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1.
Turk J Med Sci ; 52(3): 848-857, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36326331

RESUMO

BACKGROUND: Hydroxychloroquine (HCQ) is an antimalarial that is widely used in the management of rheumatoid arthritis and other autoimmune diseases. In this study, we aimed to examine the vascular effects of HCQ on rat aorta (RA). METHODS: The RA rings were suspended in isolated organ baths and tension was recorded isometrically. HCQ-induced relaxations were tested in the presence of the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME, 100 mM); the cyclooxygenase enzyme inhibitor, indomethacin (10 mM); the calcium (Ca2+) ion channel blocker, nilvadipine (10 µM); and the K+ ion channel inhibitors, tetraethylammonium (1 mM), glibenclamide (10 mM), 4-aminopyridine (1 mM), and barium chloride (30 mM). The effect of HCQ on Ca2+ channels was examined using Ca2+-free Krebs solution, and adding calcium chloride (CaCl2 , 10-5- 10-2 M) cumulatively to baths incubated with HCQ. RESULTS: Removing the endothelium resulted in less relaxation of RA rings compared to endothelium-intact rings (p < 0.05). The effect of endothelium was supported by using L-NAME where HCQ produced-vasorelaxation was decreased (p < 0.05). The contraction of vascular rings was inhibited to a significant degree following the addition of CaCl2 , PE, or KCl on HCQ-incubated RA rings (p < 0.05). The incubation of the RA rings with the Ca2+ channel blocker, the K+ channel blockers, and the COX inhibitor, indomethacin did not significantly affect vascular relaxation induced by HCQ. DISCUSSION: HCQ produced relaxation of RA rings. The relaxation mechanism differs according to the concentration of HCQ. At con-centrations of 10-6 and 10-5 M, the relaxation is endothelium-dependent and mediated by NO. We strongly suggest that Ca2+ channel inhibition is involved at concentrations of 10-5 and 10-4 M, as well as NO.


Assuntos
Hidroxicloroquina , Indometacina , Ratos , Animais , NG-Nitroarginina Metil Éster/farmacologia , Cloreto de Cálcio/farmacologia , Endotélio , Indometacina/farmacologia , Aorta , Endotélio Vascular , Vasodilatadores/farmacologia , Relação Dose-Resposta a Droga
2.
Gen Physiol Biophys ; 41(5): 473-481, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36222345

RESUMO

Cyclooxygenase 2 (COX-2) is responsible for the therapeutic effects of indomethacin, while inhibition of the COX-1 enzyme and oxidative stress are responsible for its gastro-toxic effects. It has been reported that pycnogenol increases the expression of COX-1, suppresses the expression rate of COX-2 and oxidative stress. Our aim in this study is to investigate the antiinflammatory activities of indomethacin, pycnogenol, and their combination (PI) in rats and to examine their effects on stomach tissue. In the study, anti-inflammatory activity was investigated in carrageenan-induced inflammatory paw edema in albino Wistar male rats. Effects on stomach tissue were performed by applying the previous method. PI, indomethacin and pycnogenol were the best suppressors of carrageenan inflammation and oxidative stress in paw tissue, respectively. While the groups with the lowest COX-1 activity in paw tissue were IC, PIC and PC, respectively, PIC, IC and PC were the ones that best inhibited the increase in COX-2 activity. Pycnogenol inhibited the increase of malondialdehyde, the decrease of total glutathione and COX-1 in the stomach, and significantly suppressed the formation of indomethacin ulcers. Our experimental results showed that pycnogenol reduced the toxic effect of indomethacin on the stomach and increased anti-inflammatory activity. This beneficial interaction of pycnogenol and indomethacin suggests that PI will provide superior success in the treatment of inflammatory diseases.


Assuntos
Edema , Indometacina , Animais , Anti-Inflamatórios/farmacologia , Carragenina/uso terapêutico , Carragenina/toxicidade , Ciclo-Oxigenase 2/efeitos adversos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Flavonoides , Glutationa , Indometacina/farmacologia , Masculino , Malondialdeído , Extratos Vegetais , Ratos , Ratos Wistar
3.
An Acad Bras Cienc ; 94(4): e20210145, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36228215

RESUMO

This study evaluated some biological activities of extracts from Abuta selloana. The gastroprotective potential was determined against ethanol/HCl- and indomethacin-induced gastric ulcers, whereas the antinociceptive effect was evaluated by acetic acid-induced abdominal contortions in mice. The cytotoxicity activity was measured against human cancer cell lines: U251 (glioma), MCF-7 (breast cancer) and NCI-H460 (lung cancer). The radical scavenger potential was verified; and preliminary phytochemical analyses were performed. The phytochemical screening revealed higher levels of phenolic compounds in all extracts. Moreover, the methanolic extract from pulp fruit (MEPu), peel fruit (MEPe), branches (MEB) and leaves (MEL) scavenged the DPPH radical at 100 µg/mL. Besides, only MEL presented GI50 < 30 µg/mL in all tested cells. Besides, MEPu, MEPe, MEB or MEL at 10 mg/kg (i.p) reduced the abdominal contortions at 47.22%, 63.31%, 84.59% and 37.76%, respectively. The MEPu, MEPe, MEB and MEL reduced the ethanol/HCl- and indomethacin- induced ulcer at 250 mg/kg (p.o). In conclusion, A. selloana had interesting biological activities; presenting the leaves as a promising source for compounds with cytotoxic potential, however, further studies should be performed to confirm its antitumoral activity. Besides, the whole plant can be an important source of bioactive compounds associated with gastroprotective and antinociceptive properties.


