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1.
FASEB J ; 35(10): e21852, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34499774

RESUMO

Postoperative pain and delayed healing in surgical wounds, which require complex management strategies have understudied complicated mechanisms. Here we investigated temporal changes in behavior, tissue structure, and transcriptomic profiles in a rat model of a surgical incision, using hyperalgesic behavioral tests, histological analyses, and next-generation RNA sequencing, respectively. The most rapidly (1 hour) expressed genes were the chemokines, Cxcl1 and Cxcl2. Consequently, infiltrating leukocytes were abundantly observed starting at 6 and peaking at 24 hours after incising which was supported by histological analysis and appearance of the neutrophil markers, S100a8 and S100a9. At this time, hyperalgesia was at a peak and overall transcriptional activity was most highly activated. At the 1-day timepoint, Nppb, coding for natriuretic peptide precursor B, was the most strongly upregulated gene and was localized by in situ hybridization to the epidermal keratinocytes at the margins of the incision. Nppb was basically unaffected in a peripheral inflammation model transcriptomic dataset. At the late phase of wound healing, five secreted, incision-specific peptidases, Mmp2, Aebp1, Mmp23, Adamts7, and Adamtsl1, showed increased expression, supporting the idea of a sustained tissue remodeling process. Transcripts that are specifically upregulated at each timepoint in the incision model may be potential candidates for either biomarkers or therapeutic targets for wound pain and wound healing. This study incorporates the examination of longitudinal temporal molecular responses, corresponding anatomical localization, and hyperalgesic behavioral alterations in the surgical incision model that together provide important and novel foundational knowledge to understand mechanisms of wound pain and wound healing.


Assuntos
Hiperalgesia/patologia , Dor Pós-Operatória/patologia , Placa Plantar/fisiologia , RNA-Seq/métodos , Ferida Cirúrgica/complicações , Transcriptoma , Cicatrização , Animais , Comportamento Animal , Edema/etiologia , Edema/metabolismo , Edema/patologia , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/metabolismo , Ratos , Ratos Sprague-Dawley
2.
Medicine (Baltimore) ; 100(38): e27354, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559159

RESUMO

BACKGROUND: Beta-blocking is important for critically ill patients. Although some patients are required to continue taking beta-blockers after they no longer need critical care, some of these patients have impaired swallowing abilities. Bisoprolol dermal patches have recently been introduced and appear to be a good alternative to oral bisoprolol tablets. However, it is still unclear whether the pharmacodynamics of such patches are affected by edema in patients who have experienced critical care. This study aimed to clarify the effects of systemic edema on beta-blocker absorption from dermal patches in critically ill patients. METHOD: Patients who exhibited tachycardia and impaired swallowing function after critical care were included in this study. They were assigned to either the edema group (n = 6) or no edema group (n = 6) depending on the presence/absence of edema in the lower extremities. A bisoprolol dermal patch was pasted onto each subject, and the blood bisoprolol concentration was checked at 8 timepoints over the next 24 hours. The area under the serum concentration time curve, maximum concentration observed (Cmax), and time of maximum concentration observed were also examined. RESULT: The mean blood bisoprolol concentrations of the 2 groups were not significantly different at 2, 4, 6, 8, 10, 12, 16, or 24 hours after the patch application. The area under the serum concentration time curve and maximum concentration observed were not different between the groups. The mean heart rates of the 2 groups were not significantly different at 6, 12, or 24 hours after the patch application (Student t test, P = .0588, P = .1080, and P = .2322, respectively). CONCLUSION: In this study, the blood concentration of bisoprolol and its heart rate-reducing effects after bisoprolol dermal patch application might not be affected by systemic edema in the lower extremities.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Bisoprolol/farmacocinética , Edema/metabolismo , Absorção Cutânea , Administração Cutânea , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/sangue , Idoso , Idoso de 80 Anos ou mais , Bisoprolol/administração & dosagem , Bisoprolol/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino
3.
Biomed Pharmacother ; 139: 111635, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243601

