Publications by authors named "Luís Cezar Rodrigues"

10 Publications

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MHTP, a synthetic alkaloid, attenuates combined allergic rhinitis and asthma syndrome through downregulation of the p38/ERK1/2 MAPK signaling pathway in mice.

Int Immunopharmacol 2021 Apr 13;96:107590. Epub 2021 Apr 13.

Laboratory of Immunopharmacology, Postgraduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa, PB, Brazil; Department of Physiology and Pathology, Federal University of Paraíba, João Pessoa, PB, Brazil. Electronic address:

The combined allergic rhinitis and asthma syndrome (CARAS) is a chronic airway inflammation of allergic individuals, with a type 2 immune response. Pharmacotherapy is based on drugs with relevant side effects. Thus, the goal of this study was to evaluate the synthetic alkaloid, MHTP in the experimental model of CARAS. Therefore, BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with MHTP by intranasal or oral routes. Treated animals showed a decrease (p < 0.05) of sneezing, nasal rubbings, and histamine nasal hyperactivity. Besides, MHTP presented binding energy and favorable interaction for adequate anchoring in the histamine H1 receptor. MHTP treatment inhibited the eosinophil migration into the nasal (NALF) and the bronchoalveolar (BALF) fluids. Histological analysis showed that the alkaloid decreased the inflammatory cells in the subepithelial and perivascular regions of nasal tissue and in the peribronchiolar and perivascular regions of lung tissue. The MHTP treatment also reduced the pulmonary hyperactivity by decreasing the smooth muscle layer hypertrophy and the collagen fiber deposition in the extracellular matrix. The immunomodulatory effect of the alkaloid was due to the decrease of cytokines like IL-5 and IL-17A (type 2 and 3), TSLP (epithelial), and the immunoregulatory cytokine, TGF-β. These MHTP effects on granulocytes were dependent on the p38/ERK1/2 MAP kinase signaling pathway axis. Indeed, the synthetic alkaloid reduced the frequency of activation of both kinases independent of the NF-κB (p65) pathway indicating that the molecule shut down the intracellular transduction signals underlie the cytokine gene transcription.
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http://dx.doi.org/10.1016/j.intimp.2021.107590DOI Listing
April 2021

MHTP, 2-Methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) phenol, a Synthetic Alkaloid, Induces IFN-γ Production in Murine Model of Ovalbumin-Induced Pulmonary Allergic Inflammation.

Inflammation 2018 Dec;41(6):2116-2128

Department of Physiology and Pathology, Postgraduate Program in Natural and Synthetic Bioactive Products, Federal University of Paraíba, João Pessoa, PB, Brazil.

MHTP [2-methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) phenol], a synthetic isoquinolinic alkaloid, presented anti-inflammatory activity in several experimental models of acute inflammation as lipopolysaccharide (LPS)-induced acute lung injury and phlogistic agent-induced edema and presented low preclinical toxicity. The aim of this study was to determine the MHTP effect on ovalbumin (OVA)-induced pulmonary allergic inflammation. In other to realize this study, female BALFB/c mice were sensitized and challenged with OVA (OVA group) and treated with MHTP (MHTP group) by nasal instillation. Inflammatory, allergic, and immunomodulatory parameters such as migration of inflammatory cells to the lung tissue, pulmonary histological analysis, serum level of IgE-allergen specific, cytokine secretion, and lung T cell population characterization were analyzed and the data were considered statistically significant with p < 0.05. OVA-sensitized and OVA-challenged and MHTP (5.0 mg/kg)-treated mice presented reduction on total leukocyte migration into the bronchoalveolar lavage (BALF) dependent of lymphocyte and eosinophil migration (p < 0.001 and p < 0.01) as compared with the OVA group. Flow cytometric analysis showed that MHTP treatment decreased the percentage of granulocytes (p < 0.001) into the BALF and lung tissue histological analyzes demonstrated that the MHTP treatment decreased leukocyte migration and mucus production. In addition, treatment with MHTP decreased the number of CD3CD4 T cells independently of CD8 T cell reduction into the BALF. The treatment also reduced significantly (p < 0.05) the serum level of IgE-OVA specific followed by reduction of IL-4, IL-13, and IL-17 production. Surprisingly, the MHTP treatment increased significantly (p < 0.05) the IFN-γ production in the BALF of these animals. Therefore, the results presented here showed that MHTP treatment, by nasal instillation, in a mouse model of OVA-induced pulmonary allergy has anti-allergic and immunomodulatory effects dependent on a Th1-skewed cytokine production that ameliorate the pulmonary allergic inflammation.
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http://dx.doi.org/10.1007/s10753-018-0855-yDOI Listing
December 2018

Synthesis and Antileishmanial Activity of Natural Dehydrodieugenol and Its Mono- and Dimethyl Ethers.

