RESUMO
The research about α-methylene-γ-lactams is scarce; however, their synthesis has emerged in recent years mainly because they are isosters of α-methylene-γ-lactones. This last kind of compound is structurally most common in some natural products' nuclei, like sesquiterpene lactones that show biological activity such as anti-inflammatory, anticancer, antibacterial, etc., effects. In this work, seven α-methylene-γ-lactams were evaluated by their inflammation and α-glucosidase inhibition. Thus, compounds 3-methylene-4-phenylpyrrolidin-2-one (1), 3-methylene-4-(p-tolyl)pyrrolidin-2-one (2), 4-(4-chlorophenyl)-3-methylenepyrrolidin-2-one (3), 4-(2-chlorophenyl)-3-methylenepyrrolidin-2-one (4), 5-ethyl-3-methylene-4-phenylpyrrolidin-2-one (5), 5-ethyl-3-methylene-4-(p-tolyl)pyrrolidin-2-one (6) and 4-(4-chlorophenyl)-5-ethyl-3-methylenepyrrolidin-2-one (7) were evaluated via in vitro α-glucosidase assay at 1 mM concentration. From this analysis, 7 exerts the best inhibitory effect on α-glucosidase compared with the vehicle, but it shows a low potency compared with the reference drug at the same dose. On the other side, inflammation edema was induced using TPA (12-O-tetradecanoylphorbol 13-acetate) on mouse ears; compounds 1-7 were tested at 10 µg/ear dose. As a result, 1, 3, and 5 show a better inhibition than indomethacin, at the same doses. This is a preliminary report about the biological activity of these new α-methylene-γ-lactams.
Assuntos
Anti-Inflamatórios, Inibidores de Glicosídeo Hidrolases, Lactamas, alfa-Glucosidases, Inibidores de Glicosídeo Hidrolases/farmacologia, Inibidores de Glicosídeo Hidrolases/química, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/química, Lactamas/química, Lactamas/farmacologia, Animais, alfa-Glucosidases/metabolismo, Simulação de Acoplamento Molecular, Camundongos, Relação Estrutura-Atividade, Simulação por Computador, Edema/tratamento farmacológico, Edema/induzido quimicamente, Estrutura MolecularRESUMO
A woman in her 70s presented with anasarca and exertional dyspnoea. Investigation showed severe hypoalbuminaemia with no urinary or gastrointestinal protein losses. CT thorax reported lung consolidations, and transbronchial lung biopsy demonstrated organising pneumonia. Autoimmune myositis serology was positive for anti-Jo-1, anti-Ro-52, and anti-PM/Scl-100 antibodies. She was diagnosed with anti-synthetase syndrome with organising pneumonia. She was treated with oral prednisolone and oral mycophenolate mofetil with a good clinical response.
Assuntos
Edema, Miosite, Humanos, Feminino, Miosite/tratamento farmacológico, Miosite/diagnóstico, Miosite/complicações, Miosite/imunologia, Idoso, Edema/tratamento farmacológico, Edema/etiologia, Prednisolona/uso terapêutico, Prednisolona/administração & dosagem, Ácido Micofenólico/uso terapêutico, Tomografia Computadorizada por Raios X, Pneumonia/tratamento farmacológico, Pneumonia/diagnóstico, Dispneia/etiologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Syagrus coronata, a palm tree found in northeastern Brazil, popularly known as licuri, has socioeconomic importance for the production of vegetable oil rich in fatty acids with nutritional and pharmacological effects. Licuri oil is used in traditional medicine to treat inflammation, wound healing, mycosis, back discomfort, eye irritation, and other conditions. AIM OF THE STUDY: The study aimed to evaluate the antinociceptive, anti-inflammatory, and antipyretic effects of treatment with Syagrus coronata fixed oil (ScFO), as well as to determine the safety of use in mice. MATERIALS AND METHODS: Initially, the chemical characterization was performed by gas chromatography-mass spectrometry. Acute single-dose oral toxicity was evaluated in mice at a dose of 2000 mg/kg. Antinociceptive activity was evaluated through abdominal writhing, formalin, and tail dipping tests, and the anti-inflammatory potential was evaluated through the model of acute inflammation of ear edema, peritonitis, and fever at concentrations of 25, 50, and 100 mg/kg from ScFO. RESULTS: In the chemical analysis of ScFO, lauric (43.64%), caprylic (11.7%), and capric (7.2%) acids were detected as major. No mortality or behavioral abnormalities in the mice were evidenced over the 14 days of observation in the acute toxicity test. ScFO treatment decreased abdominal writhing by 27.07, 28.23, and 51.78% at 25, 50, and 100 mg/kg. ScFO demonstrated central and peripheral action in the formalin test, possibly via opioidergic and muscarinic systems. In the tail dipping test, ScFO showed action from the first hour after treatment at all concentrations. ScFO (100 mg/kg) reduced ear edema by 63.76% and leukocyte and neutrophil migration and IL-1ß and TNF-α production in the peritonitis test. CONCLUSION: Mice treated with ScFO had a reduction in fever after 60 min at all concentrations regardless of dose. Therefore, the fixed oil of S. coronata has the potential for the development of new pharmaceutical formulations for the treatment of pain, inflammation, and fever.
