RESUMEN

Tepotinib is approved for the treatment of patients with non-small-cell lung cancer harboring MET exon 14 skipping alterations. While edema is the most prevalent adverse event (AE) and a known class effect of MET inhibitors including tepotinib, there is still limited understanding about the factors contributing to its occurrence. Herein, we apply machine learning (ML)-based approaches to predict the likelihood of occurrence of edema in patients undergoing tepotinib treatment, and to identify factors influencing its development over time. Data from 612 patients receiving tepotinib in five Phase I/II studies were modeled with two ML algorithms, Random Forest, and Gradient Boosting Trees, to predict edema AE incidence and severity. Probability calibration was applied to give a realistic estimation of the likelihood of edema AE. Best model was tested on follow-up data and on data from clinical studies unused while training. Results showed high performances across all the tested settings, with F1 scores up to 0.961 when retraining the model with the most relevant covariates. The use of ML explainability methods identified serum albumin as the most informative longitudinal covariate, and higher age as associated with higher probabilities of more severe edema. The developed methodological framework enables the use of ML algorithms for analyzing clinical safety data and exploiting longitudinal information through various covariate engineering approaches. Probability calibration ensures the accurate estimation of the likelihood of the AE occurrence, while explainability tools can identify factors contributing to model predictions, hence supporting population and individual patient-level interpretation.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Edema , Aprendizaje Automático , Humanos , Edema/inducido químicamente , Femenino , Masculino , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Anciano , Neoplasias Pulmonares/tratamiento farmacológico , Ensayos Clínicos Fase II como Asunto , Pirimidinas/efectos adversos , Pirimidinas/administración & dosificación , Ensayos Clínicos Fase I como Asunto , Adulto , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Piperidinas , Piridazinas

RESUMEN

The objective of the study was to develop a novel topical gel by mixing Potentilla tormentilla ethanolic extract, thermosensitive poloxamer 407, and carbomer 940 and evaluating its stability and rheological behavior. The irritation potential of the gel was evaluated in accordance with the Organization for Economic Cooperation and Development Guidelines 404. The potential anti-inflammatory effects of the developed gel were evaluated in vivo in rats using the carrageenan-induced paw edema test. Moreover, the in silico binding affinity for chlorogenic and ellagic acid, as dominant components in the extract, against cyclooxygenase (COX) 1 and 2 was also determined. Our findings suggest that the gel containing Potentilla tormentilla extract remained stable throughout the observation period, exhibited pseudoplastic behavior, and caused no irritation in rats, thus being considered safe for topical treatment. Additionally, the developed gel showed the capability to reduce rat paw edema, which highlights significant anti-inflammatory potential. In silico analysis revealed that chlorogenic and ellagic acid exhibited a reduced binding affinity against COX-1 but had a similar inhibitory effect on COX-2 as flurbiprofen, which was confirmed by molecular dynamics results. The study proposes the possible application of Potentilla tormentilla ethanolic extract gel for the alleviation of localized inflammatory diseases; however, future clinical evaluation is required.

Asunto(s)

Antiinflamatorios , Ciclooxigenasa 1 , Edema , Extractos Vegetales , Potentilla , Animales , Potentilla/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Antiinflamatorios/farmacología , Antiinflamatorios/química , Edema/tratamiento farmacológico , Edema/inducido químicamente , Masculino , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 1/química , Geles/química , Ácido Elágico/farmacología , Ácido Elágico/química , Ciclooxigenasa 2/metabolismo , Carragenina , Ratas Wistar , Poloxámero/química , Resinas Acrílicas/química , Ácido Clorogénico/química , Ácido Clorogénico/farmacología

RESUMEN

Mimicking the transition state of tryptophan (Trp) and O2 in the enzymatic reaction is an effective approach to design indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. In this study, we firstly assembled a small library of 2-substituted benzo-fused five membered heterocycles and found 2-sulfinyl-benzoxazoles with interesting IDO1 inhibitory activities. Next the inhibitory activity toward IDO1 was gradually improved. Several benzoxazoles showed potent IDO1 inhibitory activity with IC50 of 82-91 nM, and exhibited selectivity between IDO1 and tryptophan 2,3-dioxygenase (TDO2). Enzyme binding studies showed that benzoxazoles are reversible type II IDO1 inhibitors, and modeling studies suggested that the oxygen atom of the sulfoxide in benzoxazoles interacts with the iron atom of the heme group, which mimics the transition state of Fe-O-O-Trp complex. Especially, 10b can effectively inhibit the NO production in lipopolysaccharides (LPS) stimulated RAW264.7 cells, and it also shows good anti-inflammation effect on mice acute inflammation model of croton oil induced ear edema.

