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Herein, the isolation of secondary metabolites from the aerial parts of Justicia aequilabris guided by HPLC-MS n and molecular networking analyses is reported. Twenty-two known compounds were dereplicated. Three new lignans (aequilabrines A-C ( 1 - 3 )) and three known compounds (lariciresinol-4'- O- β-glucose ( 4 ), roseoside ( 5 ), and allantoin ( 6 )) were obtained. The anti-inflammatory activity of compounds 1 - 3 was evaluated in vitro by inhibiting the nitric oxide production (NO) and pro-inflammatory activity on the cytokine IL-1β. Compounds 2 and 3 showed significant inhibitory activity against NO production, with IC 50 values of 9.1 and 7.3 μM, respectively. The maximum inhibition of IL-1β production was 23.5% ( 1 ), 27.3% ( 2 ), and 32.5% ( 3 ).

Four new chromenones, kielmeyerones A-D ( 1 - 4 ), were obtained from the roots of Kielmeyera reticulata . Their structures were elucidated based on spectroscopic data (NMR and HRESIMS) interpretation. The pharmacological activity of kielmeyerone A ( 1 ), the major compound, was evaluated using in vitro and in vivo inflammation and pain models. During in vitro screening, 1 , at noncytotoxic concentrations (0.097-1.56 μM), inhibited NO production by J774 macrophages stimulated with LPS and IFN-γ. In the complete Freund's adjuvant-induced inflammation model in mice, 1 (12.5-50 mg/kg) inhibited paw edema, demonstrating an anti-inflammatory effect. Additionally, 1 (12.5-50 mg/kg) induced a dose-dependent antinociceptive effect in the late phase of the formalin test, a profile similar to those of nonsteroidal anti-inflammatory drugs. Mice treated with 1 (100 mg/kg) did not show motor performance alterations using a rota-rod test. Thus, the present study has characterized new chromenones from Kielmeyera reticulata and has provided evidence of the anti-inflammatory and antinociceptive properties of one of these, kielmeyerone A ( 1 ).

Ethnopharmacological Relevance: Physalis angulata is an herb found in tropical and subtropical regions of the world; it is widely applied in popular medicine due to the therapeutic properties of the whole plant and its parts. Extracts and infusions of this plant have been extensively applied in folk medicine worldwide to treat inflammatory and immune-mediated diseases, including oral inflammatory conditions such as sore throat and gingivitis., Aim of the Study: The present study was designed to investigate the protective effects of the ethanolic extract of P. angulata (EEPA) in a murine model of chronic periodontitis, aiming to corroborate its traditional use as an anti-inflammatory and immunomodulatory agent, and to point out possible mechanisms involved in these effects., Materials and Methods: EEPA was obtained from the stems of P. angulata collected in Belém (PA, Brazil). Chronic periodontitis was induced in male C57BL/6 mice by 12 administrations of lipopolysaccharide (LPS; 20 μg/1μL) into the gingival papilla in the course of 28 days. Starting from the 15 th day after the first LPS injection, mice were daily treated with EEPA (50 or 100 mg/kg), nimesulide (25 mg/kg, reference drug), or vehicle by oral route for 14 days. At the end of the experimental period, alveolar bone loss was evaluated along with the gingival expression of biomarkers of periodontitis and cytokines by RT-q-PCR and ELISA. Hematological and biochemical parameters suggestive of systemic toxicity were also evaluated. The transcriptional activity of NF-κB was investigated using the luciferase assay in macrophages., Results: Mice with chronic experimental periodontitis suffered alveolar bone loss that was prevented by the treatment with EEPA (50 or 100 mg/kg) or nimesulide (25 mg/kg). EEPA (50 and 100 mg/kg) and nimesulide (25 mg/kg) reduced mRNA levels of MMP-9 mRNA, but not of TIMP-1 in gingival tissue of periodontitis-induced mice. Both treatments also reduced the production of the pro-inflammatory cytokines IL-1β and IL-6. The treatment with EEPA (100 mg/kg) increased the production of the anti-inflammatory cytokine TGF-β. No hematological or biochemical alterations were caused by the daily treatment with EEPA. In vitro luciferase assay suggested that a putative mechanism of EEPA is reducing the transcriptional activity of NF-κB., Conclusions: EEPA exhibited a disease-modifying effect in the chronic experimental periodontitis, along with unidentifiable systemic toxicity. This work corroborates the traditional use of P. angulata in oral inflammatory conditions and provides mechanistic hypotheses to explain its therapeutic effects., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This current study presents the phytochemical analysis of Croton velutinus, describing phenylpropanoids obtained from this species. The fractionation of the roots hexane extract led to the isolation of four new