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1.
Molecules ; 27(9)2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35566223

RESUMO

Echimidine is the main pyrrolizidine alkaloid of Echium plantagineum L., a plant domesticated in many countries. Because of echimidine's toxicity, this alkaloid has become a target of the European Food Safety Authority regulations, especially in regard to honey contamination. In this study, we determined by NMR spectroscopy that the main HPLC peak purified from zinc reduced plant extract with an MS [M + H]+ signal at m/z 398 corresponding to echimidine (1), and in fact also represents an isomeric echihumiline (2). A third isomer present in the smallest amount and barely resolved by HPLC from co-eluting (1) and (2) was identified as hydroxymyoscorpine (3). Before the zinc reduction, alkaloids (1) and (2) were present mostly (90%) in the form of an N-oxide, which formed a single peak in HPLC. This is the first report of finding echihumiline and hydroxymyoscorpine in E. plantagineum. Retroanalysis of our samples of E. plantagineum collected in New Zealand, Argentina and the USA confirmed similar co-occurrence of the three isomeric alkaloids. In rat hepatocyte primary culture cells, the alkaloids at 3 to 300 µg/mL caused concentration-dependent inhibition of hepatocyte viability with mean IC50 values ranging from 9.26 to 14.14 µg/mL. Our discovery revealed that under standard HPLC acidic conditions, echimidine co-elutes with its isomers, echihumiline and to a lesser degree with hydroxymyoscorpine, obscuring real alkaloidal composition, which may have implications for human toxicity.


Assuntos
Echium , Alcaloides de Pirrolizidina , Animais , Echium/química , Hepatócitos/química , Alcaloides de Pirrolizidina/química , Ratos , Zinco
2.
Cell Mol Neurobiol ; 41(1): 63-78, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32222846

RESUMO

Complex regional pain syndrome type-I (CRPS-I) is a chronic painful condition resulting from trauma. Bradykinin (BK) is an important inflammatory mediator required in acute and chronic pain response. The objective of this study was to evaluate the association between BK receptors (B1 and B2) and chronic post-ischaemia pain (CPIP) development in mice, a widely accepted CRPS-I model. We assessed mechanical and cold allodynia, and paw oedema in male and female Swiss mice exposed to the CPIP model. Upon induction, the animals were treated with BKR antagonists (HOE-140 and DALBK); BKR agonists (Tyr-BK and DABK); antisense oligonucleotides targeting B1 and B2 and captopril by different routes in the model (7, 14 and 21 days post-induction). Here, we demonstrated that treatment with BKR antagonists, by intraperitoneal (i.p.), intraplantar (i.pl.), and intrathecal (i.t.) routes, mitigated CPIP-induced mechanical allodynia and oedematogenic response, but not cold allodynia. On the other hand, i.pl. administration of BKR agonists exacerbated pain response. Moreover, a single treatment with captopril significantly reversed the anti-allodynic effect of BKR antagonists. In turn, the inhibition of BKRs gene expression in the spinal cord inhibited the nociceptive behaviour in the 14th post-induction. The results of the present study suggest the participation of BKRs in the development and maintenance of chronic pain associated with the CPIP model, possibly linking them to CRPS-I pathogenesis.


Assuntos
Dor Crônica/etiologia , Dor Crônica/metabolismo , Isquemia/complicações , Receptores da Bradicinina/metabolismo , Animais , Antagonistas dos Receptores da Bradicinina/farmacologia , Inibidores da Colinesterase/farmacologia , Dor Crônica/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Hiperalgesia/complicações , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Receptores da Bradicinina/genética , Medula Espinal/patologia
3.
Invest New Drugs ; 38(4): 977-989, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31493129

RESUMO

Cancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of tumours to chemotherapy. Hydroxamic acid derivatives have recently aroused attention due to their potential to treat malignancies. In the present study, we sought to investigate the anticancer effects of a new series of synthetic acetohydroxamates. The in vitro cytotoxic and antiproliferative effects of 11 synthetic acetohydroxamates were evaluated against the melanoma cell line A375. Apoptosis, cell cycle, and autophagy assays were employed to elucidate the cell death pathways induced by the compounds. The in vivo pharmacokinetic profiles of the most promising compounds were determined in CD-1 mice, while the in vivo antitumour efficacies were evaluated using the A375 melanoma xenograft model in nude mice. MTT assays revealed that all compounds presented concentration-dependent cytotoxicity against the A375 cell line. AKS 61 produced the most favourable antiproliferative activity according to the sulphorhodamine B and clonogenic assays. AKS 61 treatment resulted in decreased mitochondrial membrane potential and increased apoptosis and autophagy in the A375 cell line. However, AKS 61 failed to prevent in vivo tumour growth in a melanoma xenograft, whereas compound AKS 7 was able to inhibit tumour growth when administered orally. These in vivo findings may be explained by a more favourable pharmacokinetic profile presented by AKS 7 when compared to AKS 61. Taken together, these results suggest that acetohydroxamates have potential anticancer effects and will guide future optimisation of these molecules to allow for further non-clinical development.


