasome in DM have not been elucidated to date. The present study aimed to elucidate the effects and underlying mechanism of Rg1 on streptozotocin (STZ)-induced T1DM in mice through short or long-term observation. Concurrently, we intended to explore the relationships between inflammasome, pyroptosis and oxidative stress and the role of NLRP3 and Keap1/Nrf2/HO-1 pathways in the development and progression of DM. Using ELISA and Western blot analysis, we found that Rg1 attenuated abnormally elevated blood glucose, reduced inflammatory factors IL-1ß and IL-18 in the blood, decreased ALT and AST levels, promoted insulin secretion, and weakened the function of NLRP3 in mouse liver and pancreas. In addition, Rg1 protected against STZ-induced reactive oxygen species-mediated inflammation by upregulating Nrf2/ARE pathway, which further activated antioxidant enzymes. Interestingly, Rg1 also regulated H3K9 methylation in liver and pancreas, as detected by immunohistochemistry. In summary, these data provide new understanding about the mechanism of Rg1 action, suggesting that it is a potential drug applied for preventing the occurrence and development of T1DM.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/prevenção & controle , Ginsenosídeos/farmacologia , Heme Oxigenase-1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/patologia , Histonas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metilação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia
20.
J Ethnopharmacol ; 246: 112200, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31472272

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Erythrina senegalensis is traditionally used in Cameroon for its relaxing and hypoglycemic properties in the treatment of cardiovascular diseases and diabetes. AIM OF THE STUDY: High blood pressure and diabetes mellitus are frequently linked. These pathologies represent major risk factors for cardiovascular and renal diseases. The present study was designed to evaluate the antidiabetic and antihypertensive activity of the stem bark of Erythrina senegalensis aqueous extract in male hypertensive diabetic rats (HDR). MATERIALS AND METHODS: Hypertension and diabetes were induced by oral administration of sucrose (15%) and ethanol (40°) at doses of 1.5 g/kg and 5 g/kg respectively for 30 days, followed by an intravenous injection of streptozotocin (STZ; 40 mg/kg). A control group of 5 rats received distilled water (10 mL/kg) followed by intravenous injection of 0.9% NaCl (1 mL/100 g). HDR were divided into 4 groups of 5 rats each according to their blood glucose level and continued to receive ethanol in association with: distilled water (10 mL/kg); group I, metformin (200 mg/kg)+nifedipine (10 mg/kg); group II, plant extract (100 and 200 mg/kg) group IV and V, respectively for 28 days. At the end of the treatment, hemodynamic parameters were recorded by the direct method. Animals were sacrificed; blood and organs (aorta, heart, liver, and kidneys) were collected for biochemical and histological analysis. Phytochemistry and HPLC-DAD-HRESI-MS were used to determine the major compounds of the extract. RESULTS: The administration of sucrose, alcohol, and STZ resulted in a significant increase in blood glucose, hemodynamic parameters, and body weight loss. A significant decrease in pancreatic islets size, nitrite, GSH, SOD and catalase activity was observed in HDR. There was also a significant increase in serum triglycerides, total cholesterol, creatinine, bilirubin, and transaminases activity in HDR. The aqueous extract of E. senegalensis, as well as the metformin + nifedipine combination, significantly improved all these parameters. HPLC coupled to both diode array and mass spectrometry detectors revealed the presence of 15 compounds and 11 of them were identified. CONCLUSION: These results suggest that the aqueous extract of E. senegalensis possess antihypertensive, hypoglycemic, hypolipidemic, cardiomodulator and antioxidant properties involved in the improvement of the metabolic disorders found in HDR. This may be due at least in part to the presence of Erysenegalensein (D, O, N, E), Warangalone, senegalensin and 6,8-diprenylgenistein identified in the extract.


Assuntos
Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Erythrina , Hipertensão/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Dislipidemias/patologia , Hipertensão/metabolismo , Hipertensão/patologia , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Casca de Planta , Extratos Vegetais/farmacologia , Ratos Wistar , Perda de Peso/efeitos dos fármacos
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