phenylpropanoids derivatives, velutines A-D (1-4) and three known (5-7). Their structures were established based on spectroscopic (1D-2D NMR; HRMS and IR) analysis. Cytotoxic, trypanocidal and anti-inflammatory activities of compounds 1-7 were evaluated. Only compounds 2 and 5 showed cytotoxic activity against cancer cell lines (B16F10, HL-60, HCT116, MCF-7 and HepG2), with IC 50 values ranging from 6.8 to 18.3 μM and 11.1 to 18.3 μM, respectively. Compounds 2 and 5 also showed trypanocidal activity against bloodstream trypomastigotes with EC 50 values of 9.0 and 9.58 μM, respectively. Finally, the anti-inflammatory potential of these compounds was evaluated on cultures of activated macrophages. All compounds exhibited concentration-dependent suppressive activity on the production of nitrite and IL-1β by macrophages stimulated with LPS and IFN-γ. These results indicate phenylpropanoids esters (2 and 5) from C. velutinus as promising cytotoxic, trypanocidal and anti-inflammatory candidates that warrants further studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chromones are a group of natural substances with a diversity of biological activities. Herein we assessed the pharmacological potential of three chromones (1, 2 and 3) isolated from Dictyoloma vandellianum as anti-inflammatory agents using in vitro and in vivo approaches. During in vitro screening, the production of NO and cytokines by macrophages stimulated with LPS and IFN-γ was inhibited by all chromones at concentrations (5-20 μM) that did not induce cytotoxicity. Analysis of pharmacokinetic parameters (in vitro half-life and intrinsic clearance) using human liver microsomes revealed that 3 has a superior pharmacokinetic profile, compared to 1 and 2. Treatment with 3 (100 mg/kg, ip) did not affect the mice motor performance, while 1 and 2 induced motor deficit. Taking into account the pharmacokinetic profile and absence of motor impairment, 3 was selected for further pharmacological characterization. Corroborating the data from in vitro screening, treatment of cell cultures with 3 (5-20 μM) reduced TNF-α, IL-6 and IL-1β production by stimulated macrophages. In the complete Freund's adjuvant-induced paw inflammation model in mice, 3 (25 and 50 mg/kg, ip) inhibited mechanical hyperalgesia, edema and cytokine production/release (IL-1β, IL-6 and TNF-α). 3 (5-20 μM) also reduced the transcriptional activity of NF-κB in stimulated macrophages. Furthermore, treatment with RU486, a glucocorticoid receptor (GR) antagonist, partially prevented the inhibitory effect of 3 on macrophages, indicating that this chromone exerts its anti-inflammatory effects in part through the activation of GR. The results presented herein demonstrate the pharmacological potential of natural chromones, highlighting 3 as a possible candidate for the drug discovery process targeting new anti-inflammatory drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Braylin belongs to the group of natural coumarins, a group of compounds with a wide range of pharmacological properties. Here we characterized the pharmacological properties of braylin in vitro, in silico and in vivo in models of inflammatory/immune responses. In in vitro assays, braylin exhibited concentration-dependent suppressive activity on activated macrophages. Braylin (10-40 μM) reduced the production of nitrite, IL-1β, TNF-α and IL-6 by J774 cells or peritoneal exudate macrophages stimulated with LPS and IFN-γ. Molecular docking calculations suggested that braylin present an interaction pose to act as a glucocorticoid receptor ligand. Corroborating this idea, the inhibitory effect of braylin on macrophages was prevented by RU486, a glucocorticoid receptor antagonist. Furthermore, treatment with braylin strongly reduced the NF-κB-dependent transcriptional activity on RAW 264.7 cells. Using the complete Freund's adjuvant (CFA)-induced paw inflammation model in mice, the pharmacological properties of braylin were demonstrated in vivo. Braylin (12.5-100 mg/kg) produced dose-related antinociceptive and antiedematogenic effects on CFA model. Braylin did not produce antinociception on the tail flick and hot plate tests in mice, suggesting that braylin-induced antinociception is not a centrally-mediated action. Braylin exhibited immunomodulatory properties on the CFA model, inhibiting the production of pro-inflammatory cytokines IL-1β, TNF-α and IL-6, while increased the anti-inflammatory cytokine TGF-β. Our results show, for the first time, anti-inflammatory, antinociceptive and immunomodulatory effects of braylin, which possibly act through the glucocorticoid receptor activation and by inhibition of the transcriptional activity of NF-κB. Because braylin is a phosphodiesterase-4 inhibitor, this coumarin could represent an ideal prototype of glucocorticoid receptor ligand, able to induce synergic immunomodulatory effects.