RESUMO

This study aimed to evaluate the anti-inflammatory effect of Auraptene (AUR) and Umbelliprenin (UMB) in a rat model of rheumatoid arthritis (RA) induced by using complete Freund's adjuvant (CFA). Paw swelling of adjuvant arthritis rats measured at various times after CFA injection. Over 15 days of RA induction, mediator/cytokine-mediated processes involved in managing the regulation and resolving RA's inflammation were also quantified with ELISA. Histopathological changes were also assessed under a microscope 15 days after the CFA injection. AUR at all doses and UMB administration only at a 16 mM /kg administration dose significantly reduced CFA-induced paw edema level compared to the control group. UMB (64 and 32 mM) and AUR (64, 32, and 16 mM) could reduce the PGE2 (p < .0001-.01) and NO (p < .0001-.05) levels in the treatment groups compared to the negative control group. However, these compounds showed no significant effect on the TNF-α, IFN-γ, TGF-ß, IL-4, and IL-10 levels than the control group (p > .05). Unlike indomethacin and prednisolone, treatment of rats with AUR (16, 32, and 64 mM/kg) and UMB (16 and 32 mM/kg) reduced the level of IL-2 (p < .0001). In all treatment groups, the serum level of IL-17 was significantly reduced compared to the CFA group (p < .001-0.05). We suggested AUR and UMB could diminish inflammation by reducing the serum level of IL-17 and could be considered a proper alternative in the treatment of IL-17 related inflammatory diseases such as rheumatoid arthritis. Given that AUR and UMB apply their anti-inflammatory effects by changing distinct cytokine release/inhibition patterns, their potential application in diverse inflammatory diseases seems different.


Assuntos
Artrite/tratamento farmacológico , Cumarínicos/farmacologia , Adjuvante de Freund/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Substâncias Protetoras/farmacologia , Umbeliferonas/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Artrite/metabolismo , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Inflamação/metabolismo , Masculino , Ratos , Ratos Wistar
4.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068193

RESUMO

In this study, we investigate the immunomodulatory effects of a novel antimicrobial peptide, YD1, isolated from Kimchi, in both in vitro and in vivo models. We establish that YD1 exerts its anti-inflammatory effects via up-regulation of the Nrf2 pathway, resulting in the production of HO-1, which suppresses activation of the NF-κB pathway, including the subsequent proinflammatory cytokines IL-1ß, IL-6, and TNF-α. We also found that YD1 robustly suppresses nitric oxide (NO) and prostaglandin E2 (PGE2) production by down-regulating the expression of the upstream genes, iNOS and COX-2, acting as a strong antioxidant. Collectively, YD1 exhibits vigorous anti-inflammatory and antioxidant activity, presenting it as an interesting potential therapeutic agent.


Assuntos
Anti-Inflamatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Inflamação/prevenção & controle , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Animais , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/metabolismo , Edema/patologia , Edema/prevenção & controle , Heme Oxigenase-1/genética , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Proteínas de Membrana/genética , Camundongos , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
5.
Biomed Pharmacother ; 140: 111771, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34058441

RESUMO

Danhong injection (DHI) is a compound Chinese medicine widely used in China for treatment of ischemic cardio-cerebrovascular diseases. However, limited data are available regarding the protective effect of DHI on the ischemic penumbra in ischemic stroke. This study aimed to investigate the effect of intravenous DHI on neuronal injure in the ischemic penumbra after cerebral ischemia/reperfusion (CI/R), focusing especially on the involvement of intracellular energy metabolism coupling. Male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion for 60 min followed by reperfusion with or without intravenous DHI (0.5, 1.0, or 2.0 mL/kg) once daily for 7 days. Post-treatment with DHI ameliorated neurological defects, diminished cerebral infarction, alleviated cerebral edema, improved microcirculatory perfusion after 7days of reperfusion, and inhibited apoptosis and enhanced neuronal survival in the ischemic penumbra. In addition, DHI significantly ameliorated oxidative stress, reduced DNA damage, and inhibited the activation of PARP1/AIF pathway, thereby restoring cytoplasmic glycolytic activity. Furthermore, this drug increased PDH activity by inhibiting the HIF1α/PDK1 signaling pathway, thus eliminating the inhibitory effect of CI/R on mitochondrial metabolism. The results of this study suggest that DHI can alleviate cerebral edema after CI/R and rescue the ischemic penumbra, and these protective effects are due to the regulation of intracellular energy metabolic coupling.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Dano ao DNA , Medicamentos de Ervas Chinesas/farmacologia , Edema/tratamento farmacológico , Edema/metabolismo , Edema/patologia , Metabolismo Energético/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Cetona Oxirredutases/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Ratos Sprague-Dawley
6.
Biomed Pharmacother ; 140: 111749, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34058437