Assuntos
Analgésicos, Anti-Inflamatórios, Edema, Óleos de Plantas, Animais, Analgésicos/farmacologia, Analgésicos/isolamento & purificação, Analgésicos/toxicidade, Camundongos, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/isolamento & purificação, Óleos de Plantas/farmacologia, Masculino, Edema/tratamento farmacológico, Edema/induzido quimicamente, Dor/tratamento farmacológico, Peritonite/tratamento farmacológico, Antipiréticos/farmacologia, Arecaceae/química, Feminino, Inflamação/tratamento farmacológico, Inflamação/induzido quimicamente, Febre/tratamento farmacológico, Febre/induzido quimicamente, Administração Oral, Modelos Animais de DoençasRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Chromolaenaodorata (L.) R.M. King & H. Rob, a perennial herb, has been traditionally utilized as a herbal remedy for treating leech bites, soft tissue wounds, burn wounds, skin infections, and dento-alveolitis in tropical and subtropical regions. AIM OF THE STUDY: The present study was to analyze the active fraction of C. odorata ethanol extract and investigate its hemostatic, anti-inflammatory, wound healing, and antimicrobial properties. Additionally, the safety of the active fraction as an external preparation was assessed through skin irritation and allergy tests. MATERIALS AND METHODS: The leaves and stems of C. odorata were initially extracted with ethanol, followed by purification through AB-8 macroporous adsorption resin column chromatography to yield different fractions. These fractions were then screened for hemostatic activity in mice and rabbits to identify the active fraction. Subsequently, the hemostatic effect of the active fraction was assessed through the bleeding time of the rabbit ear artery in vivo and the coagulant time of rabbit blood in vitro. The anti-inflammatory activity of the active fraction was tested on mice ear edema induced by xylene and rat paw edema induced by carrageenin. Furthermore, the active fraction's promotion effect on wound healing was evaluated using a rat skin injury model, and skin safety tests were conducted on rabbits and guinea pigs. Lastly, antimicrobial activities against two Gram-positive bacteria (G+, Staphylococcus aureus and S. epidermidis) and three Gram-negative bacteria (G-, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) were determined using the plate dilution method. RESULTS: The ethanol extract of C. odorata leaves and stems was fractionated into 30%, 60%, and 90% ethanol eluate fractions. These fractions demonstrated hemostatic activity, with the 30% ethanol eluate fraction (30% EEF) showing the strongest effect, significantly reducing bleeding time (P < 0.05). A concentration of 1.0 g/mL of the 30% EEF accelerated cutaneous wound healing in rats on the 3rd, 6th, and 9th day post-operation, with the healing effect increasing over time. No irritation or allergy reactions were observed in rabbits and guinea pigs exposed to the 30% EEF. Additionally, the 30% EEF exhibited mild inhibitory effect on mice ear and rat paw edema, as well as antimicrobial activity against tested bacteria, with varying minimal inhibitory concentration (MIC) values. CONCLUSIONS: The 30% EEF demonstrated a clear hemostatic effect on rabbit bleeding time, a slight inhibitory effect on mice ear edema and rat paw edema, significant wound healing activity in rats, and no observed irritation or allergic reactions. Antibacterial activity was observed against certain clinically isolated bacteria, particularly the G- bacteria. This study lays the groundwork for the potential development and application of C. odorata in wound treatment.
Assuntos
Anti-Inflamatórios, Chromolaena, Edema, Etanol, Hemostáticos, Extratos Vegetais, Cicatrização, Animais, Coelhos, Cicatrização/efeitos dos fármacos, Extratos Vegetais/farmacologia, Extratos Vegetais/química, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/isolamento & purificação, Camundongos, Masculino, Hemostáticos/farmacologia, Etanol/química, Chromolaena/química, Edema/tratamento farmacológico, Edema/induzido quimicamente, Ratos, Pele/efeitos dos fármacos, Feminino, Anti-Infecciosos/farmacologia, Anti-Infecciosos/isolamento & purificação, Folhas de Planta/química, Hipersensibilidade/tratamento farmacológico, Xilenos, Caules de Planta/químicaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Herbs of the genus Juniperus (family Cupressaceae) have been commonly used in ancestral folk medicine known as "Al'Araar" for treatment of rheumatism, diabetes, inflammation, pain, and fever. Bioassay-guided isolation of bioactives from medicinal plants is recognized as a potential approach for the discovery of novel drug candidates. In particular, non-addictive painkillers are of special interest among herbal phytochemicals. AIM OF THE STUDY: The current study aimed to assess the safety of J. thurifera, J. phoenicea, and J. oxycedrus aqueous extracts in oral treatments; validating the traditionally reported anti-inï¬ammatory and analgesic effects. Further phytochemical investigations, especially for the most bioactive species, may lead to isolation of bioactive metabolites responsible for such bioactivities supported with in vitro enzyme inhibition assays. MATERIALS AND METHODS: Firstly, the acute toxicity study was investigated following the OECD Guidelines. Then, the antinociceptive, and anti-inflammatory bioactivities were evaluated based on chemical and mechanical trauma assays and investigated their underlying mechanisms. The most active J. thurifera n-butanol fraction was subjected to chromatographic studies for isolating the major anti-inflammatory metabolites. Moreover, several enzymatic inhibition assays (e.g., 5-lipoxygenase, protease, elastase, collagenase, and tyrosinase) were assessed for the crude extracts and isolated compounds. RESULTS: The results showed that acute oral administration of the extracts (300-500 mg/kg, p. o.) inhibited both mechanically and chemically triggered inflammatory edema in mice (up to 70% in case of J. thurifera) with a dose-dependent antinociceptive (tail flick) and anti-inflammatory pain (formalin assay) activities. This effect was partially mediated by naloxone inhibition of the opioid receptor (2 mg/kg, i. p.). In addition, 3-methoxy gallic acid (1), quercetin (2), kaempferol (3), and ellagic acid (4) were successfully identified being involved most likely in J. thurifera extract bioactivities. Nevertheless, quercetin was found to be the most potent against 5-LOX, tyrosinase, and protease with IC50 of 1.52 ± 0.01, 192.90 ± 6.20, and 399 ± 9.05 µM, respectively. CONCLUSION: J. thurifera extract with its major metabolites are prospective drug candidates for inflammatory pain supported with inhibition of inflammatory enzymes. Interestingly, antagonism of opioid and non-opioid receptors is potentially involved.