Riparins, natural alkaloids of the alkamide group, can be synthesized by simple methods, enhancing their potential application in pharmaceutical development. Here, the pharmacological properties of riparins were investigated in in vitro and in vivo assays of pain and inflammation in Swiss mice. Inflammatory mediators were measured by radioimmunoassay and Real-Time PCR. Riparins I, II, III and IV (1.56-100 mg/kg; ip) produced dose-related antinociceptive effects in the formalin test, exhibiting ED 50 values of 22.93, 114.2, 31.05 and 6.63 mg/kg, respectively. Taking the greater potency as steering parameter, riparin IV was further investigated. Riparin IV did not produce antinociceptive effect on the tail flick, suggesting that its antinociception is not a centrally-mediated action. In fact, riparin IV (1.56-25 mg/kg) produced dose-related antinociceptive and antiedematogenic effects on the complete Freund's adjuvant (CFA)-induced paw inflammation in mice. During CFA-induced inflammation, riparin IV did not modulate either the production of cytokines, TNF-α and IL-10, or COX-2 mRNA expression. On the other hand, riparin IV decreased the PGE₂ levels in the inflamed paw. In in vitro assays, riparin IV did not exhibit suppressive activities in activated macrophages. These results indicate, for the first time, that riparin IV induces antinociceptive and anti-inflammatory effects, possibly through the inhibition of prostanoid production.

Context: Pain corresponds to the most frequent reason for visits to physicians, and its control by conventional drugs is accompanied by several side effects, making treatment difficult. For this reason, new chemical entities derived from natural products still hold great promise for the future of drug discovery to pain treatment., Objective: The objective of this study was to evaluate the antinociceptive and anti-inflammatory profiles of p-cymene (PC), a monocyclic monoterpene, and its possible mechanisms of action., Materials and Methods: Mice treated acutely with PC (25, 50, or 100 mg/kg, i.p.) were screened for carrageenan-induced hyperalgesia and the inflammatory components of its cascade (30-180 min), carrageenan-induced pleurisy (4 h), and tail-flick test (1-8 h). Also, we observed the PC effect on the generation of nitric oxide by macrophages and the activation of neurons in the periaqueductal gray (PAG) by immunofluorescence., Results: PC reduced (p < 0.001) the hyperalgesia induced by carrageenan, TNF-α, dopamine, and PGE2. PC decrease total leukocyte migration (100 mg/kg: p < 0.01), neutrophils (50 and 100 mg/kg: p < 0.05 and 0.001), and TNF-α (25, 50, and 100 mg/kg: p < 0.01, 0.05, and 0.001, respectively), besides reducing NO production (p < 0.05) in vitro. PC produced antinociceptive effect in tail-flick test (p < 0.05), which was antagonized by naloxone, naltrindole, nor-BNI, and CTOP, and increased (p < 0.001) the number of c-Fos-immunoreactive neurons in PAG., Discussion and Conclusion: These results provide information about the anti-hyperalgesic and anti-inflammatory properties of PC suggesting a possible involvement of the opioid system and modulating some pro-inflammatory cytokines.