RESUMO

Inflammation is a primary defense and immune response. However, under pathological conditions, the inflammation processes always become uncontrolled and lead to chronic diseases. Bufotenine, as a natural component from toad venom, showed great potential for development as a novel anti-inflammation and analgesia agent. This study aimed to investigate the therapeutic effects of bufotenine against inflammation and pain on animal models with a focus on lipid metabolism. In pharmacological studies, bufotenine significantly inhibited the swelling rates on formalin-induced paw edema model, and increased paw withdrawal mechanical thresholds (PWMTs) in von Frey test and thermal pain thresholds (TPTs) in hot-plate test. High-sensitivity lipidomics analysis revealed the effects might be related to the down-regulation of inflammatory mediators from cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 (CYP450), linoleic acid (LA), docosahexaenoic acid (DHA) and other pathways. The activities might result from the binding of bufotenine and its receptors, including sigma-1 receptor and 5-Hydroxytryptamine receptor 3A, thus regulating lipid metabolism pathway. The research provided a systemic evidence for the actions and mechanism of bufotenine. It suggested that the natural compound might be a potential candidate for reducing inflammatory pain disorders.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Bufotenina/uso terapêutico , Edema/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Dor/tratamento farmacológico , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Bufotenina/farmacologia , Ciclo-Oxigenase 2/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Edema/metabolismo , Feminino , Ácido Linoleico/metabolismo , Lipoxigenase/metabolismo , Masculino , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Dor/metabolismo , Receptores de Serotonina/metabolismo , Receptores sigma/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
J Biol Chem ; 296: 100670, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33864815

RESUMO

The voltage-gated potassium (Kv) 1.3 channel plays a crucial role in the immune responsiveness of T-lymphocytes and macrophages, presenting a potential target for treatment of immune- and inflammation related-diseases. FS48, a protein from the rodent flea Xenopsylla cheopis, shares the three disulfide bond feature of scorpion toxins. However, its three-dimensional structure and biological function are still unclear. In the present study, the structure of FS48 was evaluated by circular dichroism and homology modeling. We also described its in vitro ion channel activity using patch clamp recording and investigated its anti-inflammatory activity in LPS-induced Raw 264.7 macrophage cells and carrageenan-induced paw edema in mice. FS48 was found to adopt a common αßß structure and contain an atypical dyad motif. It dose-dependently exhibited the Kv1.3 channel in Raw 264.7 and HEK 293T cells, and its ability to block the channel pore was demonstrated by the kinetics of activation and competition binding with tetraethylammonium. FS48 also downregulated the secretion of proinflammatory molecules NO, IL-1ß, TNF-α, and IL-6 by Raw 264.7 cells in a manner dependent on Kv1.3 channel blockage and the subsequent inactivation of the MAPK/NF-κB pathways. Finally, we observed that FS48 inhibited the paw edema formation, tissue myeloperoxidase activity, and inflammatory cell infiltrations in carrageenan-treated mice. We therefore conclude that FS48 identified from the flea saliva is a novel potassium channel inhibitor displaying anti-inflammatory activity. This discovery will promote understanding of the bloodsucking mechanism of the flea and provide a new template molecule for the design of Kv1.3 channel blockers.


Assuntos
Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Inflamação/tratamento farmacológico , Canal de Potássio Kv1.3/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Glândulas Salivares/metabolismo , Venenos de Escorpião/química , Animais , Edema/imunologia , Edema/metabolismo , Edema/patologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Xenopsylla
8.
Drug Des Devel Ther ; 15: 1299-1313, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790541