Assuntos
Antineoplásicos/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Melanoma/tratamento farmacológico , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Ácidos Hidroxâmicos/sangue , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/farmacologia , Masculino , Melanoma/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Carga Tumoral/efeitos dos fármacos
4.
An Acad Bras Cienc ; 91 Suppl 3: e20190105, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166478

RESUMO

The global medicine market is about 1.1 trillion US dollars. About 35 percent of medicines have originated from natural products. Brazil presents the largest biodiversity in the world, with more than 50,000 species of higher plants. However, few innovative products have been developed in Brazil from active constituents derived from the Brazilian biodiversity. Scientific evidences on plants and venoms have been internationally published by Brazilian scientists over the last 4 decades; but few examples of innovative products are commercially available. Few examples include the anti-hypertensive drug captopril first identified in the venom of the Brazilian viper Bothrops jararaca by Professor Sergio Ferreira; and some phytotherapeutic agents such as Acheflan®, Syntocalmy® and Melagrião® produced by standardized plant extracts with scientific proof of safety, efficacy and quality. Still, only Acheflan® and Melagrião® are obtained from native Brazilian plants. Several issues contribute to the lack of innovative products from the Brazilian biodiversity, but in my opinion, the most challenging ones are i) the lack of specific regulations to allow researchers and companies to access biodiversity for the purposes of scientific and technological innovation; and ii) the absence of a long-term government program to support research and innovation in this field.


Assuntos
Biodiversidade , Produtos Biológicos , Cosméticos , Descoberta de Drogas , Plantas Medicinais , Animais , Produtos Biológicos/história , Brasil , Descoberta de Drogas/história , Descoberta de Drogas/legislação & jurisprudência , História do Século XX , História do Século XXI , Humanos
5.
Inflammopharmacology ; 27(3): 573-586, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30820720

RESUMO

Tumour necrosis factor (TNF) and kinins have been associated with neuropathic pain-like behaviour in numerous animal models. However, the way that they interact to cause neuron sensitisation remains unclear. This study assessed the interaction of kinin receptors and TNF receptor TNFR1/p55 in mechanical hypersensitivity induced by an intraneural (i.n.) injection of rm-TNF into the lower trunk of brachial plexus in mice. The i.n. injection of rm-TNF reduced the mechanical withdrawal threshold of the right forepaw from the 3rd to the 10th day after the injection, indicating that TNF1/p55 displays a critical role in the onset of TNF-elicited neuropathic pain. The connection between TNF1/p55 and kinin B1 and B2 receptors (B1R and B2R) was confirmed using both knockout mice and mRNAs quantification in the injected nerve, DRG and spinal cord. The treatment with the B2R antagonist HOE 140 or with B1R antagonist des-Arg9-Leu8-BK reduced both BK- and DABK-induced hypersensitivity. The experiments using kinin receptor antagonists and CPM inhibitor (thiorphan) suggest that BK does not only activate B2R as an orthosteric agonist, but also seems to be converted into DABK that consequently activates B1R. These results indicate a connection between TNF and the kinin system, suggesting a relevant role for B1R and B2R in the process of sensitisation of the central nervous systems by the cross talk between the receptor and CPM after i.n. injection of rm-TNF.


Assuntos
Plexo Braquial/metabolismo , Neuralgia/metabolismo , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Plexo Braquial/efeitos dos fármacos , Antagonistas de Receptor B1 da Bradicinina/farmacologia , Antagonistas de Receptor B2 da Bradicinina/farmacologia , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/tratamento farmacológico
7.
Molecules ; 24(8)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027179