Assuntos
Antiulcerosos , Frutas , Analgésicos/farmacologia , Animais , Brasil , Etanol/farmacologia , Frutas/química , Mucosa Gástrica , Humanos , Indometacina/análise , Indometacina/farmacologia , Metanol/análise , Metanol/química , Metanol/farmacologia , Camundongos , Compostos Fitoquímicos/análise , Fitoterapia , Extratos Vegetais/química , Folhas de Planta
4.
Int J Mol Sci ; 23(19)2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36232870

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) are inhibitors of cyclooxygenase enzyme (COX) and were found to have positive effects in reducing the risk of developing gynecological cancers. However, long-term administration of NSAIDs carries the risk of various side effects, including those in the digestive and circulatory systems. Therefore, there is a constant need to develop new NSAID derivatives. In this work, we investigated rhenium NSAIDs, comparing their effects on endometrial cancer cells with original NSAIDs, demonstrating the high activity of aspirin and indomethacin derivatives. The cytotoxic activity of rhenium derivatives against the Ishikawa and HEC-1A cancer cell lines was higher than that of the original NSAIDs. The IC50 after 24-h incubation of Ishikawa and HEC-1A were 188.06 µM and 394.06 µM for rhenium aspirin and 228.6 µM and 1459.3 µM for rhenium indomethacin, respectively. At the same time, IC50 of aspirin and indomethacin were 10,024.42 µM and 3295.3 µM for Ishikawa, and 27,255.8 µM and 5489.3 µM for HEC-1A, respectively. Moreover, these derivatives were found to inhibit the proliferation of both cell lines in a time- and state-dependent manner. The Ishikawa cell proliferation was strongly inhibited by rhenium aspirin and rhenium indomethacin after 72-h incubation (*** = p < 0.001), while the HEC-1A proliferation was inhibited by the same agents already after 24-h incubation (*** = p < 0.001). Furthermore, the ROS level in the mitochondria of the tested cells generated in the presence of rhenium derivatives was higher than the original NSAIDs. That was associated with rhenium indomethacin exclusively, which had a significant effect (*** = p < 0.001) on both Ishikawa and HEC-1A cancer cells. Rhenium aspirin had a significant effect (*** = p < 0.001) on the mitochondrial ROS level of Ishikawa cells only. Overall, the research revealed a high potential of the rhenium derivatives of aspirin and indomethacin against endometrial cancer cells compared with the original NSAIDs.


Assuntos
Neoplasias do Endométrio , Rênio , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/farmacologia , Aspirina/uso terapêutico , Linhagem Celular Tumoral , Ciclo-Oxigenase 2 , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Indometacina/farmacologia , Indometacina/uso terapêutico , Espécies Reativas de Oxigênio , Rênio/farmacologia
5.
Life Sci ; 309: 121006, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36174711

RESUMO

AIMS: Oxidative stress and inflammatory response play a vital role in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). This study investigated the effects of edaravone in rats with CI-AKI. MAIN METHODS: Male Sprague Dawley rats were randomly assigned into four groups (n = 11-14/group): control, edaravone (30 mg/kg/day intraperitoneally (IP)), CI-AKI, and edaravone with CI-AKI. The induction of CI-AKI was performed by dehydration and the administration of contrast media (iohexol) and inhibitors of prostaglandin (indomethacin) and nitric oxide synthesis (L-NAME: N-nitro L-arginine methyl ester). Edaravone was administered for two weeks before the induction of CI-AKI. Serum creatinine and urea, renal oxidative stress and inflammatory biomarkers, and histopathological alterations were evaluated after 48 h of contrast exposure. KEY FINDINGS: Rats with CI-AKI showed a significant increase in serum creatinine and urea. The levels of antioxidant biomarkers including glutathione peroxidase, superoxide dismutase and reduced glutathione were significantly decreased in CI-AKI group versus control. Pre-treatment of rats with edaravone normalized kidney function and protected the kidney from oxidative damage as demonstrated by normalization of previous biomarkers. Furthermore, edaravone partially ameliorated renal histopathological alterations relative to the CI-AKI group, notably in the nephrons. No changes were observed in inflammatory biomarkers including tumour necrosis factor-alpha and interleukin-6 among all groups. SIGNIFICANCE: The current findings suggest that edaravone could be a potential strategy to ameliorate developing CI-AKI possibly by improving renal antioxidant capacity. Further studies are warranted to expand the current understanding of the use of edaravone in the various models of AKI.