RESUMO

Background: Organocatalytic asymmetric Michael addition is a strong approach for C-C bond formation. The objective of the study is to design molecules by exploiting the efficiency of Michael Adducts. We proceeded with the synthesis of Michael adducts by tailoring the substitution pattern on maleimide and trans-ß-nitro styrene as Michael acceptors. The synthesized compounds were evaluated for dual cyclooxygenases (COX) and lipoxygenase (LOX) inhibition. Methods: The compounds (4, 9-11) were synthesized through Michael additions. The cyclooxygenases (COX-1 and 2) and lipoxygenase (5-LOX) assays were used for in vitro evaluations of compounds. After the acute toxicity studies, the in vivo analgesic potential was determined with acetic acid induced writhing, tail immersion, and formalin tests. Furthermore, the possible roles of adrenergic and dopaminergic receptors were also studied. Extensive computational studies were performed to get a better understanding regarding the binding of this compound with protein target. Results: Four Michael adducts (4, 9-11) were synthesized. Compound 4 was obtained in enantio- and diastereopure form. The stereopure compound 4 showed encouraging COX-1 and-2 inhibitions with IC50 values of 128 and 65 µM with SI of 1.94. Benzyl derivative 11 showed excellent COX-2 inhibition with the IC50 value of 5.79 µM and SI value 7.96. Compounds 4 and 11 showed good results in in vivo models of analgesia like acetic acid test, tail immersion, and formalin tests. Our compounds were not active in dopaminergic and adrenergic pathways and so were acting centrally. Through extensive computational studies, we computed binding energies, and pharmacokinetic predictions. Conclusion: Our findings conclude that our synthesized Michael products (pyrrolidinedione 4 and nitroalkane 11) can be potent centrally acting analgesics. Our in silico predictions suggested that the compounds have excellent pharmacokinetic properties. It is concluded here that dual inhibition of COX/LOX pathways provides a convincing step towards the discovery of safe lead analgesic molecules.


Assuntos
Analgésicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Edema/tratamento farmacológico , Inibidores de Lipoxigenase/farmacologia , Maleimidas/farmacologia , Estireno/farmacologia , Ácido Acético , Analgésicos/síntese química , Analgésicos/química , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Edema/induzido quimicamente , Edema/metabolismo , Feminino , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Masculino , Maleimidas/síntese química , Maleimidas/química , Camundongos , Camundongos Endogâmicos BALB C , Prostaglandina-Endoperóxido Sintases/metabolismo , Estireno/síntese química , Estireno/química
9.
Bioorg Chem ; 111: 104890, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33872924

RESUMO

A new series of pyrimidine-5-carbonitrile derivatives 8a-p carrying the 1,3-thiazole moiety has been designed and synthesized as novel anti-inflammatory EGFR inhibitors with cardiac and gastric safety profiles. 8a-p have been assessed for their inhibitory activity against COX-1/COX-2 activity. Compounds 8h, 8n, and 8p were found to be potent and selective COX-2 inhibitors (IC50 = 1.03-1.71 µM) relative to celecoxib (IC50 = 0.88 µM). The most potent COX-2 inhibitors have been further investigated for their in-vivo anti-inflammatory effect. Compounds 8h, 8n, and 8p showed anti-inflammatory activity up to 90%, 94% and 86% of meloxicam after 4 h interval. 8h, 8n, and 8p showed higher gastric safety profiles than meloxicam. A substantial reduction in serum concentrations of PGE2, TNF-α, IL-6, iNO and MDA and a significant induction of TAC was also observed. In vivo experiments on heart rate and blood pressure established the cardiovascular safety profile of 8h, 8n, and 8p. Anti-proliferative and wild-type EGFR inhibitory assays displayed similar results to selective COX-2 inhibition where compounds 8h, 8n, and 8p had a superior inhibition than other tested ones. Molecular docking study demonstrated that these compounds revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to enter the side pocket selectively. Also, they interacted with EGFR tyrosine kinase main amino acids similar to erlotinib with a strong binding energy score.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Desenho de Fármacos , Edema/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tiazóis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Carragenina , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Edema/induzido quimicamente , Edema/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Coração/efeitos dos fármacos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Relação Estrutura-Atividade , Tiazóis/química
10.
Eur J Pharmacol ; 902: 174113, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33901460

RESUMO

The transient receptor potential vanilloid channel 4 (TRPV4) is associated with the development of several pathologies, particularly gastric disorders. However, there are no studies associating this receptor with the pathophysiology of gastric erosions. The aim of this study was to investigate the role of TRPV4 in the development of ethanol-induced gastric damage in vivo. Gastric lesions were induced by ethanol in Swiss mice pretreated with TRPV4 antagonists, GSK2193874 (0.1; 0.3 and 0.9 mg/kg) or Ruthenium red (0.03; 0.1 or 0.3 mg/kg) or its agonist, GSK1016790A (0.9 mg/kg). Gastric mucosal samples were taken for histopathology, immunohistochemistry, atomic force microscopy and evaluation of antioxidant parameters. The gastric mucus content and TRPV4 mRNA expression were analyzed. Ethanol exposure induced upregulation of gastric mRNA and protein expression of TRPV4. TRPV4 blockade promoted gastroprotection against ethanol-induced injury on macro- and microscopic levels, leading to reduced hemorrhage, cell loss and edema and enhanced gastric mucosal integrity. Moreover, an increase in superoxide dismutase (SOD) and glutathione (GSH) activity was observed, followed by a decrease in malondialdehyde (MDA) levels. TRPV4 blockade during alcohol challenge reestablished gastric mucus content. The combination of TRPV4 agonist and ethanol revealed macroscopic exacerbation of gastric damage area. Our results confirmed the association of TRPV4 with the development of gastric injury, showing the importance of this receptor for further investigations in the field of gastrointestinal pathophysiology and pharmacology.


