Campomanesia lineatifolia Ruiz & Pavón (Myrtaceae), an edible species found in Brazilian Forest, possesses leaves that are traditionally used for the treatment of gastrointestinal disorders in ...Brazil. Extracts of C. lineatifolia are rich in phenolics and exhibit antioxidant, and gastric antiulcer properties. Furthermore, Campomanesia spp. have been described to possess anti-inflammatory properties, but studies related to chemical constituents of C. lineatifolia are scarce in the literature.
This work aims to identify the chemical composition of the phenolic-rich ethanol extract (PEE) from C. lineatifolia leaves and evaluate the anti-inflammatory activity that could be related to its ethnopharmacological use.
The high-speed countercurrent chromatography (HSCCC), using an isocratic and a step gradient elution method, and NMR, HPLC-ESI-QTOF-MS/MS were used to isolate and identify the chemicals of PEE, respectively. Lipopolysaccharide-(LPS)-stimulated THP-1 cells were used to evaluate the anti-inflammatory activities from PEE and the two majority flavonoids isolated by measure TNF-α and NF-κB inhibition assays.
Fourteen compounds were isolated from the PEE, further identified by NMR and HPLC-ESI-QTOF-MS/MS, twelve of them are new compounds, and two others are already known for the species. The PEE, quercitrin and myricitrin promoted a concentration-dependent inhibition of TNF-α, and PEE promoted an inhibition of NF-κB pathway.
PEE from C. lineatifolia leaves demonstrated significant anti-inflammatory activity that may be related to the traditional use to treat gastrointestinal disorders.
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•C. lineatifolia is a medicinal plant often used for gastrointestinal disorders.•Twelve new compounds were identified for the first time in the species.•Phenolic-rich extract and isolated flavonols exhibited anti-inflammatory activity.•Antiulcer mechanism may be associated with inhibition of the NF-κB/TNF-α pathway.
•LC-ESI-MS/MS method was developed for RN104 in mice plasma.•A preclinical pharmacokinetic study was performed in mice after p.o and i.p administration.•The p.o bioavailability in relation to the ...i.p. route was approximately 40%.•The overall obtained results are important for dose correction in future studies of RN104.
RN104, named 2-2-(cyclohexylmethylene)hydrazinyl)-4-phenylthiazole, is a thiazolyl hydrazone derivative with promising antifungal activity. Pharmacokinetic profile of the RN104 was evaluated in mice plasma using a developed and validated bioanalytical method by LC-MS/MS. Clotrimazole was used as internal standard. The analytes were extracted by a protein precipitation procedure and separated on a C18 end-capped column and mobile phase composed of acetonitrile – 0.1% formic acid (85:15, v/v), in isocratic mode. Electrospray ionization in positive ionization mode (ESI + ) and multiple reaction monitoring (MRM) were employed using the transitions m/z 286.1 → m/z 176.1 (quantifier) and m/z 286.1 → m/z 112.2 (qualifier) for RN104 and m/z 345.2 → m/z 277.1 (quantifier) and m/z 345.2 → m/z 165.2 (qualifier) for internal standard. The method was validated and proved to be linear, accurate, precise, and selective over the range 0.625 to 40.0 ng/mL. The pharmacokinetic model that best fit the data was the bicompartmental model. The maximum plasmatic concentration was reached 20 min after administration (per os and intraperitoneal) and the highest plasma concentration of RN104 was found after per os administration at a dosage of 50 mg/kg compared to i.p. administration at 10 mg/kg.
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Paclitaxel (PTX) has a great clinical significance as an antitumor drug, although several side effects are strongly dose-limiting. In this way, we prepared a PTX-loaded ...1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (polyethylene glycol)-2000 polymeric micelles (PM/PTX) in an attempt to improve safety and effectiveness of conventional PTX formulation (CrEL/EtOH/PTX). In this study, we evaluated from both formulations: stability after dilution, hemocompatibility, cellular uptake, acute toxicity in healthy mice, antitumor activity, and toxicity after multiple-dose treatment. PM/PTX appeared to be more stable than CrEL/EtOH/PTX after dilution. PM/PTX did not exhibit hemolytic activity (values <1%), even at high concentrations. In vitro cellular uptake study indicated that polymeric micelles were able to deliver more PTX (5.8 %) than CrEL/EtOH (2.7 %) to 4T1 cells. In the acute toxicity evaluation in healthy mice, CrEL/EtOH/PTX (single dose of 20 mg/kg) induced peripheral neuropathy, which was not observed in PM/PTX group. Similar results were observed after tumor-bearing mice received a multiple-dose regimen (seven doses of 10 mg/kg). Worth mentioning, we also evaluated vehicles, and CrEL/EtOH alone was not capable of inducing neuropathic pain. Besides, PM/PTX exhibited a higher antitumor activity with an inhibition ratio approximately 1.5-fold higher than CrEL/EtOH/PTX group. This study suggested that PM/PTX is safer than CrEL/EtOH/PTX, and was able to improve the antitumor effectiveness in a 4T1 breast cancer model.