RESUMO

Wound healing can be delayed following colonization and infection with the common bacterium Pseudomonas aeruginosa. While multiple therapies are used for their treatment, these are ineffective, expensive, and labour-intensive. Thus, there is an enormous unmet need for the treatment of infected wounds. Cinnamaldehyde, the major component of cinnamon oil, is well known for its antimicrobial properties. Herein, we investigated the effects of sub-inhibitory concentrations of cinnamaldehyde in the virulence of P. aeruginosa. We also assessed its healing potential in P. aeruginosa-infected mouse skin wounds and the mechanisms involved in this response. Sub-inhibitory concentrations of cinnamaldehyde reduced P. aeruginosa metabolic rate and its ability to form biofilm and to cause haemolysis. Daily topical application of cinnamaldehyde on P. aeruginosa-infected skin wounds reduced tissue bacterial load and promoted faster healing. Lower interleukin-17 (IL-17), vascular endothelial growth factor (VEGF) and nitric oxide levels were detected in cinnamaldehyde-treated wound samples. Blockage of transient receptor potential ankyrin 1, the pharmacological target of cinnamaldehyde, abrogated its healing activity and partially reversed the inhibitory actions of this compound on VEGF and IL-17 generation. We suggest that topical application of sub-inhibitory concentrations of cinnamaldehyde may represent an interesting approach to improve the healing of P. aeruginosa-infected skin wounds.


Assuntos
Acroleína/análogos & derivados , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Pele/microbiologia , Cicatrização/efeitos dos fármacos , Acroleína/uso terapêutico , Animais , Anti-Infecciosos/uso terapêutico , Biofilmes/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Interleucina-17/metabolismo , Camundongos , Infecções por Pseudomonas/tratamento farmacológico , Canal de Cátion TRPA1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Eur J Immunol ; 46(1): 70-80, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26464149

RESUMO

The intestinal immune system is complex and displays unique anatomic and functional characteristics. Numerous immune cell subsets are located beneath the epithelial barrier and their activity is highly regulated. Using hydrodynamic shear of IL-12 cDNA to achieve systemic expression of IL-12 in mice, we evaluated the effect of a transient burst of this cytokine on the activation status of T cells from Peyer's patches (PPs), mesenteric lymph nodes (MLNs), and colonic lamina propria (LP). Following systemic IL-12 release, intestinal T lymphocytes became activated, exhibiting a CD44(high) CD62L(-) phenotype. After 5 days of the cytokine burst, the frequency of α4ß7(+) CD4(+) and CD8(+) cells increased, and CD8(+) α4ß7(+) cells mainly expressed T bet, a critical regulator of the Th1 differentiation program. The incremental increase in α4ß7 expression involved the IL-12 receptor-signal transducer and activator of transcription (STAT)-4 axis, and occurred independently of IFN-γ, IL-4, IL-10, and TNF-α signaling. Moreover, IL-12 priming exacerbated the outcome of acute dextran sodium sulphate (DSS)-induced colitis with higher scores of weight loss, blood in stool, and diarrhea and lower hematocrit. Together, our findings demonstrate that systemic polarizing signals could effectively expand the number of effector cells able to home to the LP and contribute to local inflammation.


Assuntos
Colite/imunologia , Integrinas/imunologia , Interleucina-12/imunologia , Mucosa Intestinal/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Citometria de Fluxo , Inflamação/imunologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nódulos Linfáticos Agregados/imunologia
9.
Regul Toxicol Pharmacol ; 86: 11-17, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28232042

RESUMO

In the present study, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in rats. Single oral administration of IQG-607 (300 or 2000 mg/kg) on female rats did not result in any mortality. No gross lesions were observed in the animals at necropsy. Ninety-day administration test resulted in 20% of deaths, in both male and female rats administered with the highest dose of IQG-607, 300 mg/kg. Repeated administration of the IQG 607 (25, 100 and 300 mg/kg) did not result in any significant body mass alteration, or changes in food and water consumption. The most important clinical sign observed was salivation in both sexes. Importantly, long-term treatment with IQG-607 did not induce alterations in any hematological (for both sex) and serum biochemical (for female) parameters evaluated, even at the highest dose tested. Treatment of male rats with 100 or 300 mg/kg of IQG-607 decreased total cholesterol levels, while animals treated with 100 mg/kg also presented reduction on triglyceride levels. Of note, no treatment induced significant histopathological alterations in tissues of all organs and glands analyzed, even in that group that received the highest dose of IQG-607.


Assuntos
Compostos Ferrosos/toxicidade , Isoniazida/análogos & derivados , Administração Oral , Animais , Índice de Massa Corporal , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Compostos Ferrosos/administração & dosagem , Isoniazida/administração & dosagem , Isoniazida/toxicidade , Masculino , Ratos , Salivação/efeitos dos fármacos , Testes de Toxicidade Aguda/métodos
10.
Pharmacol Res ; 112: 4-29, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26812486

