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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.
Poult Sci ; 100(8): 101103, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34229218

RESUMO

Practical methods for preventing embryotoxicity in chickens that are caused by aflatoxin-B1 (AFB1) are currently rare. Binding absorbers are commonly used in feeding stuff to reduce laying hens' exposure to off-contaminated diets, thus reducing residue exposure to fertilized eggs. Nonetheless, several adsorbents have been shown to affect the use of nutrients and the absorption of minerals in poultry. Thus, seeking an effective strategy to counter or control embryotoxicity in broiler chicks caused by AFB1 is a problem. A total of 180 embryonated eggs were injected with 36 ng AFB1 with or without 5.90 mg L-methionine (Met) 30 embryonated eggs each, followed by incubation in an incubator until hatching time. The in ovo injection of Met significantly reduced toxicity caused by AFB1 in broiler embryos by enhancing the liver and kidney functions, lipid profiles, and alleviated oxidative stress during the incubation period. Furthermore, the relative gene expressions (SSTR5, TSH-ß, Bcl-2, GSH-Px, GST-a, and SOD in the liver) were up-regulated with in ovo injection of AFB1+Met compared to AFB1 alone. Moreover, there was a dowin-regulated trend in Bax, Caspases-3, Caspases-7, Caspases-9, CYP1A1, CYP2H1, and P53 gene expression with in ovo injection of AFB1+Met compared to AFB1 alone. The in ovo injection of Met led to less apoptotic cells in liver tissues. Such results might be necessary for the poultry industry as it is focused on managing the embryotoxicity of AFB1, which affecting poultry production and welfare. Results from this study demonstrated that in ovo Met injection could alleviate AF-induced toxicity in chicken embryos.


Assuntos
Antioxidantes , Galinhas , Aflatoxina B1/toxicidade , Animais , Apoptose , Embrião de Galinha , Feminino , Fígado , Metionina , Óvulo
3.
Curr Pharm Des ; 27(4): 505-512, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33327903

RESUMO

Flavonoids represent a large diverse group of natural products that are used as a traditional medicine against various infectious diseases. They possess many biological activities including antimicrobial, antioxidant, anti-inflammatory, anti-cancer and anti-diabetic activities. Commercially, flavonoids are mainly obtained from plants, however, several challenges are faced during their extraction. Microorganisms have been known as natural sources of a wide range of bioactive compounds including flavonoids. Actinobacteria are the most prolific group of microorganisms for the production of bioactive secondary metabolites, thus facilitating the production of flavonoids. The screening programs for bioactive compounds revealed the potential application of actinobacteria to produce flavonoids with interesting biological activities, especially anticancer activities. Since marine actinobacteria are recognized as a potential source of novel anticancer agents, they are highly expected to be potential producers of anticancer flavonoids with unusual structures and properties. In this review, we highlight the production of flavonoids by actinobacteria through classical fermentation, engineering of plant biosynthetic genes in a recombinant actinobacterium and the de novo biosynthesis approach. Through these approaches, we can control and improve the production of interesting flavonoids or their derivatives for the treatment of cancer.


Assuntos
Actinobacteria , Antineoplásicos , Produtos Biológicos , Antineoplásicos/farmacologia , Bactérias , Produtos Biológicos/farmacologia , Flavonoides/farmacologia , Humanos
4.
Biomed Res Int ; 2020: 3193725, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33381547

RESUMO

Traumatic brain injury (TBI) is among the most debilitating neurological disorders with inadequate therapeutic options. It affects all age groups globally leading to post-TBI behavioral challenges and life-long disabilities requiring interventions for these health issues. In the current study, C57BL/6J mice were induced with TBI through the weight-drop method, and outcomes of acutely administered ketamine alone and in combination with perampanel were observed. The impact of test drugs was evaluated for post-TBI behavioral changes by employing the open field test (OFT), Y-maze test, and novel object recognition test (NOR). After that, isolated plasma and brain homogenates were analyzed for inflammatory modulators, i.e., NF-κB and iNOS, through ELISA. Moreover, metabolomic studies were carried out to further authenticate the TBI rescuing potential of drugs. The animals treated with ketamine-perampanel combination demonstrated improved exploratory behavior in OFT (P < 0.05), while ketamine alone as well as in combination yielded anxiolytic effect (P < 0.05-0.001) in posttraumatic mice. Similarly, the % spontaneous alternation and % discrimination index were increased after the administration of ketamine alone (P < 0.05) and ketamine-perampanel combination (P < 0.01-0.001) in the Y-maze test and NOR test, respectively. ELISA demonstrated the reduced central and peripheral expression of NF-κB (P < 0.05) and iNOS (P < 0.01-0.0001) after ketamine-perampanel polypharmacy. The TBI-imparted alteration in plasma metabolites was restored by drug combination as evidenced by metabolomic studies. The outcomes were fruitful with ketamine, but the combination therapy proved more significant in improving all studied parameters. The benefits of this new investigated polypharmacy might be due to their antiglutamatergic, antioxidant, and neuroprotective capacity.