Asunto(s)

Benzoxazoles , Diseño de Fármacos , Inhibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenasa , Lipopolisacáridos , Animales , Ratones , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Células RAW 264.7 , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Estructura-Actividad , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Benzoxazoles/farmacología , Benzoxazoles/química , Benzoxazoles/síntesis química , Estructura Molecular , Edema/tratamiento farmacológico , Edema/inducido químicamente , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/síntesis química , Relación Dosis-Respuesta a Droga , Inflamación/tratamiento farmacológico , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis química , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Masculino

RESUMEN

Allium roseum is amongst the most important wild medicinal plants. It is known for its diverse biological properties, including antioxidant, antibacterial and antidiabetic activities. In this work, the polysaccharides (PARLs) were ultrasonically extracted from Allium roesum leaves then purified and analyzed by several techniques. Chemical composition and GC-MS analysis showed that the obtained polysaccharides were composed mainly of glucose (40.20 %), mannose (25.30 %), fructose (10.60 %) and galacturonic acid (15.11 %). Moreover, PARLs exhibited a potent antioxidant effect with higher capacities up to 69.61 % and 71.72 % for DPPH and ABTS free radicals, respectively. Furthermore, PARLs significantly modulated inflammatory response by reducing TNF-α, IL-6, and IL-8 pro-inflammatory mediators and promoting the anti-inflammatory IL-10 mediator in LPS stimulated THP-1 derived macrophages. The in-vivo tests proved that the extract was able to decrease carrageenan-induced rat paw swelling by around 68.15 % after 4 h of treatment. PARLs, significantly reduced the growth of U87 (glioblastoma) and IGROV-1 cancer cells with IC50 values of about 4.27 and 7.89 mg/mL respectively. This research clearly shows that Allium roseum polysaccharides can be used as natural antioxidants with anti-inflammatory and anticancer properties.

Asunto(s)

Allium , Antiinflamatorios , Antioxidantes , Hojas de la Planta , Polisacáridos , Polisacáridos/farmacología , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Animales , Hojas de la Planta/química , Humanos , Ratas , Antioxidantes/farmacología , Antioxidantes/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Allium/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Masculino , Edema/tratamiento farmacológico , Edema/inducido químicamente , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Células THP-1

RESUMEN

Inflammatory pain is a chronic pain caused by peripheral tissue inflammation, seriously impacting the patient's life quality. Cinobufacini injection, as a traditional Chinese medicine injection preparation, shows excellent efficacy in anti-inflammatory and analgesic treatment in patients with advanced tumors. In this study, a novel analgesic peptide CI5 with anti-inflammatory and analgesic bio-functions that naturally presents in Cinobufacini injection and its regulatory mechanism are reported. Our results showed that the administration of CI5 significantly relieved the pain of mice in the acetic acid twisting analgesic model and formalin inflammatory pain model. Furthermore, CI5 effectively reduced the inflammatory cytokines (IL-6, TNF-α and IL-1ß) and inflammatory mediator (PGE2) expressions, and prevented the carrageenan-induced paw edema in mice. Further LC-MS/MS results showed the anti-inflammatory and analgesic bio-functions of CI5 depended on its interaction with the Rac-2 protein upstream of ERK1/2 and the inflammatory signaling pathway (ERK1/2/COX-2 axis). In summary, CI5, as a novel natural candidate identified from Cinobufacini injection, showed substantial clinical promise for inflammatory pain treatments.

Asunto(s)

Analgésicos , Antiinflamatorios , Ciclooxigenasa 2 , Edema , Inflamación , Dolor , Animales , Analgésicos/uso terapéutico , Analgésicos/farmacología , Analgésicos/administración & dosificación , Ratones , Dolor/tratamiento farmacológico , Masculino , Inflamación/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Ciclooxigenasa 2/metabolismo , Edema/tratamiento farmacológico , Edema/inducido químicamente , Venenos de Anfibios/uso terapéutico , Venenos de Anfibios/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Citocinas/metabolismo , Péptidos/uso terapéutico , Péptidos/farmacología , Péptidos/administración & dosificación , Humanos , Modelos Animales de Enfermedad , Carragenina , Mediadores de Inflamación/metabolismo , Dinoprostona/metabolismo

RESUMEN

Lancehead snakes of the genus Bothrops are responsible for 90% of the snakebites in Latin America. The objective of this study was to assess the LD50, physical, and hematological manifestations induced by B. atrox venom in male and female mice inoculated by different routes. B. atrox venom was inoculated in male and female mice by intramuscular (IM), subcutaneous (SC), intravenous (IV), and intraperitoneal (IP) routes. B. atrox venom LD50 was lower in male than female groups, regardless of the injection route. However, it was the lowest when the venom was inoculated by the IP route. Moreover, comparisons between male and female responses according to the injected venom dose showed higher edema-forming, local hemorrhagic, dermonecrotic, and myotoxic activities in male than in female mice. While the minimal hemorrhagic, and necrotic doses were not statistically different between the two groups, the difference between males and females was more pronounced at high venom doses. Hematological parameter changes were also more significant in male than in female mice. The venom decreased the levels of total leukocytes after 24 h of injection in male and female mice, with a more profound decrease in the male group. The micronucleus test, a tool for genotoxicity assessment, documented the mutagenic effects of B. atrox on leucocytes. We demonstrate the higher susceptibility of male mice to B. atrox venom than females. Sex differences must be considered when conducting experimental studies on snake venoms.