RESUMO

This review article focuses on pre-clinical and clinical studies with some selected Brazilian medicinal plants in different areas of interest, conducted by research groups in Brazil and abroad. It also highlights the Brazilian market of herbal products and the efforts of Brazilian scientists to develop new phytomedicines. This review is divided into three sections. The section I describes the Brazilian large biodiversity and some attempts of Brazilian scientists to assess the pharmacological profile of most plant extracts or isolated active principles. Of note, Brazilian scientists have made a great effort to study the Brazilian biodiversity, especially among the higher plants. In fact, more than 10,000 papers were published on plants in international scientific journals between 2011 and 2013. This first part also discussed the main efforts to develop new medicines from plants, highlighting the Brazilian phytomedicines market. Despite the large Brazilian biodiversity, notably with the higher plants, which comprise over 45,000 species (20-22% of the total worldwide), and the substantial number of scientific publications on medicinal plants, only one phytomedicine is found in the top 20 market products. Indeed, this market is still only worth about 261 million American dollars. This represents less than 5% of the global Brazilian medicine market. The section II of this review focus on the use of Brazilian plant extract and/or active principles for some selected diseases, namely: central nervous systems disorders, pain, immune response and inflammation, respiratory diseases, gastrointestinal tract and metabolic diseases. Finally, section III discusses in more details some selected Brazilian medicinal plants including: Cordia verbenacea, Euphorbia tirucalli, Mandevilla velutina, Phyllanthus spp., Euterpe oleracea, Vitis labrusca, Hypericum caprifoliatum and Hypericum polyanthemum, Maytenus ilicifolia, Protium kleinii and Protium heptaphylium and Trichilia catigua. Most of these publications are preliminary and only report the effects of crude extracts, both in vitro and in vivo studies. Only very few studies have been dedicated to investigate the mechanisms of action of isolated compounds. Likewise, studies on safety (toxicology), pharmacokinetic, and especially on well-conducted clinical trials are rare. In conclusion, in spite of the abundant Brazilian biodiversity and the thousands of academic publications on plants in international peer-reviewed scientific journals, few patents and medicines have been derived from such studies. Undoubtedly, great efforts must be made to improve the development of plant-derived medicine market in Brazil, especially by involving the partnership between academia and pharmaceutical companies.


Assuntos
Descoberta de Drogas , Fitoterapia , Extratos Vegetais/uso terapêutico , Plantas Medicinais , Animais , Biodiversidade , Brasil , Doenças do Sistema Nervoso Central/tratamento farmacológico , Gastroenteropatias/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Dor/tratamento farmacológico , Extratos Vegetais/economia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Transtornos Respiratórios/tratamento farmacológico
11.
J Immunol ; 191(8): 4288-98, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24038091

RESUMO

It has been previously reported that dietary fish oils, which are rich in the polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, can exert beneficial effects in inflammatory bowel disease. In this study, we investigated the effects of docosahexaenoic acid-derived lipid mediator maresin 1 (MaR1) in dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice. Systemic treatment with MaR1 significantly attenuated both DSS- and 2,4,6-trinitrobenzene sulfonic acid-induced colonic inflammation by improving the disease activity index and reducing body weight loss and colonic tissue damage. MaR1 treatment also induced a significant decrease in levels of inflammatory mediators, such as IL-1ß, TNF-α, IL-6, and IFN-γ, in the acute protocol, as well as IL-1ß and IL-6, but not TNF-α and INF-γ, in the chronic DSS colitis protocol. Additionally, MaR1 decreased ICAM-1 mRNA expression in both the acute and chronic protocols of DSS-induced colitis. Furthermore, the beneficial effects of MaR1 seem to be associated with inhibition of the NF-κB pathway. Moreover, incubation of LPS-stimulated bone marrow-derived macrophage cultures with MaR1 reduced neutrophil migration and reactive oxygen species production, besides decreasing IL-1ß, TNF-α, IL-6, and INF-γ production. Interestingly, macrophages incubated only with MaR1 showed a significant upregulation of mannose receptor C, type 1 mRNA expression, an M2 macrophage phenotype marker. These results indicate that MaR1 consistently protects mice against different models of experimental colitis, possibly by inhibiting the NF-κB pathway and consequently multiple inflammatory mediators, as well as by enhancing the macrophage M2 phenotype.