Assuntos
Analgésicos, Anti-Inflamatórios, Juniperus, Extratos Vegetais, Folhas de Planta, Animais, Extratos Vegetais/farmacologia, Extratos Vegetais/química, Juniperus/química, Analgésicos/farmacologia, Analgésicos/química, Analgésicos/isolamento & purificação, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/isolamento & purificação, Camundongos, Masculino, Folhas de Planta/química, Marrocos, Feminino, Dor/tratamento farmacológico, Inibidores Enzimáticos/farmacologia, Inibidores Enzimáticos/isolamento & purificação, Bioensaio, Edema/tratamento farmacológico, Edema/induzido quimicamente, Inflamação/tratamento farmacológicoRESUMO
Cyclooxygenase-2 plays a vital role in inflammation by catalyzing arachidonic acid conversion toward prostaglandins, making it a prime therapeutic objective. Selective COX-2 inhibitors represent significant progress in anti-inflammatory therapy, offering improved efficacy and fewer side effects. This study describes the synthesis of novel anti-inflammatory compounds from established pharmaceutically marketed agents like fenamates III-V and ibuprofen VI. Through rigorous in vitro testing, compounds 7b-c, and 12a-b demonstrated substantial in vitro selective inhibition, with IC50 values of 0.07 to 0.09 µM, indicating potent pharmacological activity. In vivo assessment, particularly focusing on compound 7c, revealed significant anti-inflammatory effects. Markedly, it demonstrated the highest inhibition of paw thickness (58.62 %) at the 5-hr mark compared to the carrageenan group, indicating its potency in mitigating inflammation. Furthermore, it exhibited a rapid onset of action, with a 54.88 % inhibition observed at the 1-hr mark. Subsequent comprehensive evaluations encompassing analgesic efficacy, histological characteristics, and toxicological properties indicated that compound 7c did not induce gastric ulcers, in contrast to the ulcerogenic tendency associated with mefenamic acid. Moreover, compound 7c underwent additional investigations through in silico methodologies such as molecular modelling, field alignment, and density functional theory. These analyses underscored the therapeutic potential and safety profile of this novel compound, warranting further exploration and development in the realm of pharmaceutical research.
Assuntos
Anti-Inflamatórios não Esteroides, Carragenina, Inibidores de Ciclo-Oxigenase 2, Ciclo-Oxigenase 2, Fenamatos, Ibuprofeno, Ibuprofeno/farmacologia, Ibuprofeno/química, Ibuprofeno/síntese química, Ciclo-Oxigenase 2/metabolismo, Animais, Inibidores de Ciclo-Oxigenase 2/farmacologia, Inibidores de Ciclo-Oxigenase 2/síntese química, Inibidores de Ciclo-Oxigenase 2/química, Estrutura Molecular, Anti-Inflamatórios não Esteroides/farmacologia, Anti-Inflamatórios não Esteroides/química, Anti-Inflamatórios não Esteroides/síntese química, Relação Estrutura-Atividade, Fenamatos/farmacologia, Fenamatos/química, Fenamatos/síntese química, Relação Dose-Resposta a Droga, Humanos, Camundongos, Edema/tratamento farmacológico, Edema/induzido quimicamente, Simulação de Acoplamento Molecular, Ratos, MasculinoRESUMO
Callicarpa kwangtungensis Chun (CK) is a common remedy exhibits anti-inflammatory properties and has been used in Chinese herbal formulations, such as KangGongYan tablets. It is the main component of KangGongYan tablets, which has been used to treat chronic cervicitis caused by damp heat, red and white bands, cervical erosion, and bleeding. However, the anti-inflammatory effects of CK water extract remains unknown. This study assessed the anti-inflammatory effects of CK in vivo and in vitro, characterized its main components in the serum of rats and verified the anti-inflammatory effects of serum containing CK. Nitric oxide (NO), tumour necrosis factor α (TNF-α) and interleukin-6 (IL-6) release by RAW264.7 cells was examined by ELISA and Griess reagents. Inflammation-related protein expression in LPS-stimulated RAW264.7 cells was measured by western blotting. Furthermore, rat model of foot swelling induced by λ-carrageenan and a collagen-induced arthritis (CIA) rat model were used to explore the anti-inflammatory effects of CK. The components of CK were characterized by LC-MS, and the effects of CK-containing serum on proinflammatory factors levels and the expression of inflammation-related proteins were examined by ELISA, Griess reagents and Western blotting. CK suppressed IL-6, TNF-α, and NO production, and iNOS protein expression in LPS-stimulated RAW264.7 cells. Mechanistic studies showed that CK inhibited the phosphorylation of ERK, P38 and JNK in the MAPK signaling pathway, promoted the expression of IκBα in the NF-κB signaling pathway, and subsequently inhibited the expression of iNOS, thereby exerting anti-inflammatory effects. Moreover, CK reduced the swelling rates with λ-carrageenan induced foot swelling, and reduced the arthritis score and incidence in the collagen-induced arthritis (CIA) rat model. A total of 68 compounds in CK water extract and 31 components in rat serum after intragastric administration of CK were characterized. Serum pharmacological analysis showed that CK-containing serum suppressed iNOS protein expression and NO, TNF-α, and IL-6 release. CK may be an anti-inflammatory agent with therapeutic potential for acute and chronic inflammatory diseases, especially inflammatory diseases associated with MAPK activation.