Chem Biodivers 2016 Jul 4;13(7):870-4. Epub 2016 Jul 4.

Department of Biochemistry, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235 - Cidade Universitaria, Recife, PE, 50670-901, Brazil.

The study of chemistry of naturally occurring compounds and the synthesis of their derivatives is fundamentally important for the development of new drugs. In this work, dehydrodieugenol (DHDE) was obtained through oxidative coupling of eugenol, promoted by an aqueous mixture of potassium ferricyanide (K3 [Fe(CN)6 ]) and NH3  · H2 O. The partial methoxylation of DHDE with MeI and K2 CO3 mainly resulted in the molecular-shaped monomethyl ether (DHDE-1MeO) and its dimethyl ether derivative (DHDE-2MeO). The products from the reactions were characterized by (1) H- and (13) C-NMR spectroscopy. Additionally, these studies have reported the antileishmanial activity of DHDE against Leishmania amazonensis (IC50 value of 42.20 μg ml(-1) ) and shown that partial methoxylation of DHDE results in a significant increase in its antiparasitic activity (IC50 value of 13.68 μg ml(-1) ). Based on in vitro bioassays, DHDE-1MeO has shown the highest leishmanicidal activity in promastigota form. Production by direct one-step synthesis of this monomethoxylated compound can be considered to be a cost-effective and environmentally friendly method with a short reaction time.
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http://dx.doi.org/10.1002/cbdv.201500280DOI Listing
July 2016

Synthesis, toxicity study and anti-inflammatory effect of MHTP, a new tetrahydroisoquinoline alkaloid.

Immunopharmacol Immunotoxicol 2015 27;37(4):400-12. Epub 2015 Jul 27.

Centro de Ciências Exatas e da Natureza, Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal da Paraíba , João Pessoa, Paraíba , Brasil .

The alkaloid 2-methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenol (MHTP) was synthesized to prospect new compounds with therapeutic properties. Thus, the goal of this study was to evaluate the MHTP anti-inflammatory effect by in vivo and in vitro assays. The MHTP toxicity was analyzed. We found that MHTP pre-treatment (2.5-10 mg/kg) showed antiedematogenic effect (p < 0.05) in carrageenan-induced paw edema by inhibiting the PGE2 action independently of mast cell degranulation or histamine activity. MHTP also diminished (p < 0.01) total leukocyte migration in 41.5% into peritoneal cavity during carrageenan-induced peritonitis, reducing polymorphonuclear cells (PMNs) (59.6%) and proteins levels (29.4%). MHTP in an experimental model of acute lung injury inhibited (p < 0.001) total inflammatory cell migration into the lungs and PMNs in 58% and 67.5%, respectively. Additionally, MHTP did not present cytotoxicity at concentrations of 10, 25 or 50 μM but decreased (p < 0.001) the NO production in 24%, 47% and 39%, respectively. The alkaloid also reduced (p < 0.001, in lipopolysaccharide (LPS)-stimulated macrophages (1 μg/mL), IL-1β, IL-6 and IL-10 levels in 35.7%, 31.0% and 33.4%, respectively. The results obtained in this study allow us to conclude that the inedited synthetic alkaloid, MHTP has anti-inflammatory effect by inhibiting PGE2 function as well as inhibiting inflammatory cell migration to the inflamed site and attenuated the acute lung injury disease by inhibiting the migration of neutrophil to the lung. However, further studies will be carried out to demonstrate the mechanisms of action of the molecule and explore its potential as a future drug to treat inflammatory processes.
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http://dx.doi.org/10.3109/08923973.2015.1070173DOI Listing
May 2016

Antinociceptive effect of lupeol: evidence for a role of cytokines inhibition.