Assuntos
Colite/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/tratamento farmacológico , NF-kappa B/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Colite/induzido quimicamente , Colo/efeitos dos fármacos , Colo/patologia , Sulfato de Dextrana , Inflamação/induzido quimicamente , Molécula 1 de Adesão Intercelular/genética , Interferon gama/biossíntese , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Camundongos , NF-kappa B/efeitos dos fármacos , Neutrófilos/metabolismo , RNA Mensageiro/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Receptores de Superfície Celular/genética , Receptores Imunológicos , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/biossíntese
12.
Handb Exp Pharmacol ; 223: 1177-238, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24961985

RESUMO

The use of medicinal plants or other naturally derived products to relieve illness can be traced back over several millennia, and these natural products are still extensively used nowadays. Studies on natural products have, over the years, enormously contributed to the development of therapeutic drugs used in modern medicine. By means of the use of these substances as selective agonists, antagonists, enzyme inhibitors or activators, it has been possible to understand the complex function of many relevant targets. For instance, in an attempt to understand how pepper species evoke hot and painful actions, the pungent and active constituent capsaicin (from Capsicum sp.) was isolated in 1846 and the receptor for the biological actions of capsaicin was cloned in 1997, which is now known as TRPV1 (transient receptor potential vanilloid 1). Thus, TRPV1 agonists and antagonists have currently been tested in order to find new drug classes to treat different disorders. Indeed, the transient receptor potential (TRP) proteins are targets for several natural compounds, and antagonists of TRPs have been synthesised based on the knowledge of naturally derived products. In this context, this chapter focuses on naturally derived compounds (from plants and animals) that are reported to be able to modulate TRP channels. To clarify and make the understanding of the modulatory effects of natural compounds on TRPs easier, this chapter is divided into groups according to TRP subfamilies: TRPV (TRP vanilloid), TRPA (TRP ankyrin), TRPM (TRP melastatin), TRPC (TRP canonical) and TRPP (TRP polycystin). A general overview on the naturally derived compounds that modulate TRPs is depicted in Table 1.


Assuntos
Produtos Biológicos/farmacologia , Canais de Potencial de Receptor Transitório/efeitos dos fármacos , Animais , Capsaicina/farmacologia , Humanos , Canais de Cátion TRPV/efeitos dos fármacos , Terpenos/farmacologia
13.
Neurobiol Dis ; 54: 82-93, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23454198

RESUMO

Multiple sclerosis (MS) is a progressive, demyelinating inflammatory disease of the human central nervous system (CNS). While the primary symptoms of MS affect motor function, it is now recognized that chronic pain is a relevant symptom that affects both animals and MS patients. There is evidence that glial cells, such as astrocytes, play an important role in the development and maintenance of chronic pain. Kinins, notably bradykinin (BK) acting through B1 (B1R) and B2 (B2R) receptors, play a central role in pain and inflammatory processes. However, it remains unclear whether kinin receptors are involved in neuropathic pain in MS. Here we investigated by genetic and pharmacological approaches the role of kinin receptors in neuropathic pain behaviors induced in the experimental autoimmune encephalomyelitis (EAE) mouse model. Our results showed that gene deletion or antagonism of kinin receptors, especially B1R, significantly inhibited both tactile and thermal hypersensitivity in EAE animals. By contrast, animals with EAE and treated with a B1R selective agonist displayed a significant increase in tactile hypersensitivity. We also observed a marked increase in B1R mRNA and protein level in the mouse spinal cord 14days after EAE immunization. Blockade of B1R significantly suppressed the levels of mRNAs for IL-17, IFN-γ, IL-6, CXCL-1/KC, COX-2 and NOS2, as well as glial activation in the spinal cord. Of note, the selective B1 antagonist DALBK consistently prevented IFN-induced up-regulation of TNF-α and IL-6 release in astrocyte culture. Finally, both B1R and B2R antagonists significantly inhibited COX-2 and NOS2 expression in primary astrocyte culture. The B1R was co-localized with immunomarker of astrocytes in the spinal cord of EAE-treated animals. The above data constitute convincing experimental evidence indicating that both kinin receptors, especially the B1 subtype, exert a critical role in the establishment of persistent hypersensitivity observed in the EAE model, an action that seems to involve a central inflammatory process, possibly acting on astrocytes. Thus, B1 selective antagonists or drugs that reduce kinin release may have the potential to treat neuropathic pain in patients suffering from MS.


Assuntos
Astrócitos/metabolismo , Encefalomielite Autoimune Experimental/complicações , Neuralgia/metabolismo , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Animais , Western Blotting , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real
14.
Brain Behav Immun ; 33: 90-101, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23777652