Assuntos
Anti-Inflamatórios, Artrite Experimental, Óxido Nítrico, Extratos Vegetais, Animais, Camundongos, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/química, Ratos, Células RAW 264.7, Extratos Vegetais/farmacologia, Extratos Vegetais/química, Óxido Nítrico/metabolismo, Artrite Experimental/tratamento farmacológico, Água/química, Carragenina, Modelos Animais de Doenças, Fator de Necrose Tumoral alfa/metabolismo, Fator de Necrose Tumoral alfa/sangue, Masculino, Interleucina-6/metabolismo, Interleucina-6/sangue, Edema/tratamento farmacológico, Inflamação/tratamento farmacológicoRESUMO
Extracts from medicinal plants are widely used in the treatment and prevention of different diseases. Micromeria frivaldszkyana is a Balkan endemic species with reported antioxidant and antimicrobial characteristics; however, its phytochemical composition is not well defined. Here, we examined the metabolome of M. frivaldszkyana by chromatography-mass spectrometry (GC-MS), ultra-performance liquid chromatography-mass spectrometry (UPLC-MS-MS), and inductively coupled plasma mass spectrometry (ICP-MS). Amino acids, organic acids, sugars, and sugar alcohols were the primary metabolites with the highest levels in the plant extract. Detailed analysis of the sugar content identified high levels of sucrose, glucose, mannose, and fructose. Lipids are primary plant metabolites, and the analysis revealed triacylglycerols as the most abundant lipid group. Potassium (K), magnesium (Mg), zinc (Zn), and calcium (Ca) were the elements with the highest content. The results showed linarin, 3-caffeoil-quinic acid, and rosmarinic acid, as well as a number of polyphenols, as the most abundant secondary metabolites. Among the flavonoids and polyphenols with a high presence were eupatorin, kaempferol, and apigenin-compounds widely known for their bioactive properties. Further, the acute toxicity and potential anti-inflammatory activity of the methanolic extract were evaluated in Wistar rats. No toxic effects were registered after a single oral application of the extract in doses of between 200 and 5000 mg/kg bw. A fourteen-day pre-treatment with methanolic extract of M. frivaldszkyana in doses of 250, 400, and 500 mg/kg bw induced anti-inflammatory activity in the 1st, 2nd, and 3rd hours after carrageenan injection in a model of rat paw edema. This effect was also present in the 4th hour only in the group treated with a dose of 500 mg/kg. In conclusion, M. frivaldszkyana extract is particularly rich in linarin, rosmarinic acid, and flavonoids (eupatorin, kaempferol, and apigenin). Its methanolic extract induced no toxicity in male Wistar rats after oral application in doses of up to 5000 mg/kg bw. Additionally, treatment with the methanolic extract for 14 days revealed anti-inflammatory potential in a model of rat paw edema on the 1st, 2nd, and 3rd hours after the carrageenan injection. These results show the anti-inflammatory potential of the plant, which might be considered for further exploration and eventual application as a phytotherapeutic agent.
Assuntos
Anti-Inflamatórios, Extratos Vegetais, Ratos Wistar, Animais, Extratos Vegetais/farmacologia, Extratos Vegetais/química, Masculino, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/química, Ratos, Metanol/química, Edema/tratamento farmacológico, Edema/induzido quimicamente, Sapotaceae/química, Metaboloma/efeitos dos fármacosRESUMO
Most of pharmaceutical agents display a number of biological activities. It is obvious that testing even one compound for thousands of biological activities is not practically possible. A computer-aided prediction is therefore the method of choice in this case to select the most promising bioassays for particular compounds. Using the PASS Online software, we determined the probable anti-inflammatory action of the 12 new hybrid dithioloquinolinethiones derivatives. Chemical similarity search in the World-Wide Approved Drugs (WWAD) and DrugBank databases did not reveal close structural analogues with the anti-inflammatory action. Experimental testing of anti-inflammatory activity of the synthesized compounds in the carrageenan-induced inflammation mouse model confirmed the computational predictions. The anti-inflammatory activity of the studied compounds (2a, 3a-3k except for 3j) varied between 52.97% and 68.74%, being higher than the reference drug indomethacin (47%). The most active compounds appeared to be 3h (68.74%), 3k (66.91%) and 3b (63.74%) followed by 3e (61.50%). Thus, based on the in silico predictions a novel class of anti-inflammatory agents was discovered.
Assuntos
Anti-Inflamatórios, Carragenina, Relação Quantitativa Estrutura-Atividade, Quinolinas, Animais, Camundongos, Anti-Inflamatórios/química, Anti-Inflamatórios/farmacologia, Quinolinas/química, Quinolinas/farmacologia, Inflamação/tratamento farmacológico, Inflamação/induzido quimicamente, Tionas/química, Tionas/farmacologia, Masculino, Edema/tratamento farmacológico, Edema/induzido quimicamenteRESUMO
A variety of novel indole-derived γ-hydroxy propiolate esters were designed, synthesized, and evaluated for their anti-inflammatory activity in-vitro and in-vivo. According to the nitric oxide (NO) inhibitory analysis, all compounds showed potent NO inhibitory ability in a dose-dependent manner, with no apparent cytotoxicity. The model compound, L-37, also exhibited significant potency in PGE2 inhibition. In addition, compounds L-37 and L-39 can downregulate the expression of COX-2 enzyme at 5 µM via ELISA experiment. Compound L-37 (1 µM) also inhibited the PGF1 production as well as the expression of COX-1, but displayed weak inhibition activity towards the Leukotrienes (LT) and Thromboxane-B2 (TXB-2) production. However, the expression of 5-LOX was significantly inhibited by compound L-39 at 5 µM. Xylene-induced ear edema model was explored for in-vivo anti-inflammatory evaluation, compound L-37 showed similar inhibitory activity compared with celecoxib, approximately 80% at 50 mg/kg dosage. Every outcome showed that the newly synthesized compounds can effectively inhibit inflammation.