Assuntos
Úlcera Gástrica/metabolismo , Úlcera Gástrica/fisiopatologia , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/metabolismo , Animais , Edema/induzido quimicamente , Edema/metabolismo , Etanol/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/lesões , Mucosa Gástrica/metabolismo , Glutationa/metabolismo , Leucina/análogos & derivados , Leucina/farmacologia , Leucina/uso terapêutico , Masculino , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Rutênio Vermelho/farmacologia , Rutênio Vermelho/uso terapêutico , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Superóxido Dismutase/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Regulação para Cima/efeitos dos fármacos
12.
Bioorg Chem ; 109: 104742, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33647742

RESUMO

Throughout this study, we present the victorious synthesis of a novel class of 2(1H)-pyridone molecules, bearing a 4-hydroxyphenyl moiety through a one-pot reaction of 2-cyano-N-(4-hydroxyphenyl)acetamide with cyanoacetamide, acetylacetone or ethyl acetoacetate, and their corresponding aldehydes. In addition, the chromene moiety was introduced into the pyridine skeleton through the cyclization of the cyanoacetamide 2 with salicylaldehyde, followed by treatment with malononitrile, ethyl cyanoacetate, and cyanoacetamide, in order to improve their biological behaviour. Due to their anti-inflammatory, ulcerogenic, and antipyretic characters, the target molecules have undergone in-vitro and in-vivo examination, that display promising results. Moreover, in order to predict the physicochemical and ADME traits of all synthesized compounds and standard reference drugs, paracetamol and phenylbutazone, the in-silico prediction methodology was provided.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Antipiréticos/farmacologia , Edema/tratamento farmacológico , Febre/tratamento farmacológico , Piridonas/farmacologia , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Antipiréticos/síntese química , Antipiréticos/química , Relação Dose-Resposta a Droga , Edema/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Masculino , Estrutura Molecular , Piridonas/síntese química , Piridonas/química , Ratos , Saccharomyces cerevisiae/efeitos dos fármacos , Úlcera Gástrica/patologia , Relação Estrutura-Atividade
13.
J Ethnopharmacol ; 274: 114030, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-33741441

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Vernonia zeylanica (L.) Less (Family: Compositae) is a medicinal plant used as external applications for boils, bone fractures, eczema and internally for asthma in traditional medicine in Sri Lanka. Anti-nociceptive, anti-bacterial and anti-proliferative activities have been reported previously. AIM OF THE STUDY: To investigate the anti-inflammatory activity of methanol/dichloromethane extract (MDE) of leaves of V. zeylanica by assessing in vivo inhibition of rat paw-edema, in vitro inhibition of the production of nitric oxide (NO) and superoxide and inhibitory effect on inducible nitric oxide synthase (iNOS) gene expression. MATERIALS AND METHODS: In vivo anti-inflammatory activity of MDE was tested at the dose of 1500 mg/kg using rat paw-edema model. Indomethacin and Gum acacia was used as the positive and vehicle control respectively. In vitro NO inhibitory activity of 7.8-250 µg/ml MDE was tested using lipopolysaccharide (LPS)-stimulated (1 µg/ml) mouse macrophages (RAW264.7 cells) and rat peritoneal cells (RPC) obtained following carrageenan-induction (5 mg/Kg). Griess method was used to quantify the nitrite levels in culture supernatants. In vitro inhibition of superoxide production of Phorbal 12-myristate 13-acetate (PMA)-stimulated RAW cells was determined by quantitative Nitroblue Tetrazolium (NBT) assay. N-monomethyl-L-arginine acetate (NMMA) (1 mM) and Diphenyleneiodonium chloride (DPI) (10 µM) were used as the positive controls for inhibitory activity of NO and superoxide production respectively. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis was carried out to test the inhibitory effect on mRNA expression of iNOS gene. RESULTS: Treatment with MDE of V. zeylanica at 1500 mg/kg showed significant inhibition of paw-edema from 1st-5th hour (P < 0.01) compared with the control. The reference drug, indomethacin showed a biphasic pattern and its highest inhibition was (98.3 ± 7.1%) at 4th h (P < 0.01). MDE of V. zeylanica showed similar inhibition of paw-edema with highest inhibition recorded as 94.5 ± 5.28%, at 5th h (P < 0.01). The inhibitory concentration (IC50) of MDE for in vitro NO inhibitory activity was 105 µg/ml for RAW cells and 80 µg/ml for RPCs. Both NO inhibitory activities showed significant dose-dependency (r = 0.998 and r = 0.915 respectively; p < 0.05). MDE concentration of 250 µg/ml showed 55% inhibition of ROS production in RAW cells. NMMA showed 78% and 70.1% inhibition of NO production with RAW cells and RPCs whereas DPI showed 61% superoxide inhibitory activity with RAW cells. NO inhibitory activity of MDE on RAW cells was confirmed by the significant reduction (99.1%) in iNOS gene expression. CONCLUSION: These results demonstrated potent anti-inflammatory activity of MDE of V. zeylanica reflected by its significant in vivo inhibition of rat paw-edema, in vitro inhibition of NO and superoxide production, and the reduction of iNOS gene expression. Thus, further purification and isolation of bioactive compounds from V. zeylanica are emphasized.