Asunto(s)

Bothrops , Venenos de Crotálidos , Animales , Femenino , Masculino , Ratones , Venenos de Crotálidos/toxicidad , Dosificación Letal Mediana , Factores Sexuales , Mordeduras de Serpientes , Edema/inducido químicamente , Hemorragia/inducido químicamente , Pruebas de Micronúcleos , Bothrops atrox

RESUMEN

Inflammation management presents a critical challenge in modern medicine, with nonsteroidal anti-inflammatory drugs (NSAIDs) being a widely used therapeutic option. However, their efficacy is often accompanied by significant gastrointestinal adverse effects, necessitating the exploration of safer alternatives, particularly through the investigation of cyclooxygenase-2 (COX-2) inhibitors. This study endeavors to address this imperative through the synthesis and evaluation of pyrazoline-phenoxyacetic acid derivatives. Among the synthesized compounds, 6a and 6c emerged as promising candidates, demonstrating potent COX-2 inhibition with IC50 values of 0.03 µM for both and selectivity index = 365.4 and 196.9, respectively. Furthermore, these compounds exhibited efficacy in mitigating formalin-induced edema in male Wistar rats, accompanied by favorable safety profiles upon histological examination of vital organs. Comprehensive safety assessments, including evaluation of creatinine, AST, and ALT enzymatic as well as troponin T and creatine kinase-MB levels, further reinforce the promising attributes of the synthetic candidates. Molecular docking studies endorsed by molecular dynamic simulations corroborate the biological findings, elucidating significant protein-ligand interactions at COX-2 active sites indicative of therapeutic potential.

Asunto(s)

Antiinflamatorios no Esteroideos , Inhibidores de la Ciclooxigenasa 2 , Ciclooxigenasa 2 , Edema , Ratas Wistar , Animales , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Masculino , Ciclooxigenasa 2/metabolismo , Edema/tratamiento farmacológico , Edema/inducido químicamente , Ratas , Relación Estructura-Actividad , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Estructura Molecular , Acetatos/química , Acetatos/farmacología , Acetatos/síntesis química , Simulación del Acoplamiento Molecular , Humanos , Relación Dosis-Respuesta a Droga , Formaldehído , Farmacóforo

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Hymenaea eriogyne Benth (Fabaceae) is popularly known as "Jatobá". Despite its use in folk medicine to treat inflammatory disorders, there are no descriptions that show its anti-inflammatory potential. AIM OF THE STUDY: In this sense, this study aimed to evaluate the anti-inflammatory and antivenom action of bark and leaves extract of H. eriogyne. MATERIALS AND METHODS: The in vivo anti-inflammatory activity was conducted by carrageenan-induced paw edema and zymosan-induced air pouch models, evaluating the edematogenic effect, leukocyte migration, protein concentration, levels of pro-inflammatory cytokines, malondialdehyde (MDA) and myeloperoxidase (MPO) activity. The antivenom potential was investigated in vitro on the enzymatic action (proteolytic, phospholipase and hyaluronidase) of Bothrops brazili and B. leucurus venom, as well as in vivo on the paw edema model induced by B. leucurus. Furthermore, the influence of its markers (astilbin and rutin) on MPO activity was investigated in silico. For molecular docking, AutodockVina, Biovia Discovery Studio, and Chimera 1.16 software were used. RESULTS: The extracts and bark and leaves of H. eriogyne revealed a high anti-inflammatory effect, with a reduction in all inflammatory parameters evaluated. The bark extract showed superior results when compared to the leaf extract, suggesting the influence of the astilbin concentration, higher in the bark, on the anti-inflammatory action. In addition, only the H. eriogyne bark extract was able to reduce MDA, indicating an associated antioxidant effect. Regarding the in vitro antivenom action, the extracts (bark and leaves) revealed the ability to inhibit the proteolytic, phospholipase and hyaluronidase action of both bothropic venom, with a greater effect against B. leucurus venom. In vivo, extracts from the bark and leaves of H. eriogyne (50-200 mg/kg) showed antiedematogenic activity, reducing the release of MPO and pro-inflammatory cytokines, indicating the presence of bioactive components useful in controlling the inflammatory process induced by the venom. In the in silico assays, astilbin and rutin showed reversible interactions of 9 possible positions and orientations towards MPO, with affinities of -9.5 and -10.4 kcal/mol and interactions with Phe407, Gln91, His95 and Arg239, important active pockets of MPO. Rutin demonstrated more effective types of interactions with MPO. CONCLUSION: This approach reveals for the first time the anti-inflammatory action of H. eriogyne bark and leaf extracts in vivo, as well as its antiophidic potential. Moreover, the distinct effect of pharmacogens as antioxidant agents and distinct effect of astilbin and rutin under MPO sheds light on the different anti-inflammatory mechanisms of bioactive compounds present in H. eriogyne extracts, with high potential for the prospection of new pharmacological agents.

