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1.
Artigo em Inglês | MEDLINE | ID: mdl-32743741

RESUMO

Aprepitant is a selective SP/NK-1 receptor antagonist and used in postoperative and chemotherapeutics induced emesis and vomiting. The aim of our study is to show aprepitant may have beneficial effects on gastrointestinal complaints in cancer patients undergoing chemotherapeutics by indomethacin-induced gastric ulcer model. A total of 48 rats were fasted 24 h for ulcer experiment. Aprepitant doses of 5, 10, 20, and 40 mg/kg were evaluated for their antiulcer activity. Omeprazole (20 mg/kg) was used as a positive control group. Six hours after 25 mg/kg indomethacin administration, all stomachs were dissected out. After macroscopic analyses, tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), COX-1, and COX-2 mRNA levels and SOD activity, and GSH and MDA levels of stomachs were determined. Histopathological examinations were evaluated. Aprepitant administration exerted 48.14%, 49.62%, 65.92%, and 76.77% ulcer inhibition effects at 5, 10, 20, and 40 mg/kg, respectively. Aprepitant administration decreased oxidative stress and inflammatory parameters in stomach tissues dose dependently. Aprepitant administration increased stomach COX-2 mRNA levels at 20 and 40 mg/kg doses. Although aprepitant appears to be disadvantageous in terms of treating gastric ulcer due to COX enzyme inhibition according to the previous studies, aprepitant has been shown to have ulcer healing effect in our study. When aprepitant is given as an anti-nausea and vomiting drug to cancer patients undergoing chemotherapy, we can argue that it will not be necessary to add a new gastric protective agent as it also shows beneficial effects in gastrointestinal complaints.

2.
Life Sci ; 258: 118177, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738364

RESUMO

AIM: Omapatrilat is an antagonist of angiotensin-converting (ACE) and neprilysin-neuropeptidase (NEP) enzymes. The aim of our study is to show that omapatrilat may have beneficial effects as a treatment for polymicrobial sepsis. MAIN METHODS: A cecal ligation and puncture (CLP) sepsis model was used to evaluate 10 and 20 mg/kg doses of omapatrilat in mice (n = 30) fasted for 12 h. The lungs were removed 12 h after CLP, and lung levels of cytokines (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], NF-κB), iNOS and eNOS mRNA expression, GSH and MDA levels, and ACE and NEP activities were determined. Histopathological examinations were also performed. KEY FINDINGS: Omapatrilat treatment provided a dose-dependent reduction in oxidative stress and inflammatory parameters in lung tissues. Omapatrilat administration decreased lung iNOS and eNOS mRNA levels at 20 mg/kg dose. Histopathological analysis revealed a decline in the thickening and edema areas in the alveolar septa in the Sepsis+OMA20 group. SIGNIFICANCE: Omapatrilat, a dual ACE and NEP inhibitor, protected lung tissue from sepsis damage by reducing ACE and NEP activities, by decreasing the mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and NF-κB), by suppressing leukocyte infiltration and edema, by restoring iNOS and eNOS levels, and by restoring SOD activity and GSH and MDA levels, thereby reducing oxidative stress.


Assuntos
Neprilisina/metabolismo , Peptidil Dipeptidase A/metabolismo , Sepse/enzimologia , Transdução de Sinais , Animais , Biomarcadores/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmão/enzimologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sepse/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
3.
Inflammopharmacology ; 28(4): 893-902, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32504222

RESUMO

AIM: This study aimed to demonstrate the role of serotonin 7 receptor (5-HT7) and the effects of 5-HT7 agonists and antagonists in an indomethacin-induced gastric ulcer. MATERIAL AND METHOD: Male albino Wistar rats (n = 60) were used in the experiments. LP44 (5-HT7 agonist) and SB269970 (5-HT7 antagonist) were administered at 10 mg/kg as a pre-treatment. One hour after the drug treatments, 25 mg/kg of indomethacin (INDO) was administered to all groups except the healthy control group. Six hours after indomethacin administration, all the rats were euthanized. RESULTS: We analyzed the iNOS, eNOS, and 5-HT7 receptor mRNA levels in the stomach tissue of rats by real-time PCR. 5-HT7 mRNA expression was increased in the INDO group compared to the healthy group. LP44 administration exerted a significant upregulatory effect on eNOS mRNA expression and downregulatory effects on iNOS and 5-HT7 mRNA expression compared to the INDO group. However, antagonist (SB269970) administration did not result in such difference in gene expression, but even partially decreased the agonist's effect in combination. Famotidine and agonist exerted similar effects. Histopathological findings supported the beneficial effects of 5-HT7 agonist on gastric tissue. CONCLUSION: The study suggested that activation of 5-HT7 receptor showed a significant anti-ulcerogenic effect in the indomethacin-induced gastric ulcer model.