Assuntos
Injúria Renal Aguda , Iohexol , Ratos , Masculino , Animais , Edaravone/farmacologia , Edaravone/metabolismo , Iohexol/efeitos adversos , Iohexol/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Creatinina , Antioxidantes/metabolismo , Meios de Contraste/efeitos adversos , Glutationa Peroxidase/metabolismo , Ratos Sprague-Dawley , Óxido Nítrico/metabolismo , Interleucina-6/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Rim/metabolismo , Glutationa/metabolismo , Biomarcadores/metabolismo , Ureia/metabolismo , Prostaglandinas/metabolismo , Indometacina/farmacologia
6.
Eur J Pharmacol ; 933: 175259, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36113554

RESUMO

Although methylglyoxal (MGO), a highly reactive dicarbonyl compound, influences the functioning of the vasculature, modulating its effects on vascular reactivity to various substances remains unclear, especially purinoceptor ligands. Therefore, we sought to investigate the direct effects of MGO on relaxation induced by adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) in isolated rat carotid arteries. When carotid arteries were exposed to MGO (420 µM for 1 h), relaxation induced by acetylcholine or sodium nitroprusside was not affected by MGO. However, ATP- and UTP-induced relaxation was impaired by MGO compared with the control. In both ATP- and UTP-induced relaxation, endothelial denudation, incubation with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine or the selective P2Y purinoceptor 2 (P2Y2) receptor antagonist AR-C118925XX reduced relaxation in both the control and MGO groups, while the differences between the control and MGO groups were eliminated. The cyclooxygenase (COX) inhibitor indomethacin inhibited the differences in ATP/UTP-mediated relaxations between the control and MGO groups. Moreover, N-acetyl-L-cysteine (NAC), an antioxidant, could augment carotid arterial relaxation induced by ATP/UTP in the presence of MGO. MGO increased arachidonic acid-induced contraction, which was suppressed by NAC. Following both ATP/UTP stimulation, MGO increased the release of prostanoids. These results suggest that MGO impaired ATP- and UTP-induced relaxation in carotid arteries, which was caused by suppressed P2Y2 receptor-mediated signaling and reductions in endothelial NO. Moreover, MGO partially contributed to COX-derived vasoconstrictor prostanoids through increased oxidative stress.


Assuntos
Acetilcolina , Aldeído Pirúvico , Acetilcolina/farmacologia , Acetilcisteína , Adenosina , Trifosfato de Adenosina/farmacologia , Animais , Antioxidantes/farmacologia , Ácido Araquidônico , Arginina , Artérias Carótidas , Inibidores de Ciclo-Oxigenase , Indometacina/farmacologia , Óxido de Magnésio , Óxido Nítrico , Polifosfatos , Prostaglandina-Endoperóxido Sintases , Prostaglandinas , Aldeído Pirúvico/farmacologia , Ratos , Receptores Purinérgicos P2Y , Sódio , Uridina , Uridina Trifosfato/farmacologia , Vasoconstritores
7.
Eur Rev Med Pharmacol Sci ; 26(17): 6121-6128, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36111914

RESUMO

OBJECTIVE: We evaluated how efficacious indomethacin, at two different doses, is in the treatment of an experimental model of sinusitis in rats. MATERIALS AND METHODS: Twenty-one Wistar albino rats (all male) were sorted at random into one of three groups: 1st group (n=7) was placebo. 2nd group (n=7). These rats had sinusitis induced experimentally, following indomethacin 3 mg/kg, 5 days was administered to them. 3rd group (n=7). These rats had sinusitis induced experimentally, following indomethacin 6 mg/kg, 5 days was administered to them. The animals' sinonasal mucosae were examined histopathologically by standard light microscopy. RESULTS: Experimental sinusitis was observed in the 2nd and 3rd groups, but not in the rats administered a placebo. Although the inflammatory features of sinusitis were found to be significantly decreased in the animals administered indomethacin 3 mg/kg (the 2nd group), this anti-inflammatory effect was even greater in the 3rd group, where indomethacin 6 mg/kg had been administered. Indomethacin at either dose was superior to placebo in reducing inflammatory features of sinusitis. CONCLUSIONS: Topical use of indomethacin nasal drops decreased the inflammatory features in experimentally induced acute sinusitis. Moreover, a higher dose of indomethacin (6 mg/kg) was more efficacious than a lower dose (3 mg/kg). The present study is valuable as an initial step in showing the need to undertake human trials to see the effect of indomethacin nasal drops on sinusitis in humans. In acute rhinosinusitis, the use of topical anti-inflammatory drops may help to decrease the symptoms and may be used adjunctively with antibiotic treatment.