Assuntos
Anti-Inflamatórios não Esteroides, Anti-Inflamatórios, Humanos, Anti-Inflamatórios/efeitos adversos, Celecoxib, Ciclo-Oxigenase 2/metabolismo, Indóis, Edema/induzido quimicamente, Edema/tratamento farmacológico, Simulação de Acoplamento Molecular, Inibidores de Ciclo-Oxigenase 2/farmacologia, Relação Estrutura-AtividadeRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Atractylis aristata batt., as an endemic plant from the Asteraceae family, holds a significant position in the Ahaggar region of southern Algeria's traditional medicine. The aerial parts of Atractylis aristata was used to cure inflammation, fever, and stomach disorders. AIM OF THE STUDY: The objective of the present investigation was to ascertain the overall bioactive components and phytochemical components and examine the antioxidant, antidiabetic, anti-inflammatory, acute toxicity, and sedative properties of the crude extract obtained from the aerial portions of Atractylis aristata (AaME). MATERIALS AND METHODS: The AaME's antioxidant activity was assessed by the use of pyrogallol autoxidation, (1,1 diphenyl-2-picrylhydrazyl) (DPPH), 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and reducing power (RP) techniques. 1 mg/mL of AaME was used to evaluate the antidiabetic activity by applying the enzyme α-amylase inhibitory power test. At the same time, the bovine serum albumin (BSA) denaturation method was employed to quantify the in vitro anti-inflammatory activity at different concentrations (1.5625, 0.78125, 0.390625, 0.1953125 and 0.09765625 mg/mL). In contrast, following the Organization for Economic Co-operation and Development (OECD) guideline No. 423, which covers acute oral toxicity testing protocols, the limit dosage test was employed to assess in vivo acute toxicity. At the dose of 0.08 mg/mL, the carrageenan-induced paw edema approach was used to assess the anti-inflammatory efficacy in vivo, and the sedative activity was carried out at the dose of 0.08 mg/mL using the measurement of the locomotor method. Different bioactive compounds were identified within AaME using LC-MS/MS and HPLC-UV analysis. RESULTS: The acute toxicity study showed no fatalities or noticeable neurobehavioral consequences at the limit test; this led to their classification in Globally Harmonized System (GHS) category Five, as the OECD guideline No 423 recommended. At a concentration of 0.08 mg/mL (2000 mg/kg), AaME showed apparent inhibition of paw edema and a significant (p = 0.01227) reduction in locomotor activity compared to the control animals. Our findings showed that AaME exhibited considerable antioxidant (IC50 = 0.040 ± 0.003 mg/mL (DPPH), IC50 = 0.005 ± 5.77 × 10-5 mg/mL (ABTS), AEAC = 91.15 ± 3.921 mg (RP) and IR% = 23.81 ± 4.276 (Inhibition rate of pyrogallol) and rebuts antidiabetic activities (I% = 57.6241% ± 2.81772). Our findings revealed that the maximum percentage of BSA inhibition (70.84 ± 0.10%) was obtained at 1.562.5 mg/mL. Thus, the AaME phytochemical profile performed using phytochemical screening, HPLC-UV, and LC-MS/MS analysis demonstrated that A. aristata can be a valuable source of chemicals with biological activity for pharmaceutical manufacturers. CONCLUSION: The phytochemical profiling, determined through HPLC-UV and LC-MS/MS applications, reveals this plant's therapeutic value. The aerial parts of Atractylis aristata contain bioactive molecules such as gallic acid, ascorbic acid, and quercetin, contributing to its significant antioxidant capabilities. Furthermore, identifying alizarin, the active compound responsible for its anti-inflammatory properties, could provide evidence supporting the anti-inflammatory capabilities of this subspecies.
Assuntos
Anti-Inflamatórios, Antioxidantes, Hipnóticos e Sedativos, Hipoglicemiantes, Fenóis, Extratos Vegetais, Animais, Antioxidantes/farmacologia, Antioxidantes/isolamento & purificação, Antioxidantes/química, Hipoglicemiantes/farmacologia, Hipoglicemiantes/isolamento & purificação, Hipoglicemiantes/química, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/isolamento & purificação, Anti-Inflamatórios/química, Extratos Vegetais/farmacologia, Extratos Vegetais/química, Extratos Vegetais/toxicidade, Masculino, Fenóis/farmacologia, Fenóis/análise, Fenóis/isolamento & purificação, Hipnóticos e Sedativos/farmacologia, Hipnóticos e Sedativos/isolamento & purificação, Hipnóticos e Sedativos/toxicidade, Camundongos, Asteraceae/química, Ratos Wistar, Ratos, Edema/tratamento farmacológico, Edema/induzido quimicamente, Feminino, Componentes Aéreos da Planta/químicaRESUMO
Despite the high global prevalence, rheumatoid arthritis lacks a satisfactory treatment. Hence, the present study is undertaken to design and synthesize novel anti-inflammatory compounds. For this, quinoline and anthranilic acid, two medicinally-privileged moieties, were linked by pharmacophore hybridization, and following their computational assessments, three hybrids 5a-c were synthesized in good over all yields. The in vitro and in vivo anti-inflammatory potential of these hybrids was determined by anti-denaturation and anti-proteinase, and carrageenan-induced paw edema models. The computational studies of these hybrids revealed their drug-likeness, optimum pharmacokinetics, and less toxicity. Moreover, they demonstrated high binding affinity (-9.4 to -10.6 kcal mol-1) and suitable binding interactions for TNF-α, FLAP, and COX-II. A three-step synthetic route resulted in the hybrids 5a-c with 83-86% yield of final step. At 50 µg mL-1, the antiprotease and anti-denaturation activity of compound 5b was significantly higher than 5a and 5c. Furthermore, 5b significantly reduced the edema in the right paw of the rats that received carrageenan. The results of this study indicate the medicinal worth of the novel hybrids in treating inflammatory disorders such as rheumatoid arthritis.