Asunto(s)

Antiinflamatorios , Carragenina , Edema , Simulación del Acoplamiento Molecular , Corteza de la Planta , Extractos Vegetales , Hojas de la Planta , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/química , Edema/tratamiento farmacológico , Edema/inducido químicamente , Hojas de la Planta/química , Corteza de la Planta/química , Masculino , Relación Estructura-Actividad , Peroxidasa/metabolismo , Fabaceae/química , Antivenenos/farmacología , Antivenenos/química , Ratas Wistar , Venenos de Crotálidos/toxicidad , Ratones , Bothrops , Citocinas/metabolismo , Zimosan , Biomarcadores/metabolismo , Rutina/farmacología

RESUMEN

Luobuma tea is made from the leaves of Apocynum hendersonii (Bt) and A. venetum (Ht) and has been used for a very long time in China and Japan as herbal tea. This study isolated water-soluble polysaccharides from the two species` teas. Physicochemical properties, structural properties, in vitro and in vivo antioxidant and immunomodulatory activities were determined for the first time. The results showed that the Bt and Ht polysaccharides with molecular weights of 31.21 and 49.11 kDa, respectively, composed of arabinose, galactose, rhamnose, glucose, xylose, fucose, and mannose. A dose-dependent nitric oxide production and interleukin-6 inhibitory effects were obtained. Also, they suppressed the expression of cyclooxygenase-2, tumor necrosis factor-α and interleukin-6 mRNA in LPS-induced RAW 264.7 macrophages. Likewise, Bt and Ht have significantly reduced edema in the paws of mice after carrageenan injection. These results suggested that the Luobuma teas polysaccharides can be explored as potential antioxidants and anti-inflammatory agents.

Asunto(s)

Antiinflamatorios , Antioxidantes , Macrófagos , Extractos Vegetales , Polisacáridos , Animales , Ratones , Polisacáridos/química , Polisacáridos/farmacología , Células RAW 264.7 , Extractos Vegetales/química , Extractos Vegetales/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/química , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Antioxidantes/química , Antioxidantes/farmacología , Masculino , Óxido Nítrico/metabolismo , Peso Molecular , Edema/tratamiento farmacológico , Edema/inducido químicamente , Hojas de la Planta/química , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Vietnamese people use mugwort (Artemisia vulgaris L.) to treat arthritis and gout. Our previous research shows that mugwort contains flavonoids, and its extract possesses antibacterial and anti-inflammatory activities. However, no publications have been on the xanthine oxidase inhibitory activity of mugwort and acute anti-inflammatory activity in vivo. AIM OF THE STUDY: The study aimed to verify the antioxidant, xanthine oxidase inhibitory, and anti-inflammatory capabilities of mugwort extract in vitro and in vivo, isolate phyto-compounds from potential bioactive fractions, and then evaluate their potential in inhibiting xanthine oxidase. METHODS: According to established methods, the extract and the active flavonoids were obtained using different chromatographic techniques. DPPH, ABTS, reducing power, and H2O2 elimination were used to evaluate antioxidant activity. The model of LPS-induced RAW264.7 cells was used to measure the inhibition of NO production. The carrageenan-induced paw oedema model was used to assess acute inflammation in mice. In vitro, xanthine oxidase inhibition assay was applied to investigate the effects of extract/compounds on uric acid production. Chemical structures were identified by spectral analysis. RESULTS: The assessment of the acute inflammatory model in mice revealed that both the 96% ethanol and the 50% ethanol extracts significantly decreased oedema in the mice's feet following carrageenan-induced inflammation. 96% ethanol extract exhibited a better reduction in oedema at the low dose. The analysis revealed that the ethyl acetate fraction had the highest levels of total polyphenols and flavonoids. Additionally, this fraction demonstrated significant antioxidant activity in various assays, such as DPPH, ABTS, reducing power, and H2O2 removal. Furthermore, it displayed the most potent inhibition of xanthine oxidase, an anti-inflammatory activity. Five phytochemicals were isolated and determined from the active fraction such as luteolin (1), rutin (2), apigenin (3), myricetin (4), and quercetin (5). Except for rutin, the other compounds demonstrated the ability to inhibit effective xanthine oxidase compared to standard (allopurinol). Moreover, quercetin (5) inhibited NO production (IC50 21.87 µM). CONCLUSION: The results indicate that extracts from A. vulgaris effectively suppressed the activity of xanthine oxidase and exhibited antioxidant and anti-inflammatory properties, potentially leading to a reduction in the production of uric acid in the body and eliminating ROS. The study identified mugwort extract and bioactive compounds derived from Artemisia vulgaris, specifically luteolin, apigenin, and quercetin, as promising xanthine oxidase inhibitors. These findings suggest that further development of these compounds is warranted. At the same time, the above results also strengthen the use of mugwort to treat gout disease in Vietnam.