Assuntos
Indometacina , Sinusite , Doença Aguda , Animais , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Indometacina/farmacologia , Indometacina/uso terapêutico , Masculino , Ratos , Ratos Wistar , Sinusite/tratamento farmacológico
8.
Sci Rep ; 12(1): 15823, 2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-36138112

RESUMO

The aim of this study was to explore the effects of nonsteroidal anti-inflammatory drugs on biomineralization of enamel. Sixty C57Bl6 male mice were used, which were assigned into three groups: celecoxib (n = 20) or indomethacin (n = 20) treatment for a period of 28 days or received no medication (control group, n = 20). Visual inspection and microcomputed tomography were used to analyze enamel morphology. Scanning electron microscopy-Energy dispersive X-ray and Knoop microhardness test were used to quantify chemical element content (Ca, P, C, O) and enamel microhardness, respectively. Tissues were collected to investigate the synthesis, activity or nuclear translocation of metalloproteinase-20, transcription factor Runx2, dentin sialoprotein and cyclooxygenase-2 enzyme by means of immunohistochemistry, in situ zymography and indirect immunofluorescence. Treatment with indomethacin and celecoxib reduced the Ca and P content, microhardness and mineral density in enamel. Treatment with nonsteroidal anti-inflammatory drugs caused an accumulation of metalloproteinase-20 and overall increased enzymatic activity in enamel matrix, while the synthesis of the transcription factor Runx2 was inhibited by these drugs. Interestingly, indomethacin inhibited Runx2 translocation to the nucleus whereas celecoxib did not. Those findings show that non-steroidal anti-inflammatory drugs impact the enamel biomineralization and could be involved in the etiology tooth enamel defects if used during the period of tooth formation and mineralization.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core , Indometacina , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Biomineralização , Celecoxib/farmacologia , Ciclo-Oxigenase 2 , Indometacina/farmacologia , Masculino , Camundongos , Minerais , Microtomografia por Raio-X
9.
Toxicon ; 218: 57-65, 2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36113683

RESUMO

Rhinella marina toad is abundant in Brazil. Its poison contains cardiac glycosides called bufadienolides, which are extensively investigated for their bioactivity. Our aim was to characterize the vasoactivity of Rhinella marina poison (RmP) on the aorta of male Wistar rats. For this, the RmP was first collected and processed to obtain an alcoholic extract. To determine cardiovascular effects of RmP, we performed in vivo tests by administering RmP intravenously in doses of 0.1-0.8 mg/kg. Vascular reactivity was also performed through concentration-response curves to RmP (10 ng/mL to 200 µg/mL) in aortic segments with and without endothelium. RmP induced a concentration-dependent contraction in rat aorta which was partly endothelium-mediated. Nitric oxide contributes with this response in view that incubation with L-NAME increased the contractile response. Additionally, treatment with indomethacin [cyclooxygenase, (COX) inhibitor], nifedipine (L-type voltage-gated calcium channels blocker), and BQ-123 (ETA receptors antagonist) decreased maximum response, and ketanserin (5-HT2 receptors antagonist) decreased pEC50, suggesting active participation of these pathways in the contractile response. On the other hand, apocynin (NADPH oxidase inhibitor) did not alter contractility. Incubation with prazosin (α1-adrenergic receptor antagonist) abolished the contractile response, suggesting that the RmP-induced contraction is dependent on the adrenergic pathway. In the Na+/K+ ATPase protocol, a higher Emax was observed in the RmP experimental group, suggesting that RmP potentiated Na+/K+ATPase hyperpolarizing response. When this extract was injected (i.v.) in vivo, increase in blood pressure and decrease in heart rate were observed. The results were immediate and transitory, and occurred in a dose-dependent manner. Overall, these data suggest that the poison extract of R. marina toad has an important vasoconstrictor action and subsequent vasopressor effects, and its use can be investigated to some cardiovascular disorders.


Assuntos
Bufanolídeos , Venenos , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/farmacologia , Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/farmacologia , Animais , Bufanolídeos/toxicidade , Bufo marinus/metabolismo , Canais de Cálcio , Endotélio Vascular , Hemodinâmica , Indometacina/farmacologia , Ketanserina/farmacologia , Masculino , Metanol/farmacologia , NADPH Oxidases , NG-Nitroarginina Metil Éster , Nifedipino/farmacologia , Óxido Nítrico/metabolismo , Prazosina/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Ratos Wistar , Serotonina/farmacologia , Vasoconstritores
10.
Comput Biol Med ; 147: 105788, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35809412

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the worldwide spread of coronavirus disease 19 (COVID-19), and till now, it has caused death to more than 6.2 million people. Although various vaccines and drug candidates are being tested globally with limited to moderate success, a comprehensive therapeutic cure is yet to be achieved. In this study, we applied computational drug repurposing methods complemented with the analyses of the already existing gene expression data to find better therapeutics in treatment and recovery. Primarily, we identified the most crucial proteins of SARS-CoV-2 and host human cells responsible for viral infection and host response. An in-silico screening of the existing drugs was performed against the crucial proteins for SARS-CoV-2 infection, and a few existing drugs were shortlisted. Further, we analyzed the gene expression data of SARS-CoV-2 in human lung epithelial cells and investigated the molecules that can reverse the cellular mRNA expression profiles in the diseased state. LINCS L1000 and Comparative Toxicogenomics Database (CTD) were utilized to obtain two sets of compounds that can be used to counter SARS-CoV-2 infection from the gene expression perspective. Indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), and Vitamin-A were found in two sets of compounds, and in the in-silico screening of existing drugs to treat SARS-CoV-2. Our in-silico findings on Indomethacin were further successfully validated by in-vitro testing in Vero CCL-81 cells with an IC50 of 12 µM. Along with these findings, we briefly discuss the possible roles of Indomethacin and Vitamin-A to counter the SARS-CoV-2 infection in humans.