Assuntos
Anti-Inflamatórios/uso terapêutico , Edema/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Vernonia , Animais , Anti-Inflamatórios/farmacologia , Carragenina , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/genética , Edema/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Cavidade Peritoneal/citologia , Extratos Vegetais/farmacologia , Folhas de Planta , Células RAW 264.7 , Ratos Wistar , Superóxidos/metabolismo
14.
J Photochem Photobiol B ; 216: 112151, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33581679

RESUMO

Photochemoprotection of the skin can be achieved by inhibiting inflammation and oxidative stress, which we tested using Cordia verbenacea extract, a medicinal plant known for its rich content of antioxidant molecules and anti-inflammatory activity. In vitro antioxidant evaluation of Cordia verbenacea leaves ethanolic extract (CVE) presented the following results: ferric reducing antioxidant power (886.32 µM equivalent of Trolox/g extract); IC50 of 19.128 µg/ml for scavenging 2,2-diphenyl-1-picrylhydrazyl; IC50 of 12.48 µg/mL for scavenging 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid); decrease of hydroperoxides from linoleic acid (IC50 of 10.20 µg/mL); inhibition of thiobarbituric acid reactive substances (IC50 8.90 µg/mL); iron-chelating ability in bathophenanthroline iron assay (IC50 47.35 µg/mL); chemiluminescence triggered by free radicals in the H2O2/horseradish peroxidase/luminol (IC50 0.286 µg/mL) and xanthine/xanthine oxidase/luminol (IC50 0.42 µg/mL) methods. CVE (10-100 mg per kg, 30 min before and immediately after UVB exposure) treatment was performed by gavage in hairless mice. CVE inhibited skin edema, neutrophil infiltration, and overproduction of MMP-9; reduced levels of TNF-α, IL-1ß, and IL- 6; numbers of skin mast cells, epidermal thickening, number of epidermal apoptotic keratinocytes, and collagen degradation. CVE increased the skin's natural antioxidant defenses as observed by Nrf-2, NAD(P)H quinone oxidoreductase 1, and heme oxygenase 1 mRNA expression enhancement. Furthermore, CVE inhibited lipid peroxidation and superoxide anion production and recovered antioxidant reduced glutathione, catalase activity, and ROS scavenging capacity of the skin. Concluding, CVE downregulates the skin inflammatory and oxidative damages triggered by UVB, demonstrating its potentialities as a therapeutic approach.