Assuntos
Desenho de Fármacos, Edema, Simulação de Acoplamento Molecular, Quinolinas, ortoaminobenzoatos, Quinolinas/química, Quinolinas/farmacologia, Quinolinas/síntese química, Animais, Edema/tratamento farmacológico, Edema/induzido quimicamente, ortoaminobenzoatos/química, ortoaminobenzoatos/farmacologia, ortoaminobenzoatos/síntese química, Ratos, Carragenina, Masculino, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/química, Anti-Inflamatórios/síntese química, Estrutura Molecular, Ratos Wistar, Anti-Inflamatórios não Esteroides/química, Anti-Inflamatórios não Esteroides/farmacologia, Anti-Inflamatórios não Esteroides/síntese química, Relação Dose-Resposta a Droga, Relação Estrutura-Atividade, Ciclo-Oxigenase 2/metabolismo, Ciclo-Oxigenase 2/químicaRESUMO
Prolonged use of very commonly prescribed non-steroidal anti-inflammatory drugs (NSAIDs) is often associated with undesired side effects, including gastrointestinal ulcers due to the non-selective inhibition of cyclooxygenases. We describe the development of an inflammatory-stimuli-responsive turn-on fluorogenic theranostic prodrug DCF-HS for adjuvant drug delivery. Upon activation by reactive oxygen species (ROS), the prodrug releases diclofenac DCF (active drug) and the NIR fluorophore DCI-NH2 along with carbonyl sulfide (COS). The second activation of COS by the enzyme carbonic anhydrase (CA) generates hydrogen sulfide (H2S). The prodrug was conveniently synthesized using multi-step organic synthesis. The UV-Vis and fluorescence studies revealed the selective reactivity of DCF-HS towards ROS such as H2O2 in the aqueous phase and the desired uncaging of the drug DCF with turn-on NIR fluorescent reporter under physiological conditions. Furthermore, the release of fluorophore DCI-NH2 and drug DCF was confirmed using the reverse phase HPLC method. Compatibility of prodrug activation was studied next in the cellular medium. The prodrug DCF-HS was non-toxic in a representative cancer cell line (HeLa) and a macrophage cell line (RAW 264.7) up to 100 µM concentration, indicating its biocompatibility. The intracellular ROS-mediated activation of the prodrug with the release of NIR dye DCI-NH2 and H2S was investigated in HeLa cells using the H2S-selective probe WSP2. The anti-inflammatory activity of the active drug DCF from the prodrug DCF-HS was studied in the lipopolysaccharide (LPS)-induced macrophage cell line and compared to that of the parent drug DCF using western blot analysis and it was found that the active drug resulted in pronounced inhibition of COX-2 in a dose-dependent manner. Finally, the anti-inflammatory potential of the prodrug and the turn-on fluorescence were validated in the inflammation-induced Wister rat models.
Assuntos
Anti-Inflamatórios não Esteroides, Diclofenaco, Sulfeto de Hidrogênio, Pró-Fármacos, Pró-Fármacos/farmacologia, Pró-Fármacos/química, Pró-Fármacos/síntese química, Sulfeto de Hidrogênio/metabolismo, Animais, Humanos, Diclofenaco/farmacologia, Células HeLa, Anti-Inflamatórios não Esteroides/farmacologia, Anti-Inflamatórios não Esteroides/química, Anti-Inflamatórios não Esteroides/síntese química, Ratos, Nanomedicina Teranóstica, Inflamação/tratamento farmacológico, Corantes Fluorescentes/química, Corantes Fluorescentes/farmacologia, Corantes Fluorescentes/síntese química, Camundongos, Células RAW 264.7, Sistemas de Liberação de Medicamentos, Edema/tratamento farmacológico, Edema/induzido quimicamenteRESUMO
OBJECTIVE: Tolvaptan is a vasopressin V2 receptor antagonist that is commonly prescribed to alleviate edema associated with renal diseases. However, the clinical benefits of tolvaptan in chronic kidney disease (CKD) remain unclear. This study aimed to evaluate the effectiveness of tolvaptan in managing edema caused by CKD. MATERIALS AND METHODS: The efficacy and treatment regimen of tolvaptan were assessed in a cohort of 96 patients with renal edema and CKD. During the treatment, the patients' creatinine (CR), uric acid (UA), and estimated glomerular filtration rate (eGFR) were monitored as important indicators of kidney function. Coagulation-associated molecules including fibrinogen, D-dimer, and fibrin degradation products (FDPs) were measured. Electrolyte disorders and acute kidney injury were closely monitored. Tolvaptan was administered at a daily dose of 7.5 mg, and 30 mg of edoxaban was administered to manage deep vein thrombosis. RESULTS: During the course of tolvaptan therapy, the eGFR of the patients was not declined. Edema was eliminated in 82.18% of patients. Proteinuria was reduced in the patients (p < 0.05). There were no significant changes in serum sodium levels throughout treatment, and no significant difference was observed in blood volume between the end of treatment and baseline levels. Importantly, acute kidney injury did not occur, and renal edema and deep vein thrombosis were successfully treated. CONCLUSION: As long as a rational treatment regimen is followed, tolvaptan is a safe and effective diuretic for treating edema in CKD, even in the late stages of CKD without reducing residual renal function in the patients.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos, Edema, Taxa de Filtração Glomerular, Insuficiência Renal Crônica, Tolvaptan, Humanos, Tolvaptan/uso terapêutico, Masculino, Feminino, Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico, Pessoa de Meia-Idade, Insuficiência Renal Crônica/complicações, Insuficiência Renal Crônica/tratamento farmacológico, Idoso, Taxa de Filtração Glomerular/efeitos dos fármacos, Edema/tratamento farmacológico, Edema/etiologia, Resultado do Tratamento, Adulto, Creatinina/sangue, Benzazepinas/uso terapêuticoRESUMO
Inflammation is crucial to osteoarthritis (OA) pathogenesis. The aim of this study was to evaluate Siraitia grosvenorii residue extract (NHGRE) obtained by extracting S. grosvenorii fruits with water as a potential food supplement for treating arthritis based on its analgesic, anti-inflammatory, and chondroprotective effects and the remaining residue with 70% ethanol. We observed the analgesic activity of NHGRE based on the acetic acid-induced writhing response in mice, examined its anti-inflammatory efficacy against carrageenan-induced paw oedema in mice, and investigated its effect on inflammatory cytokine expression in interleukin (IL)-1ß-induced SW1353 cells. Furthermore, we determined its effects on cartilage protection in interleukin-1ß (IL-1ß)-treated SW1353 cells. NHGRE at 200 mg/kg significantly reduced the acetic acid-induced writhing response and prevented oedema formation in the carrageenan-induced paw oedema model. In IL-1ß-induced SW1353 cells, NHGRE at 400 µg/mL reduced the expression of inflammation mediators such as tumour necrosis factor (TNF)-α (55.3%), IL-6 (35.4%), and prostaglandin E2 (PGE2) (36.9%) and down-regulated the expression of matrix metalloproteinase (MMP)-1 (38.6%), MMP-3 (29.3%), and MMP-13 (44.8%). Additionally, it restored degraded collagen II levels in chondrocytes. NHGRE plays a protective role in chondrocytes by regulating Nuclear factor kappa B (NF-κB) activation. Overall, NHGRE may be a useful therapeutic agent for OA by controlling pain, oedema formation, and inflammation-related mechanisms.