Assuntos
COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Humanos , Indometacina/farmacologia , Vitaminas
11.
Life Sci ; 306: 120801, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35850247

RESUMO

Drug-induced nephrotoxicity is frequently reported. However, the mechanisms underlying nephrotoxic medications and their overlapping molecular events, which might have therapeutic value, are unclear. We performed a genome-wide analysis of gene expression and a gene set enrichment analysis to identify common and unique pathways associated with the toxicity of colistin, ifosfamide, indomethacin, and puromycin. Rats were randomly allocated into the treatment or control group. The treatment group received a toxic dose once daily of each investigated drug for 1 week. Differentially expressed genes were found in the drug-treated kidney and liver compared to the control, except for colistin in the liver. Upregulated pathways were mainly related to cell death, cell cycle, protein synthesis, and immune response modulation in the kidney. Cell cycle was upregulated by all drugs. Downregulated pathways were associated with carbon metabolism, amino acid metabolism, and fatty acid metabolism. Indomethacin, colistin, and puromycin shared the most altered pathways in the kidney. Ifosfamide and indomethacin affected molecular processes greatly in the liver. Our findings provide insight into the mechanisms underlying the renal and hepatic adverse effects of the four drugs. Further investigation should explore the combinatory drug therapies that attenuate the toxic effects and maximize the effectiveness of nephrotoxic drugs.


Assuntos
Colistina , Ifosfamida , Animais , Colistina/efeitos adversos , Expressão Gênica , Ifosfamida/efeitos adversos , Ifosfamida/metabolismo , Indometacina/farmacologia , Rim/metabolismo , Puromicina/metabolismo , Puromicina/toxicidade , Ratos
12.
Molecules ; 27(13)2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35807473

RESUMO

Introduction: Safranal, which endows saffron its unique aroma, causes vasodilatation and has a hypotensive effect in animal studies, but the mechanisms of these effects are unknown. In this study, we investigated the mechanisms of safranal vasodilation. Methods: Isolated rat endothelium-intact or -denuded aortic rings were precontracted with phenylephrine and then relaxed with safranal. To further assess the involvement of nitric oxide, prostaglandins, guanylate cyclase, and phospholipase A2 in safranal-induced vasodilation, aortic rings were preincubated with L-NAME, indomethacin, methylene blue, or quinacrine, respectively, then precontracted with phenylephrine, and safranal concentration-response curves were established. To explore the effects of safranal on Ca2+ influx, phenylephrine and CaCl2 concentration-response curves were established in the presence of safranal. Furthermore, the effect of safranal on aortic rings in the presence of ouabain, a Na+-K+ ATPase inhibitor, was studied to explore the contribution of Na+/Ca2+ exchanger to this vasodilation. Results: Safranal caused vasodilation in endothelium-intact and endothelium-denuded aortic rings. The vasodilation was not eliminated by pretreatment with L-NAME, indomethacin, methylene blue, or quinacrine, indicating the lack of a role for NO/cGMP. Safranal significantly inhibited the maximum contractions induced by phenylephrine, or by CaCl2 in Ca2+-free depolarizing buffer. Safranal also relaxed contractions induced by ouabain, but pretreatment with safranal totally abolished the development of ouabain contractions. Discussion/Conclusion: Inhibition of Na+-K+ ATPase by ouabain leads to the accumulation of Na+ intracellularly, forcing the Na+/Ca2+ exchanger to work in reverse mode, thus causing a contraction. Inhibition of the development of this contraction by preincubation with safranal indicates that safranal inhibited the Na+/Ca2+ exchanger. We conclude that safranal vasodilation is mediated by the inhibition of calcium influx from extracellular space through L-type Ca2+ channels and by the inhibition of the Na+/Ca2+ exchanger.


Assuntos
Trocador de Sódio e Cálcio , Vasodilatação , Adenosina Trifosfatases , Animais , Aorta Torácica , Cálcio/metabolismo , Cloreto de Cálcio/farmacologia , Cicloexenos , Endotélio Vascular/metabolismo , Indometacina/farmacologia , Azul de Metileno/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Ouabaína/farmacologia , Fenilefrina/farmacologia , Quinacrina/farmacologia , Ratos , Ratos Sprague-Dawley , Trocador de Sódio e Cálcio/farmacologia , Terpenos , Vasodilatadores/farmacologia
13.
J Immunother Cancer ; 10(7)2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35882449