Assuntos
Anti-Inflamatórios/química , Antioxidantes/química , Cordia/química , Extratos Vegetais/química , Folhas de Planta/química , Substâncias Protetoras/química , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Citocinas/metabolismo , Edema/metabolismo , Feminino , Heme Oxigenase-1/metabolismo , Humanos , Peróxido de Hidrogênio/química , Ácido Linoleico/química , Peroxidação de Lipídeos , Camundongos Pelados , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Quinona Redutases/metabolismo , Pele/efeitos da radiação , Superóxidos/metabolismo , Raios Ultravioleta
15.
Future Med Chem ; 13(7): 625-641, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33624540

RESUMO

New hexahydropyrimido[1,2-a]azepine derivatives bearing functionalized aryl and heterocyclic moieties were synthesized as anti-inflammatory agents with better safety profiles. All synthesized compounds were assessed in vitro for their COX-1 and COX-2 inhibition activities. The most selective compounds, 2f, 5 and 6, were further evaluated for their in vivo anti-inflammatory activity and PGE2 inhibitory activity. To rationalize their selectivity, molecular docking within COX-1 and COX-2 binding sites was performed. Their physicochemical properties and drug-like nature profile were also calculated. The good activity and selectivity of compounds 2f, 5 and 6 were rationalized using a molecular docking study and supported by in vivo studies. These promising findings are encouraging for performing future investigations of these derivatives.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Azepinas/farmacologia , Edema/tratamento farmacológico , Pirimidinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Azepinas/síntese química , Azepinas/química , Carragenina , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Edema/induzido quimicamente , Edema/metabolismo , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 213: 113171, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33482600

RESUMO

In this work, a series of structurally novel benzoxaborole derivatives were designed, synthesized and biologically evaluated as PDE4 inhibitors for battling atopic dermatitis (AD). Among them, the majority exhibited superior PDE4B inhibitory activities to that of the lead compound Crisaborole, an approved PDE4 inhibitor. In particular, 72, the most potent PDE4B inhibitor throughout this series, displayed 136-fold improved enzymatic activity (IC50 = 0.42 nM) as compared to Crisaborole (IC50 = 57.20 nM), along with favorable isoform specificity. In the phorbol ester (PMA)-induced mouse ear oedema model, 72 exerted remarkably greater efficacy than Crisaborole at the same dosage (P < 0.05). Moreover, the ointment of 72 exerted dramatically enhanced therapeutic potency than the ointment of Crisaborole (P < 0.05) in the calcipotriol-induced mouse AD model. In addition to the potent in vitro and in vivo activity, 72 displayed favorable safety in the repeated oral dose toxicity study and did not exhibit phototoxicity. With the above attractive biological performance, 72 is worthy of further functional investigation as a novel anti-AD therapeutic agent.


Assuntos
Compostos de Boro/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Fármacos , Inibidores da Fosfodiesterase 4/farmacologia , Animais , Compostos de Boro/síntese química , Compostos de Boro/química , Calcitriol/análogos & derivados , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Feminino , Cobaias , Masculino , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Acetato de Tetradecanoilforbol
17.
Molecules ; 26(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513963

RESUMO

BACKGROUND: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. METHODS: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. RESULTS: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. CONCLUSIONS: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms.


Assuntos
Anti-Inflamatórios/farmacologia , Triazóis/farmacologia , Animais , Ácido Araquidônico/farmacologia , Carragenina/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/farmacologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Naproxeno/farmacologia , Relação Estrutura-Atividade
18.
Int J Biol Macromol ; 170: 532-539, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33388321

RESUMO

Seaweed lectins are very promising biotechnological tools that also gain prominence when applied to the pharmacology field. The purpose of the present work was to isolate and characterize lectin from the red algae Amansia multifida and subsequently test it in general inflammation models. The lectin was purified by ion exchange chromatography, characterized with two-dimensional electrophoresis, automated analysis of amino acid sequences and circular dichroism spectroscopy. The pharmacological tests performed were paw edema induced by carrageenan or rapid inflammatory mediators, peritonitis induced by carrageenan and myeloperoxidase leukocyte count assays, glutathione and cytokine concentration. Our results have identified a 30 KDa molecular weight protein that presents a major secondary structure arranged in ß-strand elements (~43%). A fragment of 20 amino acid residues was sequenced and presented low identity to the known classes of lectins from marine alga. This lectin was able to modulate inflammatory parameters such as paw edema, leukocyte migration, oxidative stress and proinflammatory cytokines. Thus, the lectin from the seaweed Amansia multifida has evident anti-inflammatory properties because it acts by reducing the formation of edema by modulating the effect of vascular mediators, migration of neutrophils, proinflammatory cytokines and oxidative stress control.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Lectinas/química , Lectinas/farmacologia , Rodófitas/química , Animais , Carragenina/farmacologia , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Edema/tratamento farmacológico , Edema/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/química , Mediadores da Inflamação/farmacologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peritonite/tratamento farmacológico , Peritonite/metabolismo , Peroxidase/metabolismo
19.
Inflammation ; 44(1): 297-306, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32901390