Asunto(s)

Antiinflamatorios , Antioxidantes , Artemisia , Edema , Extractos Vegetales , Xantina Oxidasa , Animales , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Antioxidantes/farmacología , Antioxidantes/aislamiento & purificación , Ratones , Células RAW 264.7 , Edema/tratamiento farmacológico , Edema/inducido químicamente , Artemisia/química , Masculino , Ácido Úrico , Flavonoides/farmacología , Óxido Nítrico/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Carragenina

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Flos Chrysanthemi Indici (FCI), the flower of Chrysanthemum Indicum L., is a popular traditional Chinese medicine (TCM) for treatment of inflammatory diseases in China. FCI is also a functional food, and is widely used as herbal tea for clearing heat and detoxicating. AIM OF THE STUDY: To explore quality control markers of FCI based on the optimal harvest period. MATERIALS AND METHODS: First, UPLC-Q-TOF/MS based untargeted metabolomics was applied to explore the chemical profiles of FCIs collected at bud stages (BS), initial stages (IS), full bloom stages (FS) and eventual stages (ES) from eight cultivated regions in China. Subsequently, lipopolysaccharide (LPS)-induced RAW264.7 cell inflammatory model and carrageenan-induced rat paw edema model were used to confirm the anti-inflammatory effect of FCIs collected at IS/FS. Then, UPLC-PDA targeted metabolomics was used to quantitatively analyze 9 constituents with anti-inflammatory activity (7 flavonoids and 2 phenolic acids) changed significantly (VIP > 4) during flowering stages. Finally, ROC curves combined with PCA analysis based on the variation of 9 active constituents in FCIs from different flowering stages were applied to screen the quality markers of FCI. RESULTS: FCIs at IS/FS had almost same chemical characteristics, but quite different from those at BS and ES. A total of 32 constituents in FCIs including flavonoids and phenolic acids were changed during flowering development. Most of the varied constituents had the highest or higher contents at IS/FS compared with those at ES, indicating that the optimal harvest period of FCI should be at IS/FS. FCI extract could effectively suppress nitric oxide (NO) production in LPS-induced RAW264.7 cells and regulate the abnormal levels of cytokines and PGE2 in carrageenan-induced paw edema model rat. The results of quantitatively analysis revealed that the variation trends of phenolic acids and flavonoids in FCIs were different during flowering development, but most of them had higher contents at IS/FS than those at ES in all FCIs collected from eight cultivated regions, except one sample from Anhui. Finally, linarin, luteolin, apigenin and 3,5-dicaffeoylquinic acid were selected as the Q-markers based on the contribution of their AUC values in ROC and clustering of PCA analysis. CONCLUSIONS: Our study demonstrates the optimal harvest period of FCI and specifies the multi-constituents Q-markers of FCI based on the influence of growth progression on the active constituents using untargeted/targeted metabolomics. The findings not only greatly increase the utilization rate of FCI resources and improve quality control of FCI products, but also offer new strategy to identify the Q-markers of FCI.

Asunto(s)

Antiinflamatorios , Chrysanthemum , Edema , Flores , Metabolómica , Control de Calidad , Ratas Sprague-Dawley , Animales , Chrysanthemum/química , Ratones , Metabolómica/métodos , Células RAW 264.7 , Masculino , Edema/tratamiento farmacológico , Edema/inducido químicamente , Antiinflamatorios/farmacología , Ratas , Quimiometría , Carragenina , Extractos Vegetales/farmacología , Extractos Vegetales/química , Inflamación/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Lipopolisacáridos

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Angelica sinensis (AS) and Chuanxiong rhizoma (CR) are frequently prescribed in clinical settings for their ability to enrich blood, regulate menstrual cycles, and alleviate pain. Despite their widespread use, there is a relative dearth of studies exploring their anti-inflammatory properties. AIM OF THE STUDY: To evaluate the antioxidant and anti-inflammatory effects of Angelica sinensis-Chuanxiong rhizoma (ASCR) extracts and investigate its anti-inflammatory mechanisms. MATERIALS AND METHODS: AS and CR were combined in six ratios and extracted using five solvents. The quality of the resulting ASCR extracts was assessed by determining the content of ferulic acid (FA) using HPLC. The antioxidant effects of the ASCR extracts were evaluated in vitro using the DPPH and ABTS assays, as well as in HUVECs exposed to H2O2-induced oxidative damage. Additionally, the anti-inflammatory effects of the extracts were investigated in vivo through the assays of ear edema in mice and paw edema in rats. Biochemical markers including NO, MDA, and SOD in paw tissues, as well as PGE2, TNF-α, and COX-2 in rat serum, were measured to further elucidate the anti-inflammatory mechanisms of ASCR extracts. RESULTS: The WA-2-1 was obtained by combining AS and CR in a 2:1 ratio through first water then ethanol extraction, and showed favorable antioxidant and anti-inflammatory activities. The extract demonstrated effective scavenging abilities against DPPH• and ABTS+• radicals while also protecting against H2O2-induced oxidative damage. Furthermore, in vivo studies revealed that WA-2-1 had significant inhibitory effects on ear and paw edema as well as the ability to decrease NO and MDA levels, enhance SOD activity, and downregulate the expression of COX-2, PGE2, and TNF-α. CONCLUSIONS: The combination of AS and CR exhibits favorable anti-inflammatory effects, attributed to its dual actions of mitigating oxidative stress and suppressing the production of inflammatory mediators in serum or tissues during the inflammatory process.