Assuntos
Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Inflamação/tratamento farmacológico , Ketamina/administração & dosagem , Piridonas/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Subunidade p50 de NF-kappa B/metabolismo , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
5.
Int J Med Sci ; 17(18): 3098-3106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173431

RESUMO

Background and objectives: Although diabetic-induced hepatotoxicity is less common, it can be included in the list of target organ pathologies associated with diabetes. This study aimed to investigate the potential therapeutic role of sacubitril/valsartan (LCZ696) in modulating oxidative and inflammatory injuries and liver fibrosis in STZ-induced hyperglycemic rats in comparison to valsartan alone. Materials and Methods: Following the induction of diabetes using a single dose of streptozotocin (STZ), STZ-induced hyperglycemic animals were administered LCZ696 or valsartan for 6 weeks. Glucose, transaminases, lipid profile, tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin - 6 (IL-6), were estimated using the obtained serum. Oxidative stress biomarkers including thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione S-transferase (GST) were measured in the liver homogenate. Additionally, the levels of TNF-α, IL-1ß, IL-6, and nuclear factor - kappa ß (NF-κB) levels were estimated in hepatic tissue. To assess the general histopathological changes, harvested liver tissue was treated with hematoxylin and eosin or Masson's trichrome staining to detect fibrosis. Results: STZ-induced hyperglycemic rats demonstrated high blood glucose, dyslipidemia, and significant elevation in hepatic transaminases, proinflammatory cytokines, NF-κB, lipid peroxidation, and hepatic fibrosis, with impairment in antioxidant enzymes. In STZ-induced hyperglycemic rats, the administration of LCZ696 ameliorated hyperglycemia, dyslipidemia, improved liver functions, and boosted antioxidants enzymes. Furthermore, LCZ696 therapy attenuated oxidation, inflammation, progression of liver injury, and hepatic fibrosis. LCZ696 was superior to valsartan in reducing AST, hepatic fibrosis, tissue IL-1ß, TNF-α and NF-κB. In addition, compared with the valsartan group, LCZ696 significantly increased the antioxidant parameters such as GSH, SOD, CAT and GPx. Conclusion: Collectively, our data demonstrated that LCZ696 could suppress the progression of diabetes-induced hepatic fibrosis, correlating with reduced oxidative stress, hepatic inflammation and NF-κB compared with valsartan alone.

6.
Molecules ; 25(21)2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33105570

RESUMO

Wounds and burn injury are major causes of death and disability worldwide. Myricetin is a common bioactive flavonoid isolated naturally from the plant kingdom. Herein, a topical application of naturally isolated myricetin from the shoots of Tecomaria capensis v. aurea on excisional wound healing that was performed in albino rats. The wounded rats were treated every day with 10 and 20% myricetin for 14 days. During the experiment, the wound closure percentage was estimated at days 0, 7, and 14. Effects of myricetin on the inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and cluster of differentiation 68 (CD68) in the serum were evaluated using immunosorbent assay kits. The percentage of wound closure and contraction was delayed in wounded rats (67.35%) and was remarkably increased after treatment of wounded rats with myricetin; the treatment with 20% myricetin was the most potent (98.76%). Histological findings exhibited that 10% myricetin caused the formation of a large area of scarring at the wound enclosure and stratified squamous epithelium without the formation of papillae as in the control group. Treatment with 20% myricetin exhibited less area of scarring at the wound enclosure as well as re-epithelialization with a high density of fibroblasts and blood capillaries in the wound. Level elevations of serum pro-inflammatory cytokines, IL-1ß, and TNF-α and macrophage CD68 were decreased in wounded rats treated with myricetin. Thus, it can be suggested that the enhancements in inflammatory cytokines as well as systemic reorganization after myricetin treatment may be recommended to play a crucial part in the promotion of wound healing. The findings suggest that treatment with a higher dose of myricetin was better in improving wound curing in rats. It could serve as a potent anti-inflammatory agent and can be used as an adjunctive or alternative agent in the future.