RESUMO

BACKGROUND: Adoptive cell therapy (ACT) using genetically modified T cells has evolved into a promising treatment option for patients with cancer. However, even for the best-studied and clinically validated CD19-targeted chimeric antigen receptor (CAR) T-cell therapy, many patients face the challenge of lack of response or occurrence of relapse. There is increasing need to improve the efficacy of ACT so that durable, curative outcomes can be achieved in a broad patient population. METHODS: Here, we investigated the impact of indomethacin (indo), a non-steroidal anti-inflammatory drug (NSAID), on the efficacy of ACT in multiple preclinical models. Mice with established B-cell lymphoma received various combinations of preconditioning chemotherapy, infusion of suboptimal dose of tumor-reactive T cells, and indo administration. Donor T cells used in the ACT models included CD4+ T cells expressing a tumor-specific T cell receptor (TCR) and T cells engineered to express CD19CAR. Mice were monitored for tumor growth and survival. The effects of indo on donor T cell phenotype and function were evaluated. The molecular mechanisms by which indo may influence the outcome of ACT were investigated. RESULTS: ACT coupled with indo administration led to improved tumor growth control and prolonged mouse survival. Indo did not affect the activation status and tumor infiltration of the donor T cells. Moreover, the beneficial effect of indo in ACT did not rely on its inhibitory effect on the immunosuppressive cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) axis. Instead, indo-induced oxidative stress boosted the expression of death receptor 5 (DR5) in tumor cells, rendering them susceptible to donor T cells expressing TNF-related apoptosis-inducing ligand (TRAIL). Furthermore, the ACT-potentiating effect of indo was diminished against DR5-deficient tumors, but was amplified by donor T cells engineered to overexpress TRAIL. CONCLUSION: Our results demonstrate that the pro-oxidative property of indo can be exploited to enhance death receptor signaling in cancer cells, providing rationale for combining indo with genetically modified T cells to intensify tumor cell killing through the TRAIL-DR5 axis. These findings implicate indo administration, and potentially similar use of other NSAIDs, as a readily applicable and cost-effective approach to augment the efficacy of ACT.


Assuntos
Indometacina , Receptores do Ligante Indutor de Apoptose Relacionado a TNF , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Indometacina/farmacologia , Camundongos , Recidiva Local de Neoplasia , Estresse Oxidativo , Ligante Indutor de Apoptose Relacionado a TNF
14.
Spectrochim Acta A Mol Biomol Spectrosc ; 280: 121493, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-35728400

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) has a very low survival rate due to the late detection and poor response to chemotherapy. Epithelial-to-mesenchymal transition (EMT) is considered an important step in tumor progression with regard to invasion and metastasis, and Transforming Growth Factor-beta (TGF-ß) signaling has been shown to play an important role in EMT. Therefore, we aimed to investigate whether indomethacin, an anti-inflammatory and analgesic drug, has any effect on TGF-ß-induced EMT in pancreatic cancer cell line and analyze the changes in their molecular structures by Raman spectroscopy and other molecular techniques. Indomethacin treated Panc-1 cells were analyzed with Raman spectroscopy, quantitative polymerase chain reaction and immunofluorescence techniques after the induction of EMT with TGF-ß. The exposure of Panc-1 cells to TGF-ß resulted in characteristic morphological alterations of EMT, and indomethacin inhibits TGF-ß-induced EMT through up-regulation of E-cadherin and down-regulation of N-cadherin and Snail expressions. Raman spectroscopy supported by principal component analysis (PCA) confirmed the effects of both TGF-ß and indomethacin. Raman spectra were further analyzed using the PCA-assisted vector machine algorithm and it was seen that the data could be classified with 97.6% accuracy. Our results suggest that indomethacin may have a significant effect on PDAC metastasis, and Raman spectroscopy was able to probe EMT-related changes and the efficacy of indomethacin in a short time and without the need for specific reagents compared to other molecular techniques.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Indometacina/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Análise Espectral Raman , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia
15.
Pharm Biol ; 60(1): 1207-1213, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35764528

RESUMO

CONTEXT: The gastroprotective effect of Heliotropium indicum L. (Boraginaceae), a plant traditionally used in Mexico to treat gastric ulcers, has been previously reported. However, no active compound was identified. OBJECTIVE: The current contribution aimed to isolate, through a bioassay-guided study, at least one compound from H. indicum with considerable gastroprotective activity, examine its effect on ethanol-induced gastric lesions in mice, and explore possible mechanisms of action. MATERIALS AND METHODS: Three extracts (hexane, dichloromethane, and methanol) were obtained from H. indicum leaves. Their 30 and 100 mg/kg doses were assessed on ethanol-induced gastric lesions in male CD1 mice. Since the dichloromethane extract was the most active, successive chromatographies were carried out leading to the identification of the most active compound. This compound (at 3-100 mg/kg) was compared to carbenoxolone (at 10-100 mg/kg) in biological evaluations in mice. Pre-treatments with indomethacin (10 mg/kg, s.c.), L-NAME (70 mg/kg, i.p.), and NEM (10 mg/kg, s.c.) were performed independently to determine the participation of prostaglandins, nitric oxide, and/or sulfhydryl groups, respectively, in the mechanism of action of the compound. RESULTS: (E)-Ethyl-12-cyclohexyl-4,5-dihydroxydodec-2-enoate, a compound isolated from H. indicum, afforded dose-dependent gastroprotective activity. The maximum effect was observed at 100 mg/kg (90.13 ± 3.08%), with an ED50 of 5.92 ± 2.48 mg/kg. Gastroprotection was not modified by pre-treatment with indomethacin, L-NAME, or NEM. CONCLUSIONS: (E)-Ethyl-12-cyclohexyl-4,5-dihydroxydodec-2-enoate, isolated from H. indicum, was found to produce a substantial gastroprotective effect. Prostaglandins, nitric oxide, and non-protein sulfhydryl groups are not involved in its mechanism of action.