Asunto(s)

Angelica sinensis , Antiinflamatorios , Antioxidantes , Medicamentos Herbarios Chinos , Edema , Células Endoteliales de la Vena Umbilical Humana , Ratas Sprague-Dawley , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Antioxidantes/farmacología , Antioxidantes/aislamiento & purificación , Angelica sinensis/química , Edema/tratamiento farmacológico , Edema/inducido químicamente , Humanos , Masculino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Ratones , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Estrés Oxidativo/efectos de los fármacos , Ratas , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ligusticum/química , Peróxido de Hidrógeno , Ratones Endogámicos ICR , Rizoma , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo

RESUMEN

Chronic pain has emerged as a significant public health issue, seriously affecting patients' quality of life and psychological well-being, with a lack of effective pharmacological treatments. Numerous studies have indicated that macrophages play a crucial role in inflammatory pain, and targeting neuro-immune interactions for drug development may represent a promising direction for pain management. Chilobrachys jingzhao (C. jingzhao) is used as a folk medicine of the Li nationality with the efficacy of eliminating swelling, detoxicating, and relieving pain, and the related products are widely used in the market. However, the chemical constituents of C. jingzhao have not been reported, and the pharmacodynamic substance and the precise functional mechanism are unrevealed. Here we isolated a cyclic dipeptide, cyclo(L-Pro-L-Trp) (CPT) from C. jingzhao for the first time. CPT remarkably alleviated formalin-induced inflammatory pain and significantly inhibited inflammatory responses. In vivo, CPT attenuated neutrophil infiltration and plantar tissue edema and suppressed the mRNA expression of pro-inflammatory molecules. In vitro, CPT suppressed inflammation triggered by lipopolysaccharide (LPS) in both RAW 264.7 and iBMDM cells, reducing expressions of inducible nitric oxide synthase (iNOS), superoxide, and pro-inflammatory molecules. A mechanistic study revealed that CPT exerted an anti-inflammatory activity by blocking the mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, as well as alleviating the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). Our results elucidated the pharmacodynamic material basis of C. jingzhao, and CPT can be a promising lead for alleviating inflammation and inflammatory pain.

Asunto(s)

Antiinflamatorios , Formaldehído , Inflamación , FN-kappa B , Transducción de Señal , Factor 6 Asociado a Receptor de TNF , Animales , FN-kappa B/metabolismo , Ratones , Factor 6 Asociado a Receptor de TNF/metabolismo , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Masculino , Transducción de Señal/efectos de los fármacos , Inflamación/tratamiento farmacológico , Células RAW 264.7 , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/inducido químicamente , Analgésicos/uso terapéutico , Analgésicos/farmacología , Humanos , Edema/tratamiento farmacológico , Edema/inducido químicamente , Edema/inmunología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología

RESUMEN

Fucoidan from Saccharina japonica (SJF) was isolated and characterized, and its anti-inflammatory effects on fine dust/ambient particulate matter (PM)-stimulated HaCaT keratinocytes were investigated. SJF increased cell viability by reducing intracellular ROS production in PM-stimulated HaCaT keratinocytes. Moreover, SJF downregulated the expression/production of inflammatory cytokines (IL-6, IL-8, IL-13, IL-25, IL-33, TNF-α, IFN-γ, and TSLP) and chemokines (MDC and TARC) through modulating NF-κB/MAPK signaling in PM-stimulated HaCaT keratinocytes. Extended studies investigated the impact of SJF-treated HaCaT keratinocyte culture media on HDFs. Interestingly, media from SJF-treated HaCaT keratinocytes on HDFs demonstrated a notable downregulation of the production of inflammatory mediators such as TSLP, IL-6, IL-8, IL-13, and TNF-α, as well as TARC and MDC. Furthermore, the study examined the impact of SJF on 12-O-tetradecanoylphorbol 13-acetate (TPA) induced ear edema in BALB/c mice and results indicated the reduced ear thickness and decreased iNOS and COX-2 expression. Our study confirmed the effectiveness of SJF in ameliorating PM-induced skin inflammation in in vitro experiments, along with the TPA-induced in vivo inflammatory model.