Assuntos
Anti-Inflamatórios/química , Bignoniaceae/química , Queimaduras/tratamento farmacológico , Flavonoides/química , Extratos Vegetais/química , Brotos de Planta/química , Cicatrização/efeitos dos fármacos , Administração Tópica , Animais , Anti-Inflamatórios/administração & dosagem , Antígenos CD/sangue , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/sangue , Antígenos de Diferenciação Mielomonocítica/metabolismo , Capilares/efeitos dos fármacos , Citocinas/sangue , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Fibroblastos/efeitos dos fármacos , Flavonoides/administração & dosagem , Humanos , Macrófagos/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Ratos
7.
Molecules ; 25(18)2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32942704

RESUMO

Cyperus has been commonly used as a multi-use medicinal plant in folk medicine worldwide. The objectives of our study were to determine the different metabolites in the Cyperus conglomeratus Rottb. methanol extract, and to assess its in vivo gastroprotective effect in ethanol-induced gastric ulcer model in rats. Serum levels of galactin-3 and TNF-α were employed as biochemical markers. To pinpoint for active agents, comprehensive metabolites profiling of extract via UPLC-qTOF-MS/MS was employed. A total of 77 chromatographic peaks were detected, of which 70 were annotated. The detected metabolites were categorized into phenolic acids and their derivatives, flavonoids, stilbenes, aurones, quinones, terpenes, and steroids. Rats were divided into six groups; healthy control, ulcer control, standard drug group, and 25, 50, 100 mg/kg of C. conglomeratus treated rats. Pre-treatment with C. conglomeratus alcohol extract significantly reduced galactin-3, and TNF-α in ethanol-induced ulcer model at 25, 50, and 100 mg/kg. Further histopathological and histochemical studies revealed moderate erosion of superficial epithelium, few infiltrated inflammatory cells, and depletion of gastric tissue glycoprotein in the ulcer group. Treatment with the extract protected the gastric epithelial cells in a dose-dependent manner. It could be concluded that C. conglomeratus extract provides significant gastroprotective activity in ethanol-induced gastric ulcer and ought to be included in nutraceuticals in the future for ulcer treatment.


Assuntos
Antiulcerosos/química , Cyperus/química , Compostos Fitoquímicos/química , Extratos Vegetais/química , Administração Oral , Animais , Antiulcerosos/farmacologia , Antiulcerosos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Cyperus/metabolismo , Etanol/toxicidade , Feminino , Galectina 3/sangue , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Ranitidina/uso terapêutico , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Espectrometria de Massas em Tandem , Fator de Necrose Tumoral alfa/sangue
8.
Saudi Pharm J ; 28(8): 951-962, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32792840

RESUMO

In 30% of epileptic individuals, intractable epilepsy represents a problem for the management of seizures and severely affects the patient's quality of life due to pharmacoresistance with commonly used antiseizure drugs (ASDs). Surgery is not the best option for all resistant patients due to its post-surgical consequences. Therefore, several alternative or complementary therapies have scientifically proven significant therapeutic potential for the management of seizures in intractable epilepsy patients with seizure-free occurrences. Various non-pharmacological interventions include metabolic therapy, brain stimulation therapy, and complementary therapy. Metabolic therapy works out by altering the energy metabolites and include the ketogenic diets (KD) (that is restricted in carbohydrates and mimics the metabolic state of the body as produced during fasting and exerts its antiepileptic effect) and anaplerotic diet (which revives the level of TCA cycle intermediates and this is responsible for its effect). Neuromodulation therapy includes vagus nerve stimulation (VNS), responsive neurostimulation therapy (RNS) and transcranial magnetic stimulation therapy (TMS). Complementary therapies such as biofeedback and music therapy have demonstrated promising results in pharmacoresistant epilepsies. The current emphasis of the review article is to explore the different integrated mechanisms of various treatments for adequate seizure control, and their limitations, and supportive pieces of evidence that show the efficacy and tolerability of these non-pharmacological options.