Phytother Res 2013 Oct 3;27(10):1557-63. Epub 2012 Dec 3.

Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil; Universidade Estadual de Feira de Santana, Feira de Santana, Bahia, Brazil.

The present study investigates the antinociceptive properties of lupeol in models of inflammatory and post-operative pain, as well as its mechanisms of action. The effects of lupeol were tested against acetic acid-induced writhing, formalin test, carrageenan-induced hyperalgesia, and post-operative pain model. Cytokine levels were determined by ELISA. Mice motor performance was evaluated in the rota rod and open-field tests. Pre-treatment of mice with lupeol (5-100 mg/kg IP) produced a dose-related inhibition of writhing in mice. The maximal antinociception produced by lupeol (60 mg/kg) was unaffected in mice pre-treated with yohimbine (α2 adrenoceptor antagonist; 2 mg/kg IP), L-arginine (substrate for nitric oxide synthase; 600 mg/kg IP), glibenclamide (the KATP-channel blocker; 2 mg/kg IP), and methysergide maleate (serotoninergic receptors antagonist; 5 mg/kg IP). Furthermore, lupeol (25-100 mg/kg) inhibited the late phase of formalin test. Pre-treatment with lupeol (50 and 100 mg/kg) inhibited the hyperalgesia and the local increase in tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels induced by carrageenan. In contrast, lupeol did not inhibit the post-operative pain. Lupeol-treated mice did not show any motor performance alterations or apparent systemic toxicity. Our results demonstrate that lupeol has consistent antinociceptive properties during inflammatory pain, but not post-operative pain, acting through the inhibition of IL-1β and TNF-α production.
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http://dx.doi.org/10.1002/ptr.4902DOI Listing
October 2013

Synthesis, acute toxicity and anti-inflammatory effect of bornyl salicylate, a salicylic acid derivative.

Immunopharmacol Immunotoxicol 2012 Dec 20;34(6):1028-38. Epub 2012 Jun 20.

Universidade Federal da Paraíba, Departamento de Fisiologia e Patologia, Laboratório de Imunofarmacologia, João Pessoa, Paraíba, Brasil.

Bornyl salicylate (BS) is a salicylic derivative, obtained by sterification of salicylic acid and monoterpene (-)-borneol, and its topical use in inflammatory diseases was described in the early 20th century. It is also known that borneol presents neuroprotective, genoprotective and analgesic properties. The purpose of this study was to evaluate BS in experimental models of acute inflammation. The toxicity of BS was analyzed by measuring water and food intake, weight, mortality and weight of main organs. To assess its anti-inflammatory effect, BS-treated mice were challenged with carrageenan, prostaglandin E2 (PGE2), bradikynin (BK) or histamine (HIS)-induced paw edema, zymosan-induced peritonitis and vascular permeability induced by acetic acid. Nitric oxide (NO) production was analyzed in peritoneal macrophage cultures. There was no sign of acute toxicity of BS in male and female mice. Furthermore, treatment with BS was significantly (p < 0.05) effective in reducing paw edema induced by carrageenan in early and late phases; this effect was related to PGE2 and BK, but HIS independent. Neutrophil migration and cytokine release (TNF-α, IL-1β and IL-6) induced by zymosan and fluid leakage induced by acetic acid were also reduced in BS-treated animals. In vitro, BS (10 µg/mL) reduced NO production in LPS-stimulated macrophages. These data suggest that BS has an anti-inflammatory effect, which is related, at least in part, with decrease of mediators as PGE2, NO and pro-inflammatory cytokines. However, further studies should be done to explore its potential as an anti-inflammatory drug.
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http://dx.doi.org/10.3109/08923973.2012.694891DOI Listing
December 2012

Brominated compounds from marine sponges of the genus Aplysina and a compilation of their 13C NMR spectral data.

Mar Drugs 2011 10;9(11):2316-68. Epub 2011 Nov 10.

Laboratory of Pharmaceutical Technology, Federal University of Paraiba, Joao Pessoa, PB, Brazil.