Assuntos
Analgésicos, Anti-Inflamatórios, Edema, Extratos Vegetais, Animais, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/uso terapêutico, Camundongos, Extratos Vegetais/farmacologia, Extratos Vegetais/química, Analgésicos/farmacologia, Analgésicos/uso terapêutico, Edema/tratamento farmacológico, Edema/induzido quimicamente, Masculino, Humanos, Condrócitos/efeitos dos fármacos, Condrócitos/metabolismo, Interleucina-1beta/metabolismo, Carragenina/efeitos adversos, Osteoartrite/tratamento farmacológico, Osteoartrite/metabolismo, Osteoartrite/patologia, Osteoartrite/induzido quimicamente, Citocinas/metabolismoRESUMO
Selenium-containing compounds have emerged as promising treatment for redox-based and inflammatory diseases. This study aimed to investigate the in vitro and in vivo anti-inflammatory activity of a novel diselenide named as dibenzyl[diselanediyIbis(propane-3-1diyl)] dicarbamate (DD). DD reacted with HOCl (k = 9.2 x 107 M-1s-1), like glutathione (k = 1.2 x 108 M-1s-1), yielding seleninic and selenonic acid derivatives, and it also decreased HOCl formation by activated human neutrophils (IC50=4.6 µM) and purified myeloperoxidase (MPO) (IC50=3.8 µM). However, tyrosine, MPO-I and MPO-II substrates, did not restore HOCl formation in presence of DD. DD inhibited the oxidative burst in dHL-60 cells with no toxicity up to 25 µM for 48h. Next, an intraperitoneal administration of 25, 50, and 75 mg/kg DD decreased total leukocyte, neutrophil chemotaxis, and inflammation markers (MPO activity, lipid peroxidation, albumin exudation, nitrite, TNF-α, IL-1ß, CXCL1/KC, and CXCL2/MIP-2) on a murine model of carrageenan-induced peritonitis. Likewise, 50 mg/kg DD (i.p.) decreased carrageenan-induced paw edema over 5h. Histological and immunohistochemistry analyses of the paw tissue showed decreased neutrophil count, edema area, and MPO, carbonylated, and nitrated protein staining. Furthermore, DD treatment decreased the fMLP-induced chemotaxis of human neutrophils (IC50=3.7 µM) in vitro with no toxicity. Lastly, DD presented no toxicity in a single-dose model using mice (50 mg/kg, i.p.) over 15 days and in Artemia salina bioassay (50 to 2000 µM), corroborating findings from in silico toxicological study. Altogether, these results demonstrate that DD attenuates carrageenan-induced inflammation mainly by reducing neutrophil migration and the resulting damage from MPO-mediated oxidative burst.
Assuntos
Carragenina, Inflamação, Infiltração de Neutrófilos, Animais, Camundongos, Humanos, Inflamação/tratamento farmacológico, Inflamação/induzido quimicamente, Infiltração de Neutrófilos/efeitos dos fármacos, Masculino, Neutrófilos/efeitos dos fármacos, Neutrófilos/metabolismo, Edema/tratamento farmacológico, Edema/induzido quimicamente, Peroxidase/metabolismo, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/uso terapêutico, Compostos Organosselênicos/farmacologia, Compostos Organosselênicos/uso terapêutico, Ácido HipoclorosoRESUMO
N-Ethyl-2-pyrrolidinone-substituted flavan-3-ols (EPSFs) are a newly discovered compound class in tea with various bioactivities. This study aimed to develop a novel processing technique to enhance EPSF contents in white tea efficiently. Using optimal processing parameters of 125 °C and 30 min in a high-temperature sterilizing oven, total EPSF content significantly increased by 1.42-18.80-fold to 1.57-6.22 mg/g without impacting sensory characteristics. Metabolomics analysis revealed elevated levels of nucleosides, nucleotides, bases, theaflavins, flavonol aglycones, EPSFs, and most flavone-C-glycosides, as well as decreased levels of amino acids, procyanidins, theasinensins, several flavanols, and flavonol-O-glycosides after EPSF-enrichment treatment. Furthermore, the EPSF-enriched white tea exhibited notable anti-inflammatory effects, mitigating xylene-induced ear edema in mice and carrageenan-induced paw edema and cotton ball-induced granulomas in rats. This study developed a new processing technique for highly efficient enhancement of EPSFs in white tea and demonstrated that EPSF-enriched white tea has a potential to serve as effective anti-inflammatory dietary supplement.
Assuntos
Anti-Inflamatórios, Camellia sinensis, Flavonoides, Extratos Vegetais, Chá, Animais, Camundongos, Anti-Inflamatórios/química, Anti-Inflamatórios/farmacologia, Ratos, Flavonoides/química, Flavonoides/farmacologia, Flavonoides/análise, Masculino, Camellia sinensis/química, Chá/química, Extratos Vegetais/química, Extratos Vegetais/farmacologia, Edema/tratamento farmacológico, Pirrolidinonas/química, Pirrolidinonas/farmacologia, Ratos Sprague-Dawley, Humanos, Manipulação de AlimentosRESUMO
Baccharin is one of the major compounds found in Brazilian green propolis and its botanical source, Baccharis dracunculifolia. Considering the biological effects of propolis and B. dracunculifolia, this study aims to evaluate the analgesic and anti-inflammatory potential of baccharin. The neurodepressor potential was performed by the open field test, analgesia by mechanical stimulation with Dynamic Plantar Aesthesiometer, and by thermal stimulation with Hargreaves apparatus. In addition, the anti-inflammatory potential was achieved by the paw edema assay, histopathological evaluation, and NF-kB expression. Doses of 2.5, 5, and 10 mg/kg of baccharin were evaluated. After euthanasia, plantar tissue was collected and prepared for histology. As a result, analgesic activity was observed at a dose of 10 mg/kg of baccharin in thermal stimulation under an inflammatory process and anti-inflammatory potential at a dose of 5 mg/kg of baccharin from the second hour in the paw edema test. A decrease in cellular infiltrate and down-modulation of NF-kB, besides the reduction of edema in the histopathology was observed. There was no evidence of kidney and liver toxicity and neurodepressive potential at the doses tested. Thus, baccharin has a promising anti-inflammatory effect possibly associated with antiedematogenic activity by inhibiting mediators such as prostaglandins, inhibiting the migration of polymorphonuclear cells, and modulating NF-kB expression.