Assuntos
Antiulcerosos , Heliotropium , Animais , Antiulcerosos/farmacologia , Antiulcerosos/uso terapêutico , Etanol , Indometacina/farmacologia , Masculino , Cloreto de Metileno , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico , Prostaglandinas , Ratos , Ratos Wistar , Compostos de Sulfidrila
16.
ACS Biomater Sci Eng ; 8(7): 3010-3021, 2022 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-35679601

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) have drawn considerable attention in the field of cancer treatment, yet these drugs display limited potency and selectivity against cancer cells. To address these problems, we designed a peptide-based self-delivery system [Indomethacin-Phe-Phe-Tyr (H2PO3)-Ser-Val, IDM-FFpYSV] that combines an NSAID molecule (indomethacin, or IDM) and a segment of anticancer tripeptide (tyroservatide, or YSV). IDM-FFpYSV is capable of self-assembling in an aqueous solution to afford nanofibrillar hydrogels under the catalysis of alkaline phosphatases (ALPs), which are overexpressed on the plasma membrane of cancer cells. The IDM-FFpYSV + ALP hydrogel displays a continuous release profile of peptide drugs, whereas a solution mixture of pure drugs (IDM-OH + pYSV + ALP) shows burst release of drug moieties. The treatment of IDM-FFpYSV selectively inhibits the proliferation of HeLa cells in vitro, with precise regulations of intracellular targeting proteins (COX-2 and AC-H3). The enhanced potency and selectivity of IDM-FFpYSV are found to be attributed to enhanced cellular uptake of peptide drugs, which involves a caveolae-mediated endocytosis pathway. Furthermore, intravenous administration of the IDM-FFpYSV formulation significantly inhibits the tumor growth in a HeLa-xenografted mouse model, whereas treatment of solution mixtures of pure drugs (IDM-OH + pYSV) fails to do so. Taken together, the study provides a viable strategy to augment anticancer efficacies of self-delivery system through molecular integration of multiple anticancer elements with an enzyme-instructed self-assembly process.


Assuntos
Nanofibras , Neoplasias , Animais , Anti-Inflamatórios não Esteroides/química , Células HeLa , Humanos , Hidrogéis/química , Hidrogéis/farmacologia , Indometacina/química , Indometacina/farmacologia , Camundongos , Neoplasias/tratamento farmacológico , Oligopeptídeos , Peptídeos/farmacologia
17.
Chin J Traumatol ; 25(6): 379-388, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35697590

RESUMO

PURPOSE: The combined use of antibiotics and anti-inflammatory medicine to manage bacterial endotoxin-induced inflammation following injuries or diseases is increasing. The cytokine level produced by macrophages plays an important role in this treatment course. Ciprofloxacin and indomethacin, two typical representatives of antibiotics and anti-inflammatory medicine, are cost-effective and has been reported to show satisfactory effect. The current study aims to investigate the effect of ciprofloxacin along with indomethacin on the secretion of inflammatory cytokines by macrophages in vitro. METHODS: Primary murine peritoneal macrophages and RAW 264.7 cells were administrated with lipopolysaccharide (LPS) for 24 h. The related optimal dose and time point of ciprofloxacin or indomethacin in response to macrophage inflammatory response inflammation were determined via macrophage secretion induced by LPS. Then, the effects of ciprofloxacin and indomethacin on the secretory functions and viability of various macrophages were determined by enzyme-linked immunosorbent assay and flow cytometry analysis, especially for the levels of interleukin (IL)-1ß, IL-6, IL-10, and tumor necrosis factor (TNF)-α. The optimal dose and time course of ciprofloxacin affecting macrophage inflammatory response were determined by testing the maximum inhibitory effect of the drugs on pro-inflammatory factors at each concentration or time point. RESULTS: According to the levels of cytokines secreted by various macrophages (1.2 × 106 cells/well) after administration of 1 µg/mL LPS, the optimal dose and usage timing for ciprofloxacin alone were 80 µg/mL and 24 h, respectively, and the optimal dose for indomethacin alone was 10 µg/mL. Compared with the LPS-stimulated group, the combination of ciprofloxacin and indomethacin reduced the levels of IL-1ß (p < 0.05), IL-6 (p < 0.05), IL-10 (p < 0.01)), and TNF-α (p < 0.01). Furthermore, there was greater stability in the reduction of inflammatory factor levels in the combination group compared with those in which only ciprofloxacin or indomethacin was used. CONCLUSION: The combination of ciprofloxacin and indomethacin suppressed the levels of inflammatory cytokines secreted by macrophages in vitro. This study illustrates the regulatory mechanism of drug combinations on innate immune cells that cause inflammatory reactions. In addition, it provides a new potential antibacterial and anti-inflammatory treatment pattern to prevent and cure various complications in the future.