Aplysina is the best representative genus of the family Aplysinidae. Halogenated substances are its main class of metabolites. These substances contribute greatly to the chemotaxonomy and characterization of the sponges belonging to this genus. Due to their pharmacological activities, these alkaloids are of special interest. The chemistry of halogenated substances and of the alkaloids has long been extensively studied in terrestrial organisms, while the number of marine organisms studied has just started to increase in the last decades. This review describes 101 halogenated substances from 14 species of Aplysina from different parts of the world. These substances can be divided into the following classes: bromotyramines (A), cavernicolins (B), hydroverongiaquinols (C), bromotyrosineketals (D), bromotyrosine lactone derivatives (E), oxazolidones (F), spiroisoxazolines (G), verongiabenzenoids (H), verongiaquinols (I), and dibromocyclohexadienes (J). A compilation of their (13)C NMR data is also part of the review. For this purpose 138 references were consulted.
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http://dx.doi.org/10.3390/md9112316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229238PMC
April 2012

Flavonoids from Praxelis clematidea R.M. King and Robinson modulate bacterial drug resistance.

Molecules 2011 Jun 10;16(6):4828-35. Epub 2011 Jun 10.

Laboratory of Pharmaceutical Technology, Federal University of Paraíba, João Pessoa, PB 58051, Brazil.

Chemical studies of Praxelis clematidea R.M. King & Robinson resulted in the isolation of six flavones: Apigenine, genkwanine, 7,4'-dimethylapigenin, trimethylapigenin, cirsimaritin and tetramethylscutellarein, which were tested for their toxicity against Staphylococcus aureus SA-1199B, a strain possessing the NorA efflux pump. Efflux pumps are integral proteins of the bacterial membrane and are recognized as one of the main causes of bacterial drug resistance, since they expel antibiotics from the cell. The inhibition of this transporter is one form of modulating bacterial resistance to antimicrobial drugs. The flavones tested did not show any significant antibacterial activity against the Staphylococcus aureus strain used, but were able to modulate bacterial drug resistance. This property might be related to the degree of lipophilicity of the flavones conferred by the methoxyl groups, since 4',5,6,7 tetramethoxyflavone the most methoxylated compound, reduced the minimal inhibitory concentration of the drug 16-fold.
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http://dx.doi.org/10.3390/molecules16064828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264212PMC
June 2011

Structure-function relationships and crystal structures of the vitamin D receptor bound 2 alpha-methyl-(20S,23S)- and 2 alpha-methyl-(20S,23R)-epoxymethano-1 alpha,25-dihydroxyvitamin D3.

J Med Chem 2010 Feb;53(3):1159-71

Departement de Biologie et de Génomique Structurales, Centre National de la Recherche Scientifique, Institut National de la Santé de la Recherche Médicale, Université de Strasbourg, 1 Rue Laurent Fries, 67404 Illkirch, France.

The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. We recently showed that the synthetic analogue (20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (2a) acts as a 1 alpha,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1 alpha,25(OH)(2)D(3), 2 alpha-methyl-1 alpha,25(OH)(2)D(3), or 2a, we designed a novel analogue, 2 alpha-methyl-(20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.
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http://dx.doi.org/10.1021/jm9014636DOI Listing
February 2010

Structure-based design of a superagonist ligand for the vitamin D nuclear receptor.

Chem Biol 2008 Apr;15(4):383-92

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Département de Biologie et de Génomique Structurales, Université Louis Pasteur, Strasbourg F-67000, France.

Vitamin D nuclear receptor (VDR), a ligand-dependent transcriptional regulator, is an important target for multiple clinical applications, such as osteoporosis and cancer. Since exacerbated increase of calcium serum level is currently associated with VDR ligands action, superagonists with low calcium serum levels have been developed. Based on the crystal structures of human VDR (hVDR) bound to 1alpha,25-dihydroxyvitamin D(3) and superagonists-notably, KH1060-we designed a superagonist ligand. In order to optimize the aliphatic side chain conformation with a subsequent entropy benefit, we incorporated an oxolane ring and generated two stereo diasteromers, AMCR277A and AMCR277B. Only AMCR277A exhibits superagonist activity in vitro, but is as calcemic in vivo as the natural ligand. The crystal structures of the complexes between the ligand binding domain of hVDR and these ligands provide a rational approach to the design of more potent superagonist ligands for potential clinical application.
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http://dx.doi.org/10.1016/j.chembiol.2008.03.016DOI Listing
April 2008