RESUMO

Multiple sclerosis (MS) is a progressive T cell-mediated autoimmune demyelinating inflammatory disease of the central nervous system (CNS). Although it is recognized that cognitive deficits represent a manifestation of the disease, the underlying pathogenic mechanisms remain unknown. Here we provide evidence of spatial reference memory impairments during the pre-motor phase of experimental autoimmune encephalomyelitis (EAE) in mice. Specifically, these cognitive deficits were accompanied by down-regulation of choline acetyltransferase (ChAT) mRNA expression on day 5 and 11 post-immunization, and up-regulation of inflammatory cytokines in the hippocampus and prefrontal cortex. Moreover, a marked increase in B1R mRNA expression occurred selectively in the hippocampus, whereas protein level was up-regulated in both brain areas. Genetic deletion of kinin B1R attenuated cognitive deficits and cholinergic dysfunction, and blocked mRNA expression of both IL-17 and IFN-γ in the prefrontal cortex, lymph node and spleen of mice subjected to EAE. The discovery of kinin receptors, mainly B1R, as a target for controlling neuroinflammatory response, as well as the cognitive deficits induced by EAE may foster the therapeutic exploitation of the kallikrein-kinin system (KKS), in particular for the treatment of autoimmune disorders, such as MS, mainly during pre-symptomatic phase.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/fisiopatologia , Sistema Calicreína-Cinina/imunologia , Transtornos da Memória/imunologia , Transtornos da Memória/fisiopatologia , Transtornos dos Movimentos/imunologia , Transtornos dos Movimentos/fisiopatologia , Comportamento Espacial , Animais , Colina O-Acetiltransferase/antagonistas & inibidores , Colina O-Acetiltransferase/biossíntese , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Encefalomielite Autoimune Experimental/genética , Feminino , Hipocampo/enzimologia , Hipocampo/imunologia , Hipocampo/patologia , Interferon gama/antagonistas & inibidores , Interferon gama/genética , Interleucina-17/antagonistas & inibidores , Interleucina-17/genética , Sistema Calicreína-Cinina/genética , Transtornos da Memória/genética , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transtornos dos Movimentos/genética , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , Distribuição Aleatória , Receptor B1 da Bradicinina/deficiência , Receptor B1 da Bradicinina/genética , Receptor B2 da Bradicinina/agonistas , Receptor B2 da Bradicinina/deficiência , Receptor B2 da Bradicinina/genética , Regulação para Cima/genética , Regulação para Cima/imunologia
15.
J Immunol ; 187(4): 1957-69, 2011 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-21724996

RESUMO

Resolvins of the D series are generated from docosahexaenoic acid, which are enriched in fish oils and are believed to exert beneficial roles on diverse inflammatory disorders, including inflammatory bowel disease (IBD). In this study, we investigated the anti-inflammatory effects of the aspirin-triggered resolvin D1 (AT-RvD1), its precursor (17(R)-hydroxy docosahexaenoic acid [17R-HDHA]) and resolvin D2 (RvD2) in dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Our results showed that the systemic treatment with AT-RvD1, RvD2, or 17R-HDHA in a nanogram range greatly improved disease activity index, body weight loss, colonic damage, and polymorphonuclear infiltration in both colitis experimental models. Moreover, these treatments reduced colonic cytokine levels for TNF-α, IL-1ß, MIP-2, and CXCL1/KC, as well as mRNA expression of NF-κB and the adhesion molecules VCAM-1, ICAM-1, and LFA-1. Furthermore, AT-RvD1, but not RvD2 or 17R-HDHA, depended on lipoxin A4 receptor (ALX) activation to inhibit IL-6, MCP-1, IFN-γ, and TNF-α levels in bone marrow-derived macrophages stimulated with LPS. Similarly, ALX blockade reversed the beneficial effects of AT-RvD1 in DSS-induced colitis. To our knowledge, our findings showed for the first time the anti-inflammatory effects of resolvins of the D series and precursor 17R-HDHA in preventing experimental colitis. We also demonstrated the relevant role exerted by ALX activation on proresolving action of AT-RvD1. Moreover, AT-RvD1 showed a higher potency than 17R-HDHA and RvD2 in preventing DSS-induced colitis. The results suggest that these lipid mediators possess a greater efficacy when compared with other currently used IBD therapies, such as monoclonal anti-TNF, and have the potential to be used for treating IBD.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Colite/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/imunologia , Colite/induzido quimicamente , Colite/imunologia , Colite/metabolismo , Citocinas/biossíntese , Citocinas/imunologia , Sulfato de Dextrana/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/biossíntese , RNA Mensageiro/imunologia , Receptores de Formil Peptídeo/antagonistas & inibidores , Receptores de Formil Peptídeo/imunologia , Receptores de Formil Peptídeo/metabolismo , Trinitrobenzenos/efeitos adversos , Trinitrobenzenos/farmacologia , Poluentes Químicos da Água/efeitos adversos , Poluentes Químicos da Água/farmacologia
16.
Nat Commun ; 14(1): 199, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639383

RESUMO

Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized individuals. Because severe COVID-19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce error-prone virus replication. Coinhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously incorporated nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. MB-905 shows good oral absorption, its metabolites are stable, achieving long-lasting plasma and lung concentrations, and this drug is not mutagenic nor cardiotoxic in acute and chronic treatments. SARS-CoV-2-infected hACE-mice and hamsters treated with MB-905 show decreased viral replication, lung necrosis, hemorrhage and inflammation. Because kinetin is clinically investigated for a rare genetic disease at regimens beyond the predicted concentrations of antiviral/anti-inflammatory inhibition, our investigation suggests the opportunity for the rapid clinical development of a new antiviral substance for the treatment of COVID-19.