Asunto(s)

Citocinas , Edema , Inflamación , Queratinocitos , Material Particulado , Polisacáridos , Acetato de Tetradecanoilforbol , Animales , Ratones , Edema/tratamiento farmacológico , Edema/inducido químicamente , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Polisacáridos/farmacología , Acetato de Tetradecanoilforbol/toxicidad , Humanos , Material Particulado/toxicidad , Material Particulado/efectos adversos , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Inflamación/inducido químicamente , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Oído/patología , Antiinflamatorios/farmacología , Orchidaceae/química , Supervivencia Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células HaCaT , Algas Comestibles , Laminaria

RESUMEN

Chysobalanus icaco L. (C. icaco) is a plant that is native to tropical America and Africa. It is also found in the southeast region of Mexico, where it is used as food and to treat certain diseases. This study aimed to carry out a phytochemical analysis of an aqueous extract of C. icaco seed (AECS), including its total phenol content (TPC), total flavonoid content (TFC), and condensed tannins (CT). It also aimed to examine the antioxidant and metal-ion-reducing potential of the AECS in vitro, as well as its toxicity and anti-inflammatory effect in mice. Antioxidant and metal-ion-reducing potential was examined by inhibiting DPPH, ABTS, and FRAP. The acute toxicity test involved a single administration of different doses of the AECS (0.5, 1, and 2 g/kg body weight). Finally, a single administration at doses of 150, 300, and 600 mg/kg of the AECS was used in the carrageenan-induced model of subplantar acute edema. The results showed that the AECS contained 124.14 ± 0.32 mg GAE, 1.65 ± 0.02 mg EQ, and 0.910 ± 0.01 mg of catechin equivalents/g dried extract (mg EC/g de extract) for TPC, TFC and CT, respectively. In the antioxidant potential assays, the values of the median inhibition concentration (IC50) of the AECS were determined with DPPH (0.050 mg/mL), ABTS (0.074 mg/mL), and FRAP (0.49 mg/mL). Acute toxicity testing of the AECS revealed no lethality, with a median lethal dose (LD50) value of >2 g/kg by the intragastric route. Finally, for inhibition of acute edema, the AECS decreased inflammation by 55%, similar to indomethacin (59%, p > 0.05). These results demonstrated that C. icaco seed could be considered a source of bioactive molecules for therapeutic purposes due to its antioxidant potential and anti-inflammatory activity derived from TPC, with no lethal effect from a single intragastric administration in mice.

Asunto(s)

Antiinflamatorios , Antioxidantes , Edema , Extractos Vegetales , Semillas , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/química , Ratones , Antioxidantes/farmacología , Antioxidantes/química , Semillas/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Edema/tratamiento farmacológico , Edema/inducido químicamente , Carragenina/toxicidad , Flavonoides/farmacología , Flavonoides/química , Modelos Animales de Enfermedad , Pruebas de Toxicidad Aguda , Fitoquímicos/farmacología , Fitoquímicos/química , Masculino , Fenoles/química , Fenoles/farmacología

RESUMEN

Five new pyridazine scaffolds were synthesized and assessed for their inhibitory potential against both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) compared with indomethacin and celecoxib. The majority of the synthesized compounds demonstrated a definite preference for COX-2 over COX-1 inhibition. Compounds 4c and 6b exhibited enhanced potency towards COX-2 enzyme with IC50 values of 0.26 and 0.18 µM, respectively, compared to celecoxib with IC50 = 0.35 µM. The selectivity index (SI) of compound 6b was 6.33, more than that of indomethacin (SI = 0.50), indicating the most predominant COX-2 inhibitory activity. Consequently, the in vivo anti-inflammatory activity of compound 6b was comparable to that of indomethacin and celecoxib and no ulcerative effect was detected upon the oral administration of compound 6b, as indicated by the histopathological examination. Moreover, compound 6b decreased serum plasma PEG2 and IL-1ß. To rationalize the selectivity and potency of COX-2 inhibition, a molecular docking study of compound 6b into the COX-2 active site was carried out. The COX-2 inhibition and selectivity of compound 6b can be attributed to its ability to enter the side pocket of the COX-2 enzyme and interact with the essential amino acid His90. Together, these findings suggested that compound 6b is a promising lead for the possible design of COX-2 inhibitors that could be employed as safe and effective anti-inflammatory drugs.

Asunto(s)

Antiinflamatorios no Esteroideos , Inhibidores de la Ciclooxigenasa 2 , Ciclooxigenasa 2 , Simulación del Acoplamiento Molecular , Piridazinas , Piridazinas/farmacología , Piridazinas/química , Piridazinas/síntesis química , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Animales , Ciclooxigenasa 2/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Humanos , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Edema/inducido químicamente , Ratas , Masculino , Ciclooxigenasa 1/metabolismo , Ratones