Assuntos
Analgésicos, Anti-Inflamatórios, Baccharis, Edema, NF-kappa B, Própole, Animais, Própole/farmacologia, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/isolamento & purificação, Masculino, NF-kappa B/metabolismo, Baccharis/química, Edema/tratamento farmacológico, Edema/induzido quimicamente, Brasil, Analgésicos/farmacologia, Camundongos, Ratos, Ratos Wistar, TricotecenosRESUMO
A series of water-soluble PEGylated 1,2,4-triazoles 5-8 were successfully synthesized from methyl 5-(chloromethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates 1. All of the water-soluble PEGylated 1,2,4-triazoles were characterized by FT-IR and 1H NMR spectroscopy. The solubility, in vitro plasma stability, and anti-inflammatory activity were also determined and compared to original methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates. For SAR study, all PEGylated 1,2,4-triazoles 5-8 performed potential anti-inflammatory activity on LPS-induced RAW 264.7 cells (IC50 = 3.42-7.81 µM). Moreover, the western blot result showed PEGylated 1,2,4-triazole 7d performed 5.43 and 2.37 folds inhibitory activity over iNOS and COX-2 expressions. On the other hand, the cell viability study revealed PEGylated 1,2,4-triazoles 7 and 8 with PEG molecular weight more than 600 presented better cell safety (cell viability > 95 %). Through the solubility and in vitro plasma stability studies, PEGylated 1,2,4-triazoles 7a-d exhibited higher hydrophilicity and prolonged 2.01 folds of half-life in compound 7d. Furthermore, the in vivo anti-inflammatory and gastric safety results indicated PEGylated 1,2,4-triazole 7d more effectively decreased the inflammatory response in edema and COX-2 expression and exhibited higher gastric safety than Indomethacin. Following the in vitro and in vivo study results, PEGylated 1,2,4-triazole 7d possessed favorable solubility, plasma stability features, safety, and significant anti-inflammatory activity to become the potential water-soluble anti-inflammatory candidate.
Assuntos
Polietilenoglicóis, Solubilidade, Triazóis, Água, Triazóis/química, Triazóis/farmacologia, Triazóis/síntese química, Animais, Camundongos, Água/química, Polietilenoglicóis/química, Relação Estrutura-Atividade, Edema/tratamento farmacológico, Edema/induzido quimicamente, Ciclo-Oxigenase 2/metabolismo, Sobrevivência Celular/efeitos dos fármacos, Células RAW 264.7, Anti-Inflamatórios/farmacologia, Anti-Inflamatórios/síntese química, Anti-Inflamatórios/química, Estrutura Molecular, Lipopolissacarídeos/farmacologia, Lipopolissacarídeos/antagonistas & inibidores, Ratos, Anti-Inflamatórios não Esteroides/farmacologia, Anti-Inflamatórios não Esteroides/síntese química, Anti-Inflamatórios não Esteroides/química, Masculino, Relação Dose-Resposta a Droga, CarrageninaRESUMO
Joining the global demand for the discovery of potent NSAIDs with minimized ulcerogenic effect, new pyrazole clubbed thiazole derivatives 5a-o were designed and synthesized. The new derivatives were initially evaluated for their analgesic activity. Eight compounds 5a, 5c, 5d, 5e, 5f, 5h, 5m, and 5o showed higher activity than Indomethacin (potency = 105-130 % vs. 100 %). Subsequently, they were picked for further evaluation of their anti-inflammatory activity, ulcerogenic liability as well as toxicological studies. Derivatives 5h and 5m showed a potential % edema inhibition after 3 h (79.39 % and 72.12 %, respectively), with a promising safety profile and low ulcer indices (3.80 and 3.20, respectively). The two compounds 5h and 5m were subjected to in vitro COX-1 and COX-2 inhibition assay. The candidate 5h showed nearly equipotent COX-1 inhibition (IC50 = 38.76 nM) compared to the non-selective reference drug Indomethacin (IC50 = 35.72 nM). Compound 5m expressed significant inhibitory activities and a higher COX-2 selectivity index (IC50 = 87.74 nM, SI = 2.05) in comparison with Indomethacin (SI = 0.52), with less selectivity than Celecoxib (SI = 8.31). Simulation docking studies were carried out to gain insights into the binding interaction of compounds 5h and 5m in the vicinity of COX-1 and COX-2 enzymes that illustrated the importance of pyrazole clubbed thiazole core in hydrogen bonding interactions. The thiazole motif of compounds 5h and 5m exhibited a well orientation toward COX-1 Arg120 key residue by hydrogen bonding interactions. Compound 5h revealed an additional arene-cation interaction with Arg120 that could rationalize its superior COX-1 inhibitory activity. Compounds 5h and 5m overlaid the co-crystallized ligand Celecoxib I differently in the active site of COX-2. Compound 5m showed an enhanced accommodation with binding energy of - 6.13 vs. - 1.70 kcal/mol of compounds 5h. The naphthalene ring of compound 5m adopted the Celecoxib I benzene sulfonamide region that is stabilized by hydrogen-arene interactions with the hydrophobic sidechains of the key residues Ser339 and Phe504. Further, the core structure of compound 5m, pyrazole clubbed thiazole, revealed deeper hydrophobic interactions with Ala513, Leu517 and Val509 residues. Finally, a sensitive and accurate UPLC-MS/MS method was developed for the simultaneous estimation of some selected promising pyrazole derivatives in rat plasma. Accordingly, compounds 5h and 5m were suggested to be promising potent analgesic and anti-inflammatory agents with improved safety profiles and a novel COX isozyme modulation activity.