Assuntos
Antivirais , COVID-19 , Animais , Humanos , Camundongos , Antivirais/farmacologia , Antivirais/uso terapêutico , SARS-CoV-2 , Cinetina/farmacologia , Inflamação/tratamento farmacológico , Nucleotídeos , Replicação Viral
17.
Am J Pathol ; 178(3): 1153-66, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21356367

RESUMO

Cannabinoid receptor 2 (CB2) activation is suggested to trigger the peroxisome proliferator-activated receptor-γ (PPARγ) pathway, and agonists of both receptors improve colitis. Recently, the plant metabolite (E)-ß-caryophyllene (BCP) was shown to bind to and activate CB2. In this study, we examined the anti-inflammatory effect of BCP in dextran sulfate sodium (DSS)-induced colitis and analyzed whether this effect was mediated by CB2 and PPARγ. Oral treatment with BCP reduced disease activity, colonic macro- and microscopic damage, myeloperoxidase and N-acetylglucosaminidase activities, and levels and mRNA expression of colonic tumor necrosis factor-α, IL-1ß, interferon-γ, and keratinocyte-derived chemokine. BCP treatment also inhibited the activation of extracellular signal-regulated kinase 1/2, nuclear factor κB, IκB-kinase α/ß, cAMP response element binding and the expression of caspase-3 and Ki-67. Moreover, BCP enhanced IL-4 levels and forkhead box P3 mRNA expression in the mouse colon and reduced cytokine levels (tumor necrosis factor-α, keratinocyte-derived chemokine, and macrophage-inflammatory protein-2) in a culture of macrophages stimulated with lipopolysaccharide. The use of the CB2 antagonist AM630 or the PPARγ antagonist GW9662 significantly reversed the protective effect of BCP. Confirming our results, AM630 reversed the beneficial effect of BCP on pro-inflammatory cytokine expression in IEC-6 cells. These results demonstrate that the anti-inflammatory effect of BCP involves CB2 and the PPARγ pathway and suggest BCP as a possible therapy for the treatment of inflammatory bowel disease.


Assuntos
Colite/metabolismo , Colite/prevenção & controle , PPAR gama/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Caspase 3/metabolismo , Inibidores de Caspase , Claudina-4 , Colite/induzido quimicamente , Colo/efeitos dos fármacos , Colo/enzimologia , Colo/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase I-kappa B/metabolismo , Mediadores da Inflamação/metabolismo , Antígeno Ki-67/metabolismo , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , NF-kappa B/metabolismo , Oxazolona , PPAR gama/antagonistas & inibidores , Sesquiterpenos Policíclicos , Receptor CB2 de Canabinoide/antagonistas & inibidores
18.
Invest New Drugs ; 30(4): 1371-8, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21670971

RESUMO

This study evaluated the relevance of CXCR2 chemokine receptors in oral squamous cell carcinoma, by means of in vitro and in vivo approaches. The in vitro incubation of the selective and non-peptide CXCR2 receptor antagonist N-(2-hydroxy-4-nitrophenyl)-N9-(2-bromophenyl) Urea (SB225002; 25 to 800 nM) produced a time- and concentration-dependent inhibition of SCC158 (rat) and HN30 (human) cell lines viability. Conversely, this antagonist did not significantly affect the viability of the immortalized keratinocyte lineage, HaCaT. Additionally, the incubation of human IL-8 and rat CINC-1 CXCR2 agonists produced a concentration-related increase on HN30 and SCC158 proliferation. The submucosal injection of SCC158 cells (5 × 10(6) cells) into the tongue of Fischer 344 rats induced tumor development, which displayed typical clinical features. Immunohistochemical analysis of rat tongue biopsies revealed a marked increase of CXCR2 receptor immunoreactivity, which was accompanied by augumented expression of VEGF and caspase-3. Our data suggests an important role for CXCR2 receptors in oral squamous cell carcinoma.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Bucais/metabolismo , Receptores de Interleucina-8B/metabolismo , Animais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Masculino , Neoplasias Bucais/patologia , Compostos de Fenilureia/farmacologia , Ratos , Ratos Endogâmicos F344 , Receptores de Interleucina-8B/agonistas
19.
Purinergic Signal ; 8(2): 235-43, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22038661