RESUMEN

BACKGROUND: Topical corticosteroids treat cutaneous inflammation but have side effects. In earlier studies, bilirubin exhibited anti-inflammatory effect, but its hydrophobicity and poor absorption limit its potential. AIM: Synthesis of bilirubin nanoparticles (BNP) and bilirubin nanoparticles gels (BNP gel) to study the anti-inflammatory effect of topical BNP gel against carrageenan-induced rat paw edema in Wistar rats. MATERIALS AND METHODS: BNP were synthesized, and BNP gels were prepared by mixing BNP of different concentrations with pluronic F-127 (PF-127). A different group for each formulation was assigned with five rats in each group. After 1 h of carrageenan (1% [w/v]) injection in each group, different gels were applied topically to their respective groups. Paw edema size, percent inflammation, percent edema inhibition, and inhibition time50 were evaluated. Interleukin-10 (IL-10) levels and neutrophil infiltration in rat paw tissue were evaluated by enzyme-linked immunosorbent assay and hematoxylin and eosin, respectively. RESULTS: Synthesized spherical-shaped BNP had negative zeta potential. BNP gels markedly reduced paw edema size and % inflammation as compared to carrageenan and bulk bilirubin gel (Bulk B gel) treated group and significantly increased IL-10 levels and inhibited neutrophil infiltration. CONCLUSION: BNP gels exhibited a better anti-inflammatory effect than bulk B gel and comparable anti-inflammatory potential with clobetasol.

Asunto(s)

Antiinflamatorios , Bilirrubina , Carragenina , Edema , Geles , Interleucina-10 , Nanopartículas , Infiltración Neutrófila , Ratas Wistar , Animales , Edema/tratamiento farmacológico , Edema/inducido químicamente , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Bilirrubina/sangre , Masculino , Infiltración Neutrófila/efectos de los fármacos , Ratas

RESUMEN

Docetaxel (DTX) is a key drug used in perioperative chemotherapy for breast cancer. Edema is a known adverse effect of DTX, but its effect on health-related QOL (HRQOL) is unclear. In this study, we evaluated the effects of edema caused by administration of DTX on HRQOL in patients with early-stage breast cancer. We prospectively investigated patients diagnosed with early-stage breast cancer (stage I-III) who received 4 cycles of DTX as preoperative or postoperative chemotherapy between September 2021 and December 2022 at Yamanashi Prefectural Central Hospital. The circumference of each extremity was measured at each administration of DTX, and limb edema was evaluated by Common Terminology Criteria for Adverse Events version 5.0. HRQOL was evaluated using SF-12 version 2, which has a range of 0-100 (national standard, 50), and compared between the presence and absence of grade 2 or higher edema and between before and after administration of DTX. Twenty patients met the eligibility criteria and were included in the study. There was no difference in the HRQOL score according to whether grade 2 limb edema was present. The median HRQOL summary scores before and after administration of DTX were 51.1 and 50.8 (p=0.763), respectively, for mental health, 52.6 and 49.4 (p=0.005) for physical health, and 38.9 and 37.5 (p=1.000) for role/social health. We found no direct effect of DTX-induced limb edema on HRQOL in patients with early-stage breast cancer. However, HRQOL summary scores indicated that administration of DTX reduced physical health in these patients.

Asunto(s)

Neoplasias de la Mama , Docetaxel , Edema , Calidad de Vida , Humanos , Docetaxel/efectos adversos , Docetaxel/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Edema/inducido químicamente , Edema/etiología , Anciano , Estadificación de Neoplasias , Adulto , Extremidades , Antineoplásicos/efectos adversos , Atención Perioperativa

RESUMEN

BACKGROUND: TAFRO syndrome is a rare disorder that causes thrombocytopenia, generalized oedema, fever, organ enlargement, and renal impairment. Few reports have suggested an association with vaccines, and few cases have undergone renal biopsy. TAFRO syndrome is often severe and fatal, and its cause is unknown. We report a case of TAFRO syndrome that occurred after vaccination with the coronavirus disease 2019 (COVID-19) vaccine. CASE PRESENTATION: An 82-year-old woman received two doses of the BNT162b2 mRNA vaccine 3 weeks apart. Two weeks later, she was admitted to the hospital with oedema, accompanied with renal failure and thrombocytopenia. After close examination, she was diagnosed with TAFRO syndrome. She was treated with steroids, cyclosporine, and thrombopoietin receptor agonists. The patient was discharged after several months in remission. CONCLUSIONS: Although an incident of TAFRO syndrome after COVID-19 vaccination has been previously reported, this is a rare case in which the patient went into remission and was discharged. A renal biopsy was also performed in this case, which was consistent with previous reports. The favorable treatment course for TAFRO syndrome provides valuable insights.

Asunto(s)

Ciclosporina , Humanos , Femenino , Ciclosporina/uso terapéutico , Ciclosporina/efectos adversos , Anciano de 80 o más Años , Trombocitopenia/inducido químicamente , Vacuna BNT162/efectos adversos , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Vacunas contra la COVID-19/efectos adversos , Edema/etiología , Edema/inducido químicamente , COVID-19/complicaciones , COVID-19/prevención & control

RESUMEN

INTRODUCTION: Imatinib is a tyrosine kinase inhibitor and is used for the treatment of chronic myeloid leukemia (CML) since 2002. We present a patient who suffered from fluid retention and periorbital edema secondary to this drug.

Asunto(s)

Antineoplásicos , Edema , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Mesilato de Imatinib/efectos adversos , Mesilato de Imatinib/administración & dosificación , Edema/inducido químicamente , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Masculino , Persona de Mediana Edad , Femenino