Assuntos
Citocinas , Lipopolissacarídeos , Humanos , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Interleucina-10 , Indometacina/farmacologia , Indometacina/uso terapêutico , Interleucina-6/farmacologia , Interleucina-6/uso terapêutico , Ciprofloxacina/farmacologia , Ciprofloxacina/uso terapêutico , Macrófagos , Fator de Necrose Tumoral alfa , Inflamação/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antibacterianos/uso terapêutico
18.
Dalton Trans ; 51(24): 9213-9217, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35670076

RESUMO

In the presence of carboxypeptidase, the hydrolytically stable complex [Os(η6-pcym)(L2)Cl]PF6 (2) partially released the bioactive substituent indomethacin, bound through the amide bond to the chelating 2-(1,3,4-thiadiazol-2-yl)pyridine-based moiety of L2. Stability in the presence of other relevant biomolecules (GSH, NADH, GMP) and cancer cell viability were also studied.


Assuntos
Antineoplásicos , Complexos de Coordenação , Antineoplásicos/química , Carboxipeptidases A , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Indometacina/farmacologia , Ligantes
19.
Drug Deliv ; 29(1): 1800-1810, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35656937

RESUMO

Challenges associated with topical analgesics and anti-inflammatory drugs include poor drug penetration and retention at the desired lesion site. Therefore, improving these challenges would help to reduce the toxic and side effects caused by drug absorption into the systemic circulation and improve the therapeutic efficacy of topical therapeutic drugs. Pentapeptide (KTTKS) is a signal peptide in skin tissue, it can be recognized and bound by signal recognition particles. In the current study, we successfully prepared novel indomethacin (IMC) loaded KTTKS-modified ethosomes (IMC-KTTKS-Es), and the physicochemical properties and topical efficacy were investigated. Results showed that the prepared IMC-KTTKS-Es displayed a particle size of about 244 nm, a negative charge, good deformability, and encapsulation efficiency (EE) exceeding 80% for IMC, with a sustained release pattern. In vitro percutaneous permeation studies revealed that the skin retention was increased after the drug was loaded in the IMC-KTTKS-Es. Confocal laser scanning microscopy also showed improved skin retention of IMC-KTTKS-Es. In addition, IMC-KTTKS-Es showed improved topical analgesic and anti-inflammatory activity with no potentially hazardous skin irritation. This study suggested that the IMC-KTTKS-Es might be an effective drug carrier for topical skin therapy with a good safety profile.


Assuntos
Indometacina , Pele , Portadores de Fármacos/química , Indometacina/metabolismo , Indometacina/farmacologia , Microscopia Confocal , Pele/metabolismo , Absorção Cutânea
20.
Prostaglandins Other Lipid Mediat ; 162: 106660, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35714920

RESUMO

Prostanoids are potent lipid mediators involved in a wide variety of physiological functions like blood pressure regulation or inflammation as well as cardiovascular and malign diseases. Elucidation of their modes of action is mainly carried out in pre-clinical animal models by quantifying prostanoids in tissues of interest. Unfortunately, prostanoids are prone to post-mortem artifact formation and de novo synthesis can already be caused by external stimuli during the euthanasia of animals like prolonged hypercapnia or ischemia. Therefore, this study investigates the suitability and impact of fast cervical dislocation for the determination of prostanoids (6-keto-PGF1α, TXB2, PGF2α, PGD2, PGE2) in seven tissues of mice (spinal cord, brain, sciatic nerve, kidney, liver, lung, and spleen) to minimize time-dependent effects and approximate physiological concentrations. Tissues were dissected in a standardized sequence directly or after 10 min to investigate the influence of dissection delays. The enzyme inhibitor indomethacin (10 µM) in combination with low processing temperatures was employed to preserve prostanoid concentrations during sample preparation. Quantification of prostanoids was performed via LC-MS/MS. This study shows, that prostanoids are differentially susceptible to post-mortem artifact formation which is closely connected to their physiological function and metabolic stability in the respective tissues. Prostanoids in the brain, spinal cord, and kidney that are not involved in the regulatory response post-mortem, i.e. blood flow regulation (6-keto-PGF1α, PGE2, PGF2α) showed high reproducibility even after dissection delay and could be assessed after fast cervical dislocation if prerequisites like standardized pre-analytical workflows with immediate dissection and inhibition of residual enzymatic activity are in place. However, in tissues with high metabolic activity (liver, lung) more stable prostanoid metabolites should be used. Moreover, prostanoids in the spleen were strongly affected by dissection delays and presumably the method of euthanasia itself.


Assuntos
Prostaglandinas , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida , Dinoprostona , Indometacina/farmacologia , Camundongos , Prostaglandinas/metabolismo , Prostaglandinas E , Prostaglandinas F , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
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