Carvacrol, a phenolic monoterpene, has been reported to possess anti-inflammatory properties. However, the mechanisms involved in its pharmacological properties are currently not well understood. In the present study, the contribution of cytokine modulation to the anti-inflammatory effects of carvacrol was investigated in a classical inflammation model: the complete Freund's adjuvant (CFA)-induced paw inflammation in mice. The paw edema was measured using a plesthismometer. Paw tissue was removed 2h after the inflammatory stimulus to determine the levels of prostaglandin E(2) (PGE(2)) by enzyme immunoassay, the levels of interleukin-1 β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) by ELISA or the mRNA expression of cyclooxygenase-2 (COX-2), IL-1β, TNF-α, and IL-10 by real-time PCR. Administration of carvacrol produced anti-inflammatory effects against CFA-induced inflammation in mice. Treatment of mice with carvacrol at 50 and 100mg/kg attenuated the paw edema and reduced the IL-1β and PGE(2), but not TNF-α, local levels. Similarly, carvacrol (100mg/kg) reduced the COX-2 and IL-1β mRNA expression. The levels of IL-10, an anti-inflammatory cytokine, and the IL-10 mRNA expression in the inflamed paw were enhanced by carvacrol. In addition, the treatment with carvacrol did not reduce the CFA-induced paw edema in IL-10 knockout mice. The present results suggest that carvacrol causes anti-inflammatory effects by reducing the production of inflammatory mediators, such as IL-1β and prostanoids, possibly through the induction of IL-10 release., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Aim of Study: Adiantum, one of the most widely distributed genera of the family Pteridaceae, is employed in folk medicine worldwide. Adiantum latifolium Lam. has been used in Latin American traditional medicine as anxiolytic, analgesic and antiinflammatory. The present study investigates the antinociceptive and antiinflammatory properties of the methanolic extract of Adiantum latifolium (MEA) in animal models of pain and inflammation to confirm its medicinal use., Material and Methods: The antinociceptive and antiinflammatory activities of MEA were evaluated using the writhing, formalin, and tail-flick tests, carrageenan-induced paw edema and arachidonic acid-induced ear edema. Mice motor performance was evaluated in the rota rod test and the acute toxicity evaluated over 14 days., Results: Intraperitoneal (1-100mg/kg) or oral (100-400mg/kg) administration of MEA produced a dose-related inhibition of acetic acid-induced writhing in mouse. Furthermore, treatment with MEA (100mg/kg) inhibited both the early and late phases of formalin-induced hypernociception. In contrast, MEA (100mg/kg/IP) did not prevent the thermal nociception in the tail-flick test. In addition, MEA (100 and 200mg/kg/IP) inhibited important events related to the inflammatory response induced by carrageenan or arachidonic acid, namely local edema and increase in tissue interleukin-1β levels. MEA (300mg/kg/IP)-treated mice did not show any motor performance alterations. Over the study period of 14 days, there were no deaths or toxic signs recorded in the group of mice given 1000mg/kg of MEA., Conclusion: The results demonstrate that Adiantum latifolium has antinociceptive and antiinflammatory activities, acting through the inhibition of IL-1β production., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Aim of Study: Blechnum occidentale L. is a terrestrial fern that ranges from the United States to South America, and is employed in Brazilian folk medicine. In the present study we investigated the antinociceptive and antiinflammatory activities of the methanolic extract of Blechnum occidentale L. (MEB) in animal models of pain and inflammation to support its medicinal use in treatment of inflammatory and pulmonary diseases, urinary infections and liver diseases., Materials and Methods: The antinociceptive activity of MEB was evaluated using the writhing, formalin, and tail flick tests. The antiinflammatory activity of MEB was evaluated in carrageenan-induced paw oedema and neutrophil migration. In order to discard possible non-specific muscle relaxant or sedative effects of MEB, mice motor performance was evaluated in the rota rod test and its toxicity evaluated over 14 days., Results: Intraperitoneal (IP) administration of MEB (0.01-100mg/kg) produced a dose-related antinociception on acetic acid-induced writhing in mice. Oral administration of MEB, at a different range of doses (100-400 mg/kg), also produced significant antinociceptive effect on the writhing test. Furthermore, treatment with MEB (100 and 200 mg/kg IP) inhibited significantly both the early and late phases of formalin-induced hypernociception in rats. In contrast, treatment with MEB (100 and 200 mg/kg IP) did not prevent the thermal nociception in the tail flick test. The IP administration of MEB (100 and 300 mg/kg) significantly reduced the paw oedema induced by carrageenan. Moreover, systemic treatment with MEB (11-300 mg/kg) reduced the neutrophil migration in the carrageenan-induced migration to the peritoneal cavity. In the rota rod test, MEB-treated mice did not show any significant motor performance alterations with the dose of 300 mg/kg. In addition, over the study duration of 14 days, there were no deaths or toxic signs recorded in the mice given 100 or 1000 mg/kg of MEB., Conclusion: The results described here are the first report of pharmacological studies of Blechnum occidentale L. and indicate that this plant has antinociceptive and antiinflammatory activities which support its folk medicine use.