RESUMO

Gliomas are the most common and devastating type of primary brain tumor. Many non-neoplastic cells, including immune cells, comprise the tumor microenvironment where they create a milieu that appears to dictate cancer development. ATP and the phosphohydrolytic products ADP and adenosine by activating P2 and P1 receptors may participate in these interactions among malignant and immune cells. Purinergic receptor-mediated cell communication is closely regulated by ectonucleotidases, such as by members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family, which hydrolyze extracellular nucleotides. We have shown that gliomas, unlike astrocytes, exhibit low NTPDase activity. Furthermore, ATP induces glioma cell proliferation and the co-administration of apyrase decreases progression of injected cells in vivo. We have previously shown that NTPDase2 reconstitution dramatically increases tumor growth in vivo. Here we evaluated whether NTPDase2 reconstitution to gliomas modulates systemic inflammatory responses. We observed that NTPDase2 overexpression modulated pro-inflammatory cytokine production and platelet reactivity. Additionally, pathological alterations in the lungs were observed in rats bearing these tumors. Our results suggest that disruption of purinergic signaling via ADP accumulation creates an inflammatory state that may promote tumor spread and dictate clinical progression.


Assuntos
Adenosina Trifosfatases/biossíntese , Neoplasias Encefálicas/enzimologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Glioma/enzimologia , Mediadores da Inflamação/fisiologia , Lesão Pulmonar/enzimologia , Adenosina Trifosfatases/genética , Animais , Apirase/biossíntese , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioma/patologia , Inflamação/enzimologia , Inflamação/patologia , Lesão Pulmonar/patologia , Masculino , Ratos , Ratos Wistar
20.
Am J Physiol Renal Physiol ; 300(5): F1223-34, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21367919

RESUMO

The ankyrin-repeat transient receptor potential 1 (TRPA1) has been implicated in pathological conditions of the bladder, but its role in overactive bladder (OAB) following spinal cord injury (SCI) remains unknown. In this study, using a rat SCI model, we assessed the relevance of TRPA1 in OAB induced by SCI. SCI resulted in tissue damage, inflammation, and changes in bladder contractility and in voiding behavior. Moreover, SCI caused upregulation of TRPA1 protein and mRNA levels, in bladder and in dorsal root ganglion (DRG; L6-S1), but not in corresponding segment of spinal cord. Alteration in bladder contractility following SCI was evidenced by enhancement in cinnamaldehyde-, capsaicin-, or carbachol-induced bladder contraction as well as in its spontaneous phasic activity. Of relevance to voiding behavior, SCI induced increase in the number of nonvoiding contractions (NVCs), an important parameter associated with the OAB etiology, besides alterations in other urodynamic parameters. HC-030031 (TRPA1 antagonist) treatment decreased the number and the amplitude of NVCs while the TRPA1 antisense oligodeoxynucleotide (AS-ODN) treatment normalized the spontaneous phasic activity, decreased the cinnamaldehyde-induced bladder contraction and the number of NVCs in SCI rats. In addition, the cinnamaldehyde-induced bladder contraction was reduced by exposure of the bladder preparations to HC-030031. The efficacy of TRPA1 AS-ODN treatment was confirmed by means of the reduction of TRPA1 expression in the DRG, in the corresponding segment of the spinal cord and in the bladder, specifically in detrusor muscle. The present data show that the TRPA1 activation and upregulation seem to exert an important role in OAB following SCI.


Assuntos
Acetanilidas/farmacologia , Anquirinas/antagonistas & inibidores , Gânglios Espinais/efeitos dos fármacos , Oligonucleotídeos Antissenso/farmacologia , Purinas/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Bexiga Urinária Hiperativa/prevenção & controle , Bexiga Urinária/efeitos dos fármacos , Acroleína/análogos & derivados , Acroleína/farmacologia , Animais , Anquirinas/genética , Anquirinas/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Capsaicina/farmacologia , Carbacol/farmacologia , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Contração Muscular/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Canal de Cátion TRPA1 , Canais de Cátion TRPC , Bexiga Urinária/inervação , Bexiga Urinária/metabolismo , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/genética , Bexiga Urinária Hiperativa/metabolismo , Bexiga Urinária Hiperativa/fisiopatologia , Urodinâmica/efeitos dos fármacos
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