RESUMO

Heterophragma adenophyllum is a traditional medicinal plant that has been used as anti-inflammatory and to relief muscular tension. In the current research, four isolated constitutes namely lapacho (1), peshawaraquinone (2), indanone derivatives (3), α-lapachone (4) of H. adenophyllum were tested for anti-inflammatory effect using the carrageenan- and histamine-induced paw edema paradigm. The tested compounds (1-4) were evaluated for anti-inflammatory effect during the early and late phase of edema induction. In the early phase, all tested compounds (0.5 2.5 mg/kg each i.p.) demonstrated less than 50% effect, while in the later phase, compounds (2 and 3) demonstrated 85.66 and 89.87% attenuation. In addition, compounds (1-4) were subjected to histamine-induced inflammation, where compounds 2 and 3 exhibited excellent effects 86.87 and 89.98%, respectively at 5 mg/kg after the 2nd hour of administration, whereas compounds 1 and 4 did not exhibit any significant effect as compared with the negative control. Molecular docking results revealed a very high potency of compound based on the protein-ligand interaction (PLI) profile, which was further evaluated through a molecular dynamic simulation study. Therefore, the anti-inflammatory effect of H. adenophyllum attributed to the presence of these bioactive compounds (1-4) strongly supports the traditional uses of H. adenophyllum for treatment of inflammation. However, compounds 2 and 3 which exerted anti-inflammatory effect must be subjected for further mechanistic studies.


Assuntos
Anti-Inflamatórios/administração & dosagem , Simulação por Computador , Simulação de Acoplamento Molecular/métodos , Extratos Vegetais/administração & dosagem , Plantas Medicinais , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/metabolismo , Sítios de Ligação/fisiologia , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Edema/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/metabolismo , Estrutura Secundária de Proteína
20.
J Intensive Care Med ; 36(3): 376-380, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33034231

RESUMO

PURPOSE: Purpose of this report is to describe the feasibility of lingual pulse oximetry and lingual near-infrared spectroscopy (NIRS) in a COVID-19 patient to assess lingual tissue viability after several days of mechanical ventilation in the prone position. MATERIALS & METHODS: In a COVID-19 ICU-patient, the tongue became grotesquely swollen, hardened and protruding from the oral cavity after 20 h of mechanical ventilation uninterrupted in the prone position. To assess the doubtful viability of the tongue, pulse-oximetric hemoglobin O2-saturation (SpO2; Nellcor, OxiMax MAX-NI, Covidien, MA, USA) and NIRS-based, regional tissue O2-saturation measurements (rSO2; SenSmart, Nonin, MN, USA) were performed at the tongue. RESULTS: At the tongue, regular pulse-oximetric waveforms with a pulse-oximetric hemoglobin O2-saturation (SpO2) of 88% were recorded, i.e. only slightly lower than the SpO2 reading at the extremities at that time (90%). Lingual NIRS-based rSO2 measurements yielded stable tissue rSO2-values of 76-78%, i.e. values expected also in other adequately perfused and oxygenated (muscle-) tissues. CONCLUSION: Despite the alarming, clinical finding of a grotesquely swollen, rubber-hard tongue and clinical concerns on the adequacy of the tongue perfusion and oxygenation, our measurements of both arterial pulsatility (SpO2) and NIRS-based tissue oxygenation (rSO2) suggested adequate perfusion and oxygenation of the tongue, rendering non-vitality of the tongue, e.g. by lingual venous thrombosis, unlikely. To our knowledge, this is the first clinical report of lingual rSO2 measurement.


Assuntos
COVID-19/terapia , Edema/fisiopatologia , Oximetria , Fluxo Pulsátil , Espectroscopia de Luz Próxima ao Infravermelho , Doenças da Língua/fisiopatologia , Língua/irrigação sanguínea , Idoso , COVID-19/fisiopatologia , Síndromes Compartimentais/diagnóstico , Edema/metabolismo , Humanos , Masculino , Posicionamento do Paciente , Decúbito Ventral , SARS-CoV-2 , Língua/metabolismo , Doenças da Língua/metabolismo , Trombose Venosa/diagnóstico
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