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Inflammation is a biological process in response to injury, resulting in altered blood flow, increased vascular permeability, tissue destruction, and the production of reactive oxygen species (ROS) and inflammatory mediators. Zygophyllum simplex L., a medicinal plant traditionally used in the Arabian Peninsula for inflammatory disorders, has demonstrated promising in vitro anti-inflammatory activity due to its phenolic content. Additionally, the ethyl acetate fraction has exhibited notable in vivo anti-inflammatory effects. This research aimed to evaluate the in vivo anti-inflammatory effects of a Z. simplex plant extract and its principal ethyl acetate isolate, isorhamnetin-3- O -β-D-glucoside (Isor-3-Glu). The study seeks to develop a straightforward and robust HPLC method for quantifying Isor-3-Glu within the total methanolic extract of Z. simplex. The total methanol extract of Z. simplex was successively partitioned with a variety of organic solvents and the ethyl acetate fraction was used to isolate Isor-3-Glu on a Sephadex LH-20 column. The in vivo anti-inflammatory activity was investigated using carrageenan-triggered inflammation in rats. Histological features and immunohistochemical expression of cyclooxygenase-2 (COX-2) and tumor necrosis factor-alpha (TNF-α) were analyzed, and the levels of interleukins (IL-1β and IL-6) as well as prostaglandin E2 (PGE2) of the paw tissues were examined by qRT-PCR and ELISA, respectively. Quantification of Isor-3-Glu was achieved using an HPLC-PDA method. Isor-3-Glu considerably (p < 0.05) lowered the weight of the paw edema. The histological abnormalities were improved, and the percentage of the COX-2 and TNF-α immunoreactive cells substantially decreased in the Isor-3-Glu-treated group in comparison with the positive control and Z. simplex extract group. Isor-3-Glu significantly ameliorated PGE2, IL-1β, and IL-6 levels. A straightforward and dependable HPLC technique was established for quantifying Isor-3-Glu in the total extract. The proposed methodology effectively determined Isor-3-Glu in less than 5 min. The calibration curve exhibited a linear relationship over the concentration range of 1.0–40.0 μg/mL, with a correlation coefficient (r) ≥ 0.9995. The developed method demonstrated a high level of sensitivity, with a detection limit as low as 0.139 μg/mL. The concentration of Isor-3-Glu in the total extract of Z. simplex was determined to be 0.05% w/w of dry extract. Isor-3-Glu could be considered a promising anti-inflammatory compound that necessitates future clinical research. Isor-3-Glu was accurately quantified using a meticulously developed and optimized HPLC-PDA technique. [Display omitted] • Zygophyllum simplex is used as an anti-inflammatory plant in the Arabian Peninsula. • Isorhamnetin-3-glucoside is a main component of this plant. • Isorhamnetin-3-glucoside considerably lowered the weight of the paw edema in rats. • It ameliorated PGE2, IL-1 β and IL-6 level and decreased COX-2 and TNF- α expression. • Its analysis was successfully conducted using a developed simple HPLC-PDA method. [ABSTRACT FROM AUTHOR]

Endometriosis (EMS) is a common gynecological disease that causes dysmenorrhea, chronic pelvic pain and infertility. Luoshi Neiyi Prescription (LSNYP), a traditional Chinese medicine (TCM) formula, is used to relieve EMS in the clinic. This study aimed to examine the active components of LSNYP and the possible mechanism involved in its treatment of EMS. Ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was used to identify the chemical components of LSNYP. Human primary ectopic endometrial stromal cells (ecESCs) and eutopic endometrial stromal cells (euESCs) were isolated, and the expression levels of hypoxia inducible factor 1A (HIF1A), enhancer of zeste homolog 2 (EZH2) and steroidogenic factor 1 (SF-1) were detected by immunofluorescence and qPCR. Cobalt chloride (CoCl 2) was utilized to construct an in vitro hypoxic environment, and lentiviruses were engineered to downregulate HIF1A and EZH2 and upregulate EZH2. Subsequently, the expression levels of HIF1A, EZH2, and SF-1 were measured using qPCR or western blotting. The binding of EZH2 to the SF-1 locus in ESCs was examined via ChIP. Furthermore, the effects of LSNYP on the HIF1A/EZH2/SF-1 pathway were evaluated both in vitro and in vivo. A total of 185 components were identified in LSNYP. The protein and gene expression levels of HIF1A and SF-1 were increased, whereas those of EZH2 were decreased in ecESCs. After treating euESCs with 50 μmol L−1 CoCl 2 for 24 h, cell viability and estradiol (E 2) production were enhanced. Hypoxia decreased EZH2 protein expression, while si-HIF1A increased it. SF-1 was increased when EZH2 was downregulated in normal and hypoxic environments, whereas the overexpression of EZH2 led to a decrease in SF-1 expression. ChIP revealed that hypoxia reduced EZH2 binding to the SF-1 locus in euESCs. In vitro , LSNYP-containing serum decreased E 2 and prostaglandin E 2 (PGE 2) production, inhibited cell proliferation and invasion, and reduced the expression of HIF1A, SF-1, steroidogenic acute regulatory protein (StAR), and aromatase cytochrome P450 (P450arom). In vivo , LSNYP suppressed inflammation and adhesion and inhibited the HIF1A/EZH2/SF-1 pathway in endometriotic tissues. LSNYP may exert pharmacological effects on EMS by inhibiting E 2 synthesis and inflammation through regulation of the HIF1A/EZH2/SF-1 pathway. These results suggest that LSNYP may be a promising candidate for the treatment of EMS. [Display