9.
PeerJ ; 8: e9196, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32596035

RESUMO

Background: Diabetic nephropathy (DN) is among the most common microvascular complications of diabetes resulting in end-stage renal disease and therefore search for candidates which can ameliorate the kidney function is needed simultaneously with standard diabetic pharmacotherapy. The current study was aimed to investigate the effect of long term sacubitril/valsartan therapy (LCZ696) in diabetic rats to assess its ameliorative impact against various pathological parameters such as oxidative stress, inflammation and glomerulosclerosis associated with chronic DN. Methods: A single dose (60 mg/kg/day) of STZ was used to induce type 1 diabetes in adult male wistar rats. 2 weeks after diabetes induction, these rats were treated orally with valsartan (31 mg/kg) or LCZ696 (68 mg/kg) for 6 weeks. At end of the treatment period, serum and kidney samples were collected and analyzed. The serum levels of glucose, insulin, urea, creatinine, TNF-α, IL-1ß, IL-6 and IL-10 levels were estimated. In renal tissue homogenate, the levels of inflammatory markers such as TNF-α, IL-1ß, IL-6, NF-kB along with oxidative stress biomarkers including thiobarbituric acid-reacting substances (TBARs), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST) were assessed. Histological changes were observed in kidney. Results: Time course therapy withLCZ696 and valsartan in diabetic rats resulted in significant reduction of serum glucose, urea and creatinine levels (P < 0.05). Additionally, serum of treated diabetic rats showed a diminution in inflammatory (TNF-α, IL-1ß, IL-6) and increment in anti-inflammatory (IL-10) cytokines levels (P < 0.05). Tissue homogenate of the kidney extracted from LCZ696 and valsartan treated diabetic rats revealed a substantial reduction in the levels of inflammatory markers such as TNF-α, IL-1ß, IL-6, NF-kB and sufficient restoration of anti-oxidant enzyme levels (P < 0.05). Finally, in the histological sections of the kidney, prevention of renal injury was observed with limited necrosis and inflammatory cells infiltration. Conclusion: Present data suggest that LCZ696 has sufficient therapeutic potential to restrict DN progression through inhibiting inflammation, oxidative stress and glomerulosclerosis.

10.
Int J Med Sci ; 17(9): 1156-1166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547311

RESUMO

Hypercholesterolemia is a major risk factor for several cardiovascular and metabolic diseases as it triggers oxidative and pro-inflammatory cascades. Baicalein (BL) is a natural flavone with multiple therapeutic properties. The present study aimed to evaluate the potential protective effect of BL supplementation in hypercholesterolaemic rats. Rats were fed a high-cholesterol diet (HCD) for six weeks and then orally administered BL at two doses (25 and 50 mg/kg body weight/day) for four weeks. Serum lipids, liver enzymes, cardiac enzymes, renal markers, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), interleukin-10 (IL-10), caspase-3, nitric oxide (NO) and prostaglandin-2 (PGE-2) were measured. In renal, hepatic, and cardiac tissues, thiobarbituric acid-reactive (TBARS) substance, glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were measured. The altered levels of lipoproteins, aminotransferases, creatine kinases, and urea in hypercholesterolemic animals were significantly corrected by BL. Inflammatory and apoptotic biomarkers were also markedly attenuated in the HCD group following BL treatment. Hypercholesterolemia considerably induced the lipid peroxidation product, TBARS, and oxidative radicals in cardiac, hepatic, and renal tissues, which were attenuated by BL treatment, particularly, at the 50 mg/kg/day dose. BL enhanced the activities of superoxide dismutase, catalase, and glutathione peroxidase that were suppressed by HCD. Histological alterations induced by cholesterol overload in cardiac, hepatic, and renal tissues were ameliorated by BL supplementation. Our results show that the BL treatments (25 and 50 mg/kg/day) to HCD fed rats improved all the altered parameters. These results demonstrate that BL treatment improves cardiac, renal and hepatic dysfunctions in hypercholesterolaemic rats by activation of cellular antioxidant enzymes and/or suppression of inflammatory cytokines.


Assuntos
Flavanonas/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Animais , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
11.
Redox Rep ; 25(1): 51-58, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32396454

RESUMO

ABSTRACTObjectives: This study explores the protective role of losartan (LT) against oxidative and inflammatory damages in different physiological systems including heart, liver, and kidney tissue in hypercholesterolemic rats.Methods: After induction of hypercholesterolemia by high cholesterol diet for 6 weeks, LT was administered for 4 weeks. In serum, the levels of lipoproteins, aminotransferases, creatine kinases, urea, apoptosis, and inflammatory markers were measured. In cardiac, hepatic, and renal tissues, lipid peroxidation product and GSH as well as antioxidant enzymatic activities were assayed. Finally, histopathological assessment evaluated the structural damage in cardiac, hepatic, and renal tissues.Results: Serum markers of cardiac, hepatic, and renal toxicities including creatine kinases, aminotransferases, and urea were attenuated by LT in hypercholesterolemic animals. Moreover, LT markedly corrected the elevated levels of lipoproteins, apoptosis, and inflammatory biomarkers. Hypercholesterolemia-induced lipid peroxidation, low GSH levels, and diminished activities of antioxidant enzymes were prominently improved in LT treated animals. Histopathological alterations by hypercholesterolemia in heart, liver, and kidney tissues were ameliorated by LT.Conclusion: This study confirmed the pathological enrollment of renin-angiotensin system in hypercholesterolemia-associated metabolic alterations. LT had a significant cardiac, hepatic, and renal protective role against these impairments through down-regulation of oxidative damage, inflammation and necrosis.


Assuntos
Anti-Hipertensivos/farmacologia , Colesterol na Dieta/toxicidade , Hipercolesterolemia/complicações , Inflamação/tratamento farmacológico , Losartan/farmacologia , Estresse Oxidativo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Hipercolesterolemia/induzido quimicamente , Hipercolesterolemia/patologia , Inflamação/etiologia , Inflamação/patologia , Masculino , Ratos , Ratos Wistar
12.
Pharmaceutics ; 11(11)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694244

RESUMO

The physiologically based pharmacokinetic (PBPK) approach facilitates the construction of novel drug-disease models by allowing incorporation of relevant pathophysiological changes. The aim of the present work was to explore and identify the differences in rifampicin pharmacokinetics (PK) after the application of its single dose in healthy and diseased populations by using PBPK drug-disease models. The Simcyp® simulator was used as a platform for modeling and simulation. The model development process was initiated by predicting rifampicin PK in healthy population after intravenous (i.v) and oral administration. Subsequent to successful evaluation in healthy population, the pathophysiological changes in tuberculosis and cirrhosis population were incorporated into the developed model for predicting rifampicin PK in these populations. The model evaluation was performed by using visual predictive checks and the comparison of mean observed/predicted ratios (ratio(Obs/pred)) of the PK parameters. The predicted PK parameters in the healthy population were in adequate harmony with the reported clinical data. The incorporation of pathophysiological changes in albumin concentration in the tuberculosis population revealed improved prediction of clearance. The developed PBPK drug-disease models have efficiently described rifampicin PK in tuberculosis and cirrhosis populations after administering single drug dose, as the ratio(Obs/pred) for all the PK parameters were within a two-fold error range. The mechanistic nature of the developed PBPK models may facilitate their extension to other diseases and drugs.

13.
Animals (Basel) ; 9(7)2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31284654

RESUMO

The current study examined the influence of Citrus limon (dry lemon) on the hemato-biochemical profiles, and antioxidant indices of growing rabbits. Forty-eight growing New Zealand White rabbits (age, eight weeks; weight, 1543.33 ± 25 g) were allocated into three groups (16 animals each), the first group was (control) fed a basal diet, whereas the second and third groups were supplemented with dried lemon, 1% or 2% DLP, respectively. A GC-MS analysis of more than 27 active constituents was performed. Feed conversion efficiency was (p < 0.05) better with diets containing 1% or 2% dry lemon, compared to the control group. Hematological indexes were increased significantly with the addition of DLP compared to those in the control group. Adding 1% or 2% dry lemon to rabbit diet increased (p < 0.05) enzymatic and non-enzymatic antioxidant activities (TAC, SOD, GSH, GST, and CAT) in serum and liver tissues. Taken together, these data reveal the advantages and antioxidant effects of dry lemon supplementation for growing rabbits once supplemented at a maximum of 2% in their daily diet.

14.
Drug Dev Res ; 80(4): 475-480, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30701566

RESUMO

An overdose of acetaminophen (APAP) causes liver injury in experimental animals and humans. The activation step (formation of reactive metabolite, N-acetyl-p-benzoquinone imine by cytochrome P450 system) and the consequent downstream pathway of oxidative stress, nitrosative stress, and inflammation play an important role in APAP-induced hepatotoxicity. Formulation of APAP with an inhibitor of the activation step would be ideal to prevent accidental and intentional APAP toxicity. Dimethyl sulfoxide (DMSO) is a common colorless, inexpensive solvent, and considered safe in human. We hypothesized that a less hepatotoxic APAP if co-formulated with DMSO. To test this hypothesis, C57BL/6 mice were given toxic dose of APAP (250 mg kg-1 , i.p.) mixed with different doses of DMSO (25, 50, 100, and 200 µl kg-1 ). Six hours after APAP treatment, blood and lives were collected for analysis. In DMSO treated groups, there was dose-dependent decrease in markers of liver injury, alanine aminotransferase, and aspartate aminotransferase. Maximum protection was obtained with 200 µl DMSO kg-1 . DMSO was shown to inhibit the activation step by decreasing the rate of GSH depletion in vivo and inhibiting cytochrome P450 system in vitro. Also the levels of lipid peroxides, nitrate/nitrite, tumor necrosis factor-alpha, and interleukin 1ß were decreased significantly. In conclusion, DMSO exerts its protective action by inhibiting the metabolic activation of APAP and thus alleviating the downstream, oxidative stress, nitrosative stress, and inflammation via indirect inhibition. Our findings suggest that replacing the current APAP with APAP/DMSO formulation could prevent accidental and intentional APAP toxicity.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Dimetil Sulfóxido/farmacologia , Fígado/efeitos dos fármacos , Acetaminofen/administração & dosagem , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Dimetil Sulfóxido/administração & dosagem , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Composição de Medicamentos , Fígado/metabolismo , Testes de Função Hepática , Camundongos Endogâmicos C57BL , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
15.
J Anim Physiol Anim Nutr (Berl) ; 103(2): 534-546, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30597625

RESUMO

Using nutritional antioxidants in livestock systems is considered the key in improving animal production. The current study assumes that dietary tomato powder (TP) supplementation positively affects haemato-immunological, biochemical, and antioxidant parameters for New Zealand rabbits. A total of 30 rabbits (45 days old) were assigned to three groups, including a diet with no additives (control), and two dietary treatments with the providing of 1% or 2% TP. Mass spectrometric study for TP methanolic extract showed some phenolic compounds. Consumption of TP supplemented diets significantly (p < 0.001) affected body weight gain and feed efficiency. Red blood cells and white blood cells count exhibited a significant increase (p < 0.001) in both TP groups compared with the control. In addition to, feeding rabbits on TP enhanced cell-mediated and humoral immune responses through a significant increase in phagocytosis, chemotaxis, and levels of immunoglobulins (TIg, IgG, IgM and IgA). Supplementation of TP significantly (p < 0.01) reduced lipid profile induces except high-density lipoprotein cholesterol values. A remarkable significant (p < 0.001) effect on serum and hepatic oxidative stress responses were observed with TP addition. Ultimately, TP supplementation could play a potential role as a growth and health enhancer for fattening rabbits.


Assuntos
Ração Animal/análise , Dieta/veterinária , Suplementos Nutricionais , Lycopersicon esculentum , Pós , Coelhos/crescimento & desenvolvimento , Fenômenos Fisiológicos da Nutrição Animal , Animais , Antioxidantes/metabolismo , Biomarcadores , Manipulação de Alimentos , Frutas , Estresse Oxidativo
16.
Environ Sci Pollut Res Int ; 26(4): 3834-3847, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30539391

RESUMO

The aim of this study was to investigate the potential protective effect of two extracts derived from two soil actinomycete strains, designated S19 and G30, against CCl4-induced hepatotoxicity in male rats. Sixty-four male rats were divided into four groups of 16 rats per group. The first group was a control group given corn oil and the nutritive medium which is composed of a mixture of the two used media. The second group received CCl4 only, the third group was administered CCl4 and the extract S19, and the fourth group was administered CCl4 and the extract G30. The results were taken after a treatment period of 8 weeks. Our data demonstrated that the two actinomycete extracts significantly (P < 0.01) lowered the CCl4-induced elevation of serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) after 8 weeks of treatment. The extract S19 had no effect on serum lactate dehydrogenase (LDH) and total bilirubin, whereas the extract G30 significantly decreased (P < 0.01) the elevated levels of these parameters in the serum, especially after 4 weeks of treatment. The levels of hepatic glutathione (GSH), glutathione peroxidase (GSH-Px), peroxidase (Px), catalase (CAT), and superoxide dismutase (SOD) significantly increased (P < 0.01), while those of malondialdehyde (MDA) markedly decreased in rats treated with the two extracts. Furthermore, histopathological lesions in the liver, including necrosis, inflammatory cell infiltration, hydropic degeneration, and congestion of the central vein, were partially reversed by treatment with the two microbial extracts. Our results provided evidence for the protective effect of the two used actinomycete extracts against CCl4-induced liver damage occurred through the reduction of oxidative stress and improvement of antioxidant defense markers.


Assuntos
Actinobacteria/química , Antioxidantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/isolamento & purificação , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Testes de Função Hepática , Masculino , Ratos
17.
Med Princ Pract ; 28(2): 178-185, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30537701

RESUMO

OBJECTIVE: Diabetic complications involve multiple pathological pathways, including hyperglycemia-induced oxidative stress and inflammation. Combination therapy is usually employed to improve treatment outcomes and to lower potential adverse effects. In this study, we evaluated the effects of antidiabetic and antihypertensive agents, glibenclamide (GLI) and losartan (LT), on diabetes mellitus (DM)-associated metabolic changes in rats. MATERIALS AND METHODS: Streptozotocin-induced diabetic animals were orally treated with GLI 5 mg/kg and/or LT 25 mg/kg for 4 weeks. Blood glucose, insulin, aspartate aminotransferase, alanine aminotransferase, urinary creatinine, and urea levels were measured. Serum, liver, and kidney values of inflammatory markers, such as interleukin-1ß, tumor necrosis factor alpha, and interleukin-6 were assessed, along with lipid peroxidation products (e.g., thiobarbituric acid reactive substances), endogenous antioxidants (e.g., glutathione), as well as antioxidant enzyme activities (e.g., catalase, superoxide dismutase, and glutathione peroxidase). Finally, histological changes in liver and kidney tissues were evaluated. RESULTS: DM markedly induced systemic, hepatic, and renal inflammation and lowered antioxidant defense mechanisms. Treatment of diabetic rats with either GLI or LT significantly improved liver and kidney functions and histological structure. Moreover, both medications reduced signs of oxidative stress and inflammation in blood, liver, and kidney samples. Combining GLI and LT showed similar protective potential against systemic, hepatic, and renal oxidative stress and inflammation. CONCLUSION: Adding LT to GLI therapy revealed prospective antioxidant and anti-inflammatory action, while no synergistic or additive effects were observed.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Glibureto/farmacologia , Hipoglicemiantes/farmacologia , Losartan/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Glutationa Redutase/efeitos dos fármacos , Estudos Prospectivos , Ratos , Superóxido Dismutase/metabolismo
18.
Asian Pac J Cancer Prev ; 19(3): 777-783, 2018 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-29582634

RESUMO

Background: Breast cancer is affected by the immune system in that different cytokines play roles in its initiation and progression. Interleukin-10 (IL-10), an anti-inflammatory cytokine, is an immunosuppressive factor involved in tumorigenesis. The present study was conducted to investigate the gene silencing effect of a small interference RNA (siRNA) targeting IL-10 on the apoptotic pathway in breast cancer cell line. Methods: The siRNA targeting IL-10 and a glyceraldehyde 3-phosphate dehydrogenase (GAPDH) clone were introduced into MDA-MB-231 cells. Real-time PCR assays were used to determine IL-10 and GAPDH gene expression levels, in addition to those for protein kinase B (AKT), phosphoinositide 3-kinase (PI3K), B-cell lymphoma 2 (Bcl2), caspase-3 and caspase-9 genes related to apoptosis. Results: Inhibition of IL-10 by the siRNA accelerated apoptosis and was accompanied by significant increase in caspase-3 and caspase-9 and a significant decrease in PI3K, AKT and Bcl2 expression levels compared to the non-transfected case. Conclusions: In conclusion, the production of IL-10 may represent a new escape mechanism by breast cancer cells to evade destruction by the immune system. IL-10 gene silencing causes down regulation of both PI3K/AKT and Bcl2 gene expression and also increases the Bbc3, BAX caspase3, and caspase 3 cleavage expression levels. IL­10 might represent a promising new target for therapeutic strategies.


Assuntos
Apoptose , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Interleucina-10/antagonistas & inibidores , RNA Interferente Pequeno/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proliferação de Células , Feminino , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
19.
Biomed Pharmacother ; 97: 1303-1310, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29156519

RESUMO

Estrogen deficiency following menopausal provokes alveolar bone loss, remodeling and inflammation. Eugenol is a phenolic compound with wide dental applications and anti-inflammatory properties. In the present study, the potential protective role of eugenol against alveolar bone deformities was investigated in an ovariectomized (OVX) rodent model. Two doses of eugenol (2.5 and 5 mg/kg/d) were administered to OVX animals for 12 weeks. In Serum, markers of bone metabolism and pro-inflammatory cytokines were estimated using ELISA. Alveolar bone morphometry was analyzed using high-resolution micro-computed tomography (CT). Bone histological analysis (H&E stain) was also performed. Alveolar bone expression of osteoclastogenesis modulating factors, such as osteoprotegerin (OPG), receptor activator of nuclear factor kappa-b ligand (RANKL) and inflammatory mediators, were measured using immunohistochemistry. Eugenol failed to correct elevated body weights and uterine atrophy in OVX rats. The significant elevation of bone metabolic markers and inflammatory cytokines in OVX animals were markedly improved by eugenol treatment, particularly the higher dose. Eugenol treatment considerably attenuated morphometric trabecular alterations of the alveolar bone and improved alveolar resorption and gingival infiltration. Alveolar bone of OVX animals showed augmented expression of RANKL, OPG and inflammatory cytokines, which were corrected by eugenol treatment. Alveolar bone loss and remodeling associated with estrogen insufficiency was ameliorated by eugenol owing to its anti-inflammatory properties, suggesting an extra dental impact for eugenol.


Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Osso e Ossos/efeitos dos fármacos , Eugenol/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estrogênios/deficiência , Eugenol/administração & dosagem , Feminino , Mediadores da Inflamação/metabolismo , Menopausa , Ovariectomia , Ratos , Ratos Wistar , Microtomografia por Raio-X
20.
Nutrients ; 9(10)2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-29064407

RESUMO

Diabetic retinopathy (DR) is one of the leading causes of decreased vision and blindness worldwide. Diabetes-induced oxidative stress is believed to be the key factor that initiates neuronal damage in the diabetic retina leading to DR. Experimental approaches to utilize dietary flavonoids, which possess both antidiabetic and antioxidant activities, might protect the retinal damage in diabetes. The aim of this study was to investigate the potential protective effects of naringenin in the retina of streptozotocin-induced diabetic rats. Diabetic rats were orally treated and untreated with naringenin (50 mg/kg/day) for five weeks and retinas were analyzed for markers of oxidative stress, apoptosis and neurotrophic factors. Systemic effects of naringenin treatments were also analyzed and compared with untreated groups. The results showed that elevated levels of thiobarbituric acid reactive substances (TBARs) and decreased level of glutathione (GSH) in diabetic rats were ameliorated with naringenin treatments. Moreover, decreased levels of neuroprotective factors (Brain derived neurotrophic factor (BDNF)), tropomyosin related kinase B (TrkB) and synaptophysin in diabetic retina were augmented with naringenin treatments. In addition, naringenin treatment ameliorated the levels of apoptosis regulatory proteins; B cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax) and caspase-3 in the diabetic retina. Thus, the study demonstrates the beneficial effects of naringenin that possesses anti-diabetic, antioxidant and antiapoptotic properties, which may limit neurodegeneration by providing neurotrophic support to prevent retinal damage in diabetic retinopathy.


Assuntos
Apoptose/efeitos dos fármacos , Flavanonas/farmacologia , Flavonoides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Retina/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Glicemia/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Modelos Animais de Doenças , Glutationa/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Wistar , Retina/metabolismo , Sinaptofisina/sangue , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
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