4.
Eur J Pharmacol ; 880: 173168, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32423870

RESUMO

Cisplatin is widely used chemotherapeutic drug and have some serious side effects as tissue toxicity and nausea and vomiting. Aprepitant is used in clinic as an anti-emetic drug for cisplatin treated patient to prevent nausea and vomiting. We aimed to investigate the protective effects of Aprepitant on cisplatin-induced nephrotoxicity and hepatotoxicity. In total 42 male rats were separated into six groups (n = 7). A single dose of cisplatin (10 mg/kg i.p.) was administered to induce toxicity on first day. Different doses of Aprepitant (5, 10 and 20 mg/kg, p.o.) were given to treatment groups during 3 days. After the experimental procedures serum enzymes (ALT, AST, ALP, BUN and Creatinin), kidney and liver oxidative parameters (SOD, GSH and MDA), inflammatory cytokines (TNF-α and NF-κB) and Cyp2e1 expressions analyzed. Histopathological investigations also performed for all groups. Cisplatin caused tissue toxicity in both kidney and liver. Serum enzymes, tissue cytokines and oxidative stress were increased after the Cis treatment. Aprepitant treatment normalized all parameters compared to cisplatin treated group. Cisplatin significantly increased the Cyp2e1 expression in the kidney while significantly decreased in the liver compared to Healthy group. Histopathologically, it was shown that cisplatin causes a lot of abnormal structures as inflammatory infiltration and necrosis on the liver and kidney. Similar the biochemical and molecular results, aprepitant showed positive effects on tissue pathological parameters. With its main anti-emetic effect, Aprepitant treatment may be an effective option for cancer patients if they have additional injury as nephrotoxicity and hepatotoxicity due to cisplatin.

5.
J Nanosci Nanotechnol ; 20(2): 680-691, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31383063

RESUMO

BN has important roles in several physiological events, including bone growth and immune system. New infection-free cranioplasty and has an osteogenic activities material that are compatible with tissue are being developed. We aimed in our study to examine whether different combinations of Boron-nitride/Hydroxyapatite are embedded into the scaffold in the treatment of calvarial defects. 200 adult female Sprague-Dawley rats divided into 10 equal groups. Osteotomy was made by trepan drill in 8 mm diameter. The scaffolds were placed in the rats and were left to recovery for 2 months. During the experiment, CT scans were taken from the calvarial areas of the rats in the 2nd, 4th and 8th weeks. Significant healing was observed in defect diameters in 2.5% BN+10% HA, 2.5% BN and 5% BN+10% HA, respectively. After 8 weeks, it was seen that the amounts of OPN, BMP-2, RunX2 and ALP mRNA expression significantly decreased in 2.5% BN+10% HA, 2.5% BN, 5% BN+10% HA and 5% BN groups. It was shown that bone recovery was at the best grade in the groups, which contained 2.5% BN and 2.5% BN+10% HA when compared to the other groups. BN is a very promising agent that will be used in reconstructive surgery for the treatment of calvarial bone defects.

6.
Inflammopharmacology ; 27(6): 1169-1178, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31309486

RESUMO

AIM: This study aimed to investigate the role of the 5-HT7 receptor in fever mechanisms and its possible effect on the antipyretic mechanism of paracetamol. MATERIALS AND METHODS: The study consisted of eight experimental groups and one control group. Group I: healthy, II: LPS, III: LPS + PARA, IV: LPS + AGO, V: LPS + ANTA, VI: LPS + AGO + ANTA, VII: LPS + AGO + PARA, VIII: LPS + ANTA + PARA, and IX: LPS + AGO + ANTA + PARA. Rectal temperatures were measured with a rectal thermometer. At the end of the experiment, tissues were examined molecularly. Real-time PCR mRNA expression analyses were performed for the 5-HT7 receptor, IL-6, and TNF-α in hypothalamus tissue. RESULTS: The mean differences in rectal temperature increased in the LPS, LPS + ANTA, and LPS + AGO + ANTA groups when compared to the healthy group and decreased in the LPS + PARA, LPS + AGO, LPS + AGO + PARA, and LPS + AGO + ANTA + PARA groups when compared to the healthy group. The IL-6 and TNF-α mRNA expression increased in the LPS, LPS + ANTA, and LPS + AGO + ANTA groups when compared to the healthy group in the 2nd and 4th hours. The IL-6 and TNF-α expression decreased in the LPS + PARA, LPS + AGO, LPS + AGO + PARA, and LPS + AGO + ANTA + PARA groups when compared to the LPS group in the 2nd and 4th hours. The 5-HT7 receptor mRNA expression increased in the LPS group when compared to the healthy group in the 2nd hour. The 5-HT7 receptor mRNA expression decreased in the LPS + AGO and LPS + AGO + PARA groups when compared to the LPS group in the 2nd hour. The 5-HT7 receptor mRNA expression increased the in LPS + ANTA and LPS + ANTA + PARA groups when compared to the LPS group in the 2nd hour. CONCLUSION: The 5-HT7 receptor is a potential defense mechanism in stopping fever and the antipyretic property of paracetamol is not due to the 5-HT7 receptor.


Assuntos
Acetaminofen/farmacologia , Antipiréticos/farmacologia , Febre/tratamento farmacológico , Receptores de Serotonina/fisiologia , Animais , Temperatura Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Interleucina-6/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/análise , Receptores de Serotonina/genética , Fator de Necrose Tumoral alfa/genética
7.
Burns ; 45(6): 1410-1417, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31126777

RESUMO

BACKGROUND: Beeswax, Olive oil and Butter (BOB) are nutritive products that could support wound healing by adsorption to bandage. This study demonstrated the therapeutic effects of BOB on second degree burn. METHODS: Second degree burn model was created in rats. Experimental groups were assigned to Healthy, Burn, Silver Sulfadiazine (SS) and BOB. The effects of BOB were evaluated on skin regeneration, vesicles and bullae and fibroblast activity by histopathological analyses and wound contraction percent were determined. Transforming Growth Factor-Beta1 (TGF-ß1) and Vascular Endothelial Growth Factor-alpha (VEGF-α) mRNA expressions were analyzed with Real Time-Polymerase Chain Reaction. All parameters analyzed at 3rd, 7th, 14th days. RESULTS: The BOB treatment increased TGF-ß1 and VEGF-α expressions compared to Burn group. The histopathological analyses showed that epidermis and dermis layers injured due to burn. BOB treatment augmented the regeneration of these layers and increased fibroblast activity and keratinization which are play important role on the new blood vessels production. Also with the BOB treatment we showed wound contraction levels were higher than Burn and SS treatment. CONCLUSION: This study demonstrated that beeswax-olive oil-butter mixture impregnated bandage treatment in a second-degree burn rat model improved burn wound healing and encouraged skin renewal via modulating tissue TGF-ß1 and VEGF-α.


Assuntos
Bandagens , Queimaduras/terapia , Manteiga , Azeite de Oliva/farmacologia , Pele/efeitos dos fármacos , Ceras/farmacologia , Cicatrização , Animais , Anti-Infecciosos Locais/farmacologia , Queimaduras/genética , Queimaduras/metabolismo , Queimaduras/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Sulfadiazina de Prata/farmacologia , Pele/metabolismo , Pele/patologia , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética
8.
Life Sci ; 221: 327-334, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30797018

RESUMO

AIMS: Sepsis is a complex pathophysiological event involving systemic inflammatory response syndrome, multiple organ dysfunction syndrome and tissue damage such as acute lung injury (ALI). Although many new mechanisms are being investigated to enlighten the pathophysiology of sepsis, there is no effective treatment protocol yet. Antioxidant, antibacterial and antiinflammatory effects of gossypin (GOS)-like flavonoids have been shown and we have hypothesized that GOS have roles in sepsis induced inflammation of lungs. MAIN METHODS: Cecal ligation and puncture (CLP) induced sepsis model was induced in rats. Effects of GOS on oxidative stress, histopathology, nuclear factor kappa B (NF-κB), IL-6 positivity and NLRP3, HMGß1, TNF-α, NF-κB, IL-1ß mRNA expression levels were evaluated in lung tissues of the septic rats. KEY FINDINGS: GOS 20 (20 mg/kg) administration to septic rats decreased oxidative stress and supported antioxidant system in lungs. GOS administration also decreased the tissue NF-κB and IL-6 immunopositivity, which is high in septic rats; and decreased the sepsis-induced lung injury. HMGß1, NLRP3, NF-κB, IL-1ß, and TNF-α mRNA expression significantly increased in the CLP group. Both doses of GOS significantly reduced these mRNA expression as compared with the levels in the CLP group demonstrating its anti-inflammatory potential. SIGNIFICANCE: GOS administration, may represent a novel treatment for the prevention of lung damage occurred after sepsis induction. This effect of GOS might be related to its anti-inflammatory potential that result in decreased cytokine response and improved oxidative status.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Flavonoides/farmacologia , Sepse/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Animais , Antioxidantes , Citocinas , Modelos Animais de Doenças , Feminino , Flavonoides/metabolismo , Proteínas HMGB , Inflamação , Interleucina-1beta , Interleucina-6 , Pulmão/citologia , Pulmão/fisiologia , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Estresse Oxidativo , Ratos , Ratos Wistar , Sepse/induzido quimicamente , Sepse/fisiopatologia , Fator de Necrose Tumoral alfa
9.
Neurotoxicol Teratol ; 72: 22-28, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30685503

RESUMO

Serotonin exerts anti-inflammatory, antioxidant and antiapoptotic effects through 5-HT7 receptors. The present study determined the role of 5-HT7 receptors in glutamate-induced neurotoxicity by using human SH-SY5Y neuroblastoma cells. The cells were pretreated with different concentrations of 5-HT7 receptor agonist LP44 and antagonist SB269970 for 60 min, followed by treatment with glutamate. Cell proliferation was measured using xCELLigence system. Treatment with all the concentrations of LP44 significantly protected the cells from the toxic effects of glutamate after 24, 48 and 72 h. Although 5-HT7 receptor expression was significantly upregulated in glutamate-treated cells, it was downregulated in LP44-pretreated cells. Furthermore, LP44 treatment significantly decreased malondialdehyde levels and increased superoxide dismutase activities and glutathione levels. Moreover, LP44 treatment significantly decreased tumor necrosis factor alpha (TNF-α) levels and inhibited caspase 3 and caspase 9 mRNA expression. In contrast, SB269970 treatment exerted an insignificant effect on oxidative stress, inflammation and apoptosis. These findings suggest that exogenous stimulation of the 5-HT7 receptors may be protective in glutamate-induced neurotoxicity and that 5-HT7 receptor agonists can be used as therapeutic agents for preventing glutamate-induced neurological disorders.

10.
Phytomedicine ; 55: 191-199, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668429

RESUMO

BACKGROUND: Veratrum, hellebore is an important plant species of the Liliaceae family and jervine is the characteristic steroidal alkaloid constituent of Veratrum album. PURPOSE: In the current study, anti-inflammatory and antioxidant effects of jervine isolated from NH4OH-benzene extract of V. album rhizomes were investigated on CAR induced paw edema in rats. METHODS/STUDY DESIGN: In inflammatory study, 50, 100, 200 and 400  mg/kg doses of jervine, 25  mg/kg doses of DIC and IND were orally administered, and the volume of the foots were measured up to their knee arthrosis by plethismometer. After one hour of the oral administration of the all treatments, 0.1 ml of CAR solution (1%) was injected into the foot of the all rat groups and the volume of the foots were measured during 5 h after CAR injection. GPx, SOD, GR, MPO, CAT enzymes activities and GSH, LPO levels of the supernatants of paw homogenates and inflammation biomarkers such as TNF-α and IL-1ß in the rats serums were also estimated. RESULTS: According to the present results, jervine exerted 50.4-73.5% anti-inflammatory effects in carrageenan induced paw edema. Inflammation biomarkers such as TNF-α, IL-1ß and MPO that increased by CAR injection were suppressed by the administrations of all doses of jervine, IND and DIC. In all paw tissues, LPO levels as indicator of oxidative tissue damage were found to be high in CAR-treated group and it was found to be decreased in all doses of jervine. CONCLUSION: Jervine, DIC and IND reduced the negative effects of CAR due to increasing effects on the SOD, CAT, GSH, GPx and GR antioxidants.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Alcaloides de Veratrum/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/metabolismo , Carragenina/toxicidade , Avaliação Pré-Clínica de Medicamentos/métodos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Enzimas/metabolismo , Inflamação/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Extratos Vegetais/química , Ratos Sprague-Dawley , Rizoma/química , Fator de Necrose Tumoral alfa/metabolismo , Veratrum/química , Alcaloides de Veratrum/administração & dosagem , Alcaloides de Veratrum/isolamento & purificação
11.
Naunyn Schmiedebergs Arch Pharmacol ; 392(2): 135-145, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30353214

RESUMO

Sepsis is a life-threatening organ dysfunction condition response resulting in acute lung injury. Urotensin II (UII), an endogenous vasoactive peptide, is widely distributed in pulmonary, cardiovascular, central nervous, renal and metabolic systems, and especially in inflammatory regions. This study aimed to investigate whether urotensin II (UII) and UII receptor (UTR) antagonists play a role in the inflammatory response to sepsis-induced lung damage and they are possible therapeutic targets. In the study, 78 male Balb-c mice were used. A cecal ligation and puncture (CLP)-induced polymicrobial sepsis model was applied, and the effects of human urotensin II (agonist) and urantide and palosuran (antagonists) were investigated on lung tissues. Glutathione and malondialdehyde levels and SOD activity of lung tissues were investigated in addition to TNF-α, IL-1ß, IL-6, NF-κB, and UTR mRNA levels. Also, lung sections were histopathologically evaluated. Urantide and palosuran, UII receptor antagonists, decreased proinflammatory cytokines such as TNF-α, IL-1ß, IL-6, NF-κB, and also decreased oxidative stress parameters in lung tissue, which are markers of damage. UTR mRNA expression was increased in septic lungs, and both antagonists significantly decreased the elevated receptor level. Also, histopathological examination showed beneficial effects of both agonists on lung tissue. The results of this study help to understand the inflammatory and therapeutic contribution of the UII/UTR system on sepsis-induced lung damage. We can suggest that UTR receptor antagonists may be evaluated as a potential drug which reduces sepsis-induced lung damage in the future.


Assuntos
Lesão Pulmonar Aguda/genética , Receptores Acoplados a Proteínas-G/genética , Sepse/genética , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Ceco/cirurgia , Citocinas/genética , Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Ligadura , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , NF-kappa B/genética , Fragmentos de Peptídeos/farmacologia , Quinolinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/patologia , Superóxido Dismutase/metabolismo , Ureia/análogos & derivados , Ureia/farmacologia , Urotensinas/farmacologia
12.
An Acad Bras Cienc ; 91(1): e20180106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30569967

RESUMO

Our aim is to investigate the potentially preventive effects of Aliskiren in a carrageenan-induced lung pleurisy model and to compare the standard anti-inflammatory agents, indomethacin and dexamethasone. The pleurisy model was induced through the injection of carrageenan (0.2 ml-%2) into the pleural cavity. After the experiment, serum and lung tissues were collected and biochemical, molecular and pathological examinations were performed. In our study, pleural inflammation decreased superoxide dismutase activity and the glutathione level and increased the malondialdehyde level in the lung of rats, while Aliskiren increased the superoxide dismutase activity and glutathione level and decreased the malondialdehyde level. In addition, carrageenan-induced pleurisy caused a significant increase in pro-inflammatory cytokines mRNA expressions (TNF-α, IL-1ß, and NF-KB), while Aliskiren administration decreased their expressions as well as the standard treatments, indomethacin and dexamethasone, did. Aliskiren administration at the 200 mg/kg dose protected the lungs in the pathological evaluation, especially against inflammatory cell infiltration and edematous lesions. It appears that Aliskiren protects the lung from carrageenan-induced pleurisy damage by regulating inflammation and antioxidant-oxidant balance via Renin Angiotensin Aldosterone System inhibition.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios/farmacologia , Fumaratos/farmacologia , Pleurisia/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Carragenina , Modelos Animais de Doenças , Glutationa/análise , Interleucina-1beta/análise , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Malondialdeído/análise , NF-kappa B/análise , Estresse Oxidativo/efeitos dos fármacos , Pleurisia/induzido quimicamente , Pleurisia/patologia , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Fator de Necrose Tumoral alfa/análise
13.
Eur J Pharmacol ; 818: 457-469, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29133126

RESUMO

This study aimed to investigate the potential role of urotensin-II receptors in sepsis-induced lung injury in diabetic mice using urotensin-II receptor agonists and antagonists. A total of 110 male CD1 mice were used in this study. Diabetes was induced by 200mg/kg streptozotocin. One month after diabetes induction, the cecal ligation and puncture-induced polymicrobial sepsis model was applied in the diabetic and non-diabetic mice. Low and high doses of human urotensin-II agonist (HU-II) and antagonist (palosuran) were administered one hour after sepsis induction. HU-II administration was repeated in two-hour intervals. Blood and tissue samples were collected at 6 and 12H after sepsis induction for biochemical, molecular, and histopathologic examinations. Regarding to the lungs mRNA expression and immunohistochemistry results of TNF-α, IL1 ß, IL6, and NF-κB, it was observed that cytokine levels significantly increased in the diabetes group and the sepsis groups compared to the healthy group; this increase was significantly higher in the diabetes-sepsis groups. Our biochemical (superoxide dismutase, glutathione, and malondialdehyde) and histopathological findings in the lungs also supported these results. All increased parameters were significantly reduced dose-dependently by the administration of palosuran, an urotensin receptor antagonist. mRNA expression of urotensin-II and its receptor were examined in the lung tissue. Palosuran administration significantly reduced the urotensin-II and urotensin-II receptor levels that increased in the damaged tissue. This study has shown that urotensin-II and urotensin-II receptors contribute to the aggravation of sepsis-induced lung injury in diabetic mice; palosuran prevents this damage by antagonizing urotensin-II receptors.


Assuntos
Diabetes Mellitus Experimental/complicações , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Sepse/complicações , Urotensinas/metabolismo , Animais , Peso Corporal , Jejum/sangue , Regulação da Expressão Gênica , Interleucina-6/genética , Lesão Pulmonar/genética , Masculino , Camundongos , NF-kappa B/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/genética , Fator de Necrose Tumoral alfa/genética , Urotensinas/genética
14.
Eurasian J Med ; 49(1): 53-58, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28416934

RESUMO

Sepsis is a complex condition characterized by the simultaneous activation of inflammation and coagulation in response to microbial insult. These events manifest as systemic inflammatory response syndrome or sepsis symptoms through the release of proinflammatory cytokines, procoagulants, and adhesion molecules from immune cells and/or damaged endothelium. Today, sepsis is a severe multisystem disease with difficult treatments for its manifestations and high mortality rates. In the last two decades in particular, many studies have been conducted on sepsis that cause shock, multiorgan dysfunction, and organ failure by especially leading to hemodynamic changes. In sepsis, increasing antibiotic resistance and medicine-resistant hemodynamic changes have resulted in further research on new treatment modalities in addition to classical treatments. In the last decade, the sepsis physiopathology has been elucidated. Various therapeutic agents have been used in addition to antibiotherapy, but no satisfactory results have been obtained. This review summarizes the sepsis pathophysiology, current treatment protocols, and new approaches.

15.
Int Immunopharmacol ; 43: 227-235, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28043031

RESUMO

BACKGROUND AND AIM: Hepatocellular cancer (HCC) is the sixth most common cancer and liver fibrosis is strongly associated with HCC. Treatment options are limited, and preventive strategies should be developed. An important step in the beginning of liver fibrosis is a strong inflammatory response. 5-HT7 is the last recognized member of the serotonin receptor family and is expressed in both central nerve system and peripheral system and have a lot of functions like learning, memory, smooth muscular relaxation, in the control of circadian rhythms and thermoregulation, pain and migraine, schizophrenia, anxiety, cognitive disturbances, and even inflammation. METHODS: We therefore examined the biochemical, histopathological and molecular effects of the 5-HT7 receptor agonist and antagonist on inflammatory liver fibrogenesis in animal models of progressive cirrhosis: a mouse model induced by carbon tetrachloride (CCl4) and in Hep3b cells. RESULTS: 5-HT7 expression was observed in the liver in vivo and in vitro in CCl4-induced damage. 5-HT7 receptor agonist but not the antagonist reduced liver markers in mice and in Hep3b cells in carbon tetrachloride (CCl4) induced damage. 5-HT7 agonist, but not antagonist, protected liver tissue from oxidative stress in fibrosis. 5-HT7 agonist but not antagonist induces anti-inflammatory, anti-fibrinotic and anti-cytokine features in liver fibrosis in vivo and in vitro. CONCLUSIONS: 5-HT7 receptors have modulatory function and are an up-and-coming pharmacological target in the inflammatory fibrotic process. 5-HT7 receptor agonist LP-44 showed significant hepatoprotective effects against liver fibrosis, and LP-44 might become a useful therapeutic target for chronic liver inflammation and fibrosis.


Assuntos
Carcinoma Hepatocelular/imunologia , Inflamação , Neoplasias Hepáticas/imunologia , Fígado/metabolismo , Lesão Pulmonar/imunologia , Receptores de Serotonina/metabolismo , Animais , Tetracloreto de Carbono , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular , Fibrose , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Receptores de Serotonina/genética , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Sulfonamidas/farmacologia
16.
Ren Fail ; 39(1): 314-322, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28100100

RESUMO

Contrast media (CM) is known to have nephrotoxic adverse effects. Epigallocatechin-3-gallate (EGCG) is the most abundant and active catechin in green tea, and has strong antioxidant and anti-inflammatory properties. This study investigated whether EGCG can reduce contrast-induced nephrotoxicity (CIN), alone or with glycerol (GLY)-induced renal damage, and to understand its mechanisms of protection against toxicity, using models of GLY and CIN in rats. The rats were separated into eight groups (n = 6 in each), as follows: Healthy, GLY, CM, GLY + CM, CM + EGCG 50 mg/kg (po), GLY + CM + EGCG 50 mg/kg (po), CM + EGCG 100 mg/kg (po), and GLY + CM + EGCG 100 mg/kg (po). Both doses of EGCG protected against CM-induced renal dysfunction, as measured by serum creatinine and blood urea nitrogen (BUN). In addition, EGCG treatment markedly improved CIN-induced oxidative stress, and resulted in a significant down-regulatory effect on tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB mRNA expression. Moreover, histopathological analysis showed that EGCG also attenuated CM-induced kidney damage. Considering the potential clinical use of CM and the numerous health benefits of EGCG, this study showed the protective role of multi-dose EGCG treatment on CIN and GLY-aggravated CIN through different mechanisms.


Assuntos
Antioxidantes/farmacologia , Catequina/análogos & derivados , Meios de Contraste/efeitos adversos , Glicerol/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Animais , Nitrogênio da Ureia Sanguínea , Catequina/farmacologia , Citocinas/sangue , Rim/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Chá
17.
Curr Eye Res ; 42(2): 225-232, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27348425

RESUMO

PURPOSE: To compare the safety and efficacy of intravitreal anidulafungin injection with voriconazole and amphotericin B (Amp B) in an experimental Candida endophthalmitis (CE) model. METHODS: Intravitreal 1 × 105 CFU/0.1 ml Candida albicans was injected into the right eyes of 24 New Zealand rabbits, which were divided into 4 groups. Voriconazole 50 µg/0.1 ml, Amp B 10 µg/0.1 ml, and Anidulafungin 50 µg/0.1 ml were injected by intravitreal injection 72 h after inoculation. The control group was injected with 0.1 ml 0.9% NaCl. Clinical scoring was performed by assessing the cornea, conjunctiva, iris, and vitreous on days 3 and 7 of therapy. At the end of the study, the right eyes of all rabbits were enucleated and histopathological evaluation was performed. Therapy groups were compared according to the clinical, histopathological, and microbiological analysis scores. RESULTS: Total clinical scores were significantly different between treatment groups and the control group (p < 0.05). On day 7 of the therapy, clinical scores of the anidulafungin group were found to be significantly lower when compared with the other therapy groups, while a significant improvement was observed in the eyes of rabbits in the anidulafungin group (p < 0.05). Also, microbiological scores of the anidulafungin group were lower than those of the control group (p < 0.05). Histopathological scores of the anidulafungin treatment group were significantly better than the voriconazole and control groups. Inflammation was evidently suppressed and marked retinal toxicity was not observed with anidulafungin. CONCLUSIONS: This is the first study comparing the efficacy of anidulafungin with other antifungal agents. In this CE model, an intravitreal single dose of anidulafungin was shown to be noninferior to voriconazole and Amp B. As an alternative to Amp B or voriconazole, intravitreal anidulafungin is suggested as an effective antifungal agent for the treatment of CE.


Assuntos
Anfotericina B/administração & dosagem , Candidíase/tratamento farmacológico , Equinocandinas/administração & dosagem , Endoftalmite/tratamento farmacológico , Infecções Oculares Fúngicas/tratamento farmacológico , Voriconazol/administração & dosagem , Anidulafungina , Animais , Antifúngicos/administração & dosagem , Candida albicans/isolamento & purificação , Candidíase/diagnóstico , Candidíase/microbiologia , Túnica Conjuntiva/microbiologia , Túnica Conjuntiva/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Endoftalmite/diagnóstico , Endoftalmite/microbiologia , Infecções Oculares Fúngicas/diagnóstico , Infecções Oculares Fúngicas/microbiologia , Injeções Intravítreas , Iris/microbiologia , Iris/patologia , Masculino , Coelhos , Corpo Vítreo/microbiologia , Corpo Vítreo/patologia
18.
Biochem Genet ; 55(1): 34-47, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27586707

RESUMO

This study aimed to investigate the effects of the 5-HT7 receptor agonist (LP44) and antagonist (SB269970) on LPS-induced in vivo tissue damage and cell culture by molecular methods. This study was conducted in two steps. For in vivo studies, 24 female rats were divided into four groups. Group I: healthy; II (2nd h): LPS 5 mg/kg administered intraperitoneally (i.p.); III (4th h): LPS 5 mg/kg administered i.p.; IV (8th h): LPS 5 mg/kg administered i.p. For in vitro studies, we used the A549 cell line. Groups: I control (healthy) (2-4 h); II LPS: 1 µg/ml E. Coli O55:B5 strain (2-4 h); III agonist (LP44) 10-9 M (2-4 h); IV antagonist (SB269970) 10-9 M (2-4 h); V LPS+agonist 10-9 M (LP44 1 µg/ml) (2-4 h); VI LPS+antagonist 10-9 M (2-4 h). In molecular analyses, we determined increased TNF-α, IL-1ß, NF-κB, and 5-HT7 mRNA expressions in rat lung tissues and increased TNF-α, iNOS, and 5-HT7 mRNA expressions in the A549 cell line. In in vitro parameters, LP44 agonist administration-related decrease was observed. Our study showed that lung 5-HT7 receptor expression is increased in LPS-induced endotoxemia. All this data suggest that 5-HT7 receptor overexpression is an important protective mechanism during LPS-induced sepsis-related cell damage.


Assuntos
Lesão Pulmonar , Receptores de Serotonina/metabolismo , Células A549 , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
19.
Chem Biol Interact ; 258: 266-75, 2016 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-27645307

RESUMO

PURPOSE: Previously blocking the renin angiotensin system (RAAS) has been effective in the prevention of gastric damage. Therefore, the aim of this study was to investigate the effects of aliskiren, and thus, direct renin blockage, in indomethacin-induced gastric damage model. METHODS: Effects of aliskiren were evaluated in indomethacin-induced gastric damage model on Albino Wistar rats. Effects of famotidine has been investigated as standard antiulcer agent. Stereological analyses for ulcer area determination, biochemical analyses for oxidative status determination and molecular analyses for tissue cytokine and cyclooxygenase determination were performed on stomach tissues. In addition, to clarify antiulcer effect mechanism of aliskiren pylorus ligation-induced gastric acid secretion model was applied on rats. RESULTS: Aliskiren was able to inhibit indomethacin-induced ulcer formation. It also inhibited renin, and thus, decreased over-produced Angiotensin-II during ulcer formation. Aliskiren improved the oxidative status and cytokine profile of the stomach, which was most probably impaired by increased Angiotensin II concentration. Aliskiren also increased gastroprotective prostaglandin E2 concentration. Finally, aliskiren did not change the gastric acidity in pylorus ligation model. CONCLUSION: Aliskiren exerted its protective effects on stomach tissue by decreasing inflammatory cytokines and oxidative stress as a result of inhibiting the RAAS, at a rate-limiting step, as well as its end product, angiotensin II. Aliskiren also significantly increased protective factors such as PGE2, but not affect aggressive factors such as gastric acidity.


Assuntos
Amidas/farmacologia , Amidas/uso terapêutico , Fumaratos/farmacologia , Fumaratos/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/prevenção & controle , Animais , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Citocinas/genética , Citocinas/metabolismo , Dinoprostona/metabolismo , Glutationa/metabolismo , Concentração de Íons de Hidrogênio , Indometacina , Cinética , Masculino , Malondialdeído/metabolismo , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Estômago/efeitos dos fármacos , Estômago/enzimologia , Estômago/patologia , Úlcera Gástrica/genética , Superóxido Dismutase/metabolismo
20.
Peptides ; 82: 35-43, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27208703

RESUMO

This study investigated possible role of U-II and its receptor expression in inflammation by using UTR agonist and antagonist in carrageenan induced acute inflammation. Rats were divided into 5 groups as (1) Healthy control, (2) Carrageenan control, (3) Carrageenan +Indomethacin 20mg/kg, orally, (4) Carrageenan +AC7954 (U-II receptor agonist, intraperitoneally) 30mg/kg and (5) Carrageenan +SB657510 (UTR antagonist, intraperitoneally) 30mg/kg. 1h after drug administration, carrageenan was injected. At the 3rd hour after carrageenan injection, agonist produced no effect while antagonist 63% anti-inflammatory effect respectively. UTR and UT-II expression increased in carrageenan induced paw tissue. Antagonist administration prevented the decrease in an antioxidant system and also capable to decrease TNF-α and IL-6 mRNA expressions. This study showed the role of urotensin II receptors in the physiopathogenesis of acute inflammatory response that underlying many diseases accompanied by inflammation.


Assuntos
Inflamação/tratamento farmacológico , Receptores Acoplados a Proteínas-G/metabolismo , Urotensinas/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Carragenina/toxicidade , Cromanos/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Indometacina/administração & dosagem , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-6/genética , Ratos , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/genética , Fator de Necrose Tumoral alfa/genética , Urotensinas/genética
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