•A LC-ESI-MS/MS method was developed for the quantification of kavain in mice plasma.•This simple and fast method was fully validated according to regulatory guidelines.•Isotopically labeled kavain ...was used as internal standard for the developed method.•Pharmacokinetic profiles of kavain isolated and in kava-kava extract were compared.•Higher bioavailability for kavain present in the extract was observed due to pharmacokinetic synergism.
A simple and fast bioanalytical method for the quantification of kavain in mice plasma was developed using liquid chromatography (LC)-tandem mass spectrometry (MS/MS). A full method validation was performed, according to regulatory guidelines, employing isotopically labeled kavain as the internal standard (racemic-kavain-d3). For the quantification, M+H+ was formed using an electrospray ionization (ESI) source in the positive ion mode and multiple reaction monitoring (MRM) was employed using a quadrupole-linear ion trap (4000 QTRAP®) instrument. The monitored MRM transitions were 231.0 → 115.1 and 231.0 → 152.8 for kavain; and 234.2 → 199.2 for the internal standard. A linear response was obtained at the concentration range of 10 to 200 ng/mL with intra- and inter-day variations within the acceptable criteria for all quality control samples. After validation, the method was successfully applied for the quantification of kavain in mice plasma after oral administration of the kavain standard and Kava-kava extract. The plasma concentration over time results were applied for a pharmacokinetics study. The obtained pharmacokinetic parameters indicated a considerably higher bioavailability for kavain when Kava-kava extract was administered due to a pharmacokinetic synergism between the analyte and the other compounds present in the extract.
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•Nitrooxy compound 1 (NC1) potentially releases nitric oxide.•Plasma nitrite concentration was increased after administration of NC1.•NC1 inhibited the tactile hypersensitivity and ...paw edema in mice.•NC1 reduced neutrophil recruitment and IL-6, IL-1β, TNF-α and CXCL-1 concentrations.•NC1 increased the production of IL-10.
Considering the many biological activities of nitric oxide (NO), some lines of research focused on the modulation of these activities through the provision of this mediator by designing and synthesizing compounds coupled with an NO donor group. Thus, the objectives of the present study were to carry out an electrochemical investigation of the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid (1) and evaluate its activities and putative mechanisms in experimental models of pain and inflammation. Voltammetric studies performed in aprotic medium (mimetic of membranes) showed important electrochemical reduction mechanisms: nitroaromatic reduction, self-protonation, and finally reductive elimination, which leads to nitrate release. Systemic administration of the nitrooxy compound (1) inhibited the nociceptive response induced by heat and the tactile hypersensitivity and paw edema induced by carrageenan in mice. The activities in the models of inflammatory pain and edema were associated with reduced neutrophil recruitment and production of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α and CXCL-1, and increased production of IL-10. Concluding, electrochemical analysis revealed unequivocally that electron transfer at the nitro group of the nitrooxy compound (1) results in the cleavage of the organic nitrate, potentially resulting in the generation of NO. This electrochemical mechanism may be compared to a biochemical electron-transfer mediated nitrate release that, by appropriate in vivo bioreduction (enzymatic or not) would lead to NO production. Compound (1) exhibits activities in models of inflammatory pain and edema that may be due to reduced recruitment of neutrophils and production of inflammatory cytokines and increased production of IL-10. These results reinforce the interest in the investigation of NO donor compounds as candidates for analgesic and anti-inflammatory drugs.
The gasotransmitter hydrogen sulfide (H2S) is known to regulate many pathophysiological processes. Preclinical assays have demonstrated that H2S donors exhibit anti-inflammatory and antinociceptive ...activities, characterized by reduction of inflammatory mediators production, leukocytes recruitment, edema and mechanical allodynia. In the present study, the effects induced by 4-methylbenzenecarbothioamide (4-MBC) in models of pain and inflammation in mice, the mechanisms mediating such effects and the H2S-releasing property of this compound were evaluated. 4-MBC spontaneously released H2S in vitro in the absence of organic thiols. Intraperitoneal (i.p.) administration of 4-MBC (100 or 150 mg/kg) reduced the second phase of the nociceptive response induced by formaldehyde and induced a long lasting inhibitory effect on carrageenan mechanical allodynia. 4-MBC antiallodynic effect was not affected by previous administration of naltrexone or glibenclamide. 4-MBC (50, 100 or 150 mg/kg, i.p.) induced a long lasting inhibitory effect on paw edema induced by carrageenan. The highest dose (150 mg/kg, i.p.) of 4-MBC inhibited tumor necrosis factor-α and CXCL1 production and myeloperoxidase activity induced by carrageenan. Mechanical allodynia and paw edema induced by carrageenan were not inhibited by the 4-MBC oxo analogue (p-toluamide). In summary, 4-MBC, an H2S releasing thiobenzamide, exhibits antinociceptive and anti-inflammatory activities. These activities may be due to reduced cytokine and chemokine production and neutrophil recruitment. The H2S releasing property is likely essential for 4-MBC activity. Our results indicate that 4-MBC may represent a useful pharmacological tool to investigate the biological roles of H2S.
Curcumin and its analogues exhibited anti-inflammatory activity in different experimental models. Recently, we synthesized (2
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...)-3-buten-2-one-4-(4-hydroxy-3-methoxyphenyl)-2-(4-(4-methoxyphenyl)-2-thiazolyl)hydrazone (RI75), a curcumin analogue with a thiazolyl hydrazone moiety. In the present study, we investigated the effects induced by RI75 in different models of inflammation and pain in mice, as well as some underlying mechanisms. Pre-treatment with RI75 (40 mg/kg, intraperitoneal; i.p.) or curcumin (40 mg/kg, i.p.) reduced the mechanical allodynia and paw edema induced by intraplantar (i.pl) injection of carrageenan. RI75 antiallodynic activity was reduced by pre-treatment with naltrexone (5 and 10 mg/kg, i.p.) and cyproheptadine (10 mg/kg, i.p.), but not glibenclamide (20 and 40 mg/kg, i.p.). In a model of neuropathic pain, a single i.p. administration of RI75 (40 mg/kg) or curcumin (40 mg/kg) attenuated the ongoing mechanical allodynia induced by repeated administrations of paclitaxel. Pre-treatment with RI75 (40 mg/kg, i.p.) or curcumin (40 mg/kg, i.p.) also reduced tumor necrosis factor-α and interleukin-6 production and myeloperoxidase activity induced by carrageenan. The results of the present study demonstrate that RI75, a synthetic curcumin analogue, exhibits antiallodynic and antiedematogenic activities. Activation of opioidergic and serotonergic mechanisms and reduced production of inflammatory mediators and neutrophil recruitment may underlie RI75 activities.
The aim of this study was to evaluate the involvement of TNF-α and insulin resistance (IR) in the inflammatory process, oxidative stress, and disease activity in patients with rheumatoid arthritis ...(RA). This cross-sectional study included 270 subjects (control group, n = 97 ) and RA patients ( n = 173 ). RA patients were divided into four groups: the first group without IR and not using antitumor necrosis factor-α ( T N F - ) (G1, IR− TNF−); the second group without IR and using anti-TNF-α (G2, I R - TNF+); the third group with IR and not using anti-TNF-α (G3, IR+ T N F - ); and the fourth group with IR and using anti-TNF-α (G4, IR+ TNF+). G3 and G4 had higher ( p < 0.05 ) advanced oxidation protein products (AOPPs) and oxidative stress index (OSI) compared to G1. G4 group presented higher ( p < 0.05 ) AOPPs and OSI than G2. TRAP was significantly lower in G3 compared to G1. Plasma TNF-α levels were significantly higher in G4 and G2 compared to G1 ( p < 0.0001 ) and G3 ( p < 0.0001 and p < 0.01 , resp.). The presence of insulin resistance was robustly associated with both oxidative stress and TNF-α levels. More studies are warranted to verify if IR can be involved in therapeutic failure with TNF-α inhibitors. This trial is registered with Brazilian Clinical Trials Registry Register number RBR-2jvj92.
The aim of this study was to evaluate the involvement of TNF-α and insulin resistance (IR) in the inflammatory process, oxidative stress, and disease activity in patients with rheumatoid arthritis ...(RA). This cross-sectional study included 270 subjects (control group, n = 97 ) and RA patients ( n = 173 ). RA patients were divided into four groups: the first group without IR and not using antitumor necrosis factor-α ( T N F - ) (G1, IR- TNF-); the second group without IR and using anti-TNF-α (G2, I R - TNF+); the third group with IR and not using anti-TNF-α (G3, IR+ T N F - ); and the fourth group with IR and using anti-TNF-α (G4, IR+ TNF+). G3 and G4 had higher ( p < 0.05 ) advanced oxidation protein products (AOPPs) and oxidative stress index (OSI) compared to G1. G4 group presented higher ( p < 0.05 ) AOPPs and OSI than G2. TRAP was significantly lower in G3 compared to G1. Plasma TNF-α levels were significantly higher in G4 and G2 compared to G1 ( p < 0.0001 ) and G3 ( p < 0.0001 and p < 0.01 , resp.). The presence of insulin resistance was robustly associated with both oxidative stress and TNF-α levels. More studies are warranted to verify if IR can be involved in therapeutic failure with TNF-α inhibitors. This trial is registered with Brazilian Clinical Trials Registry Register number RBR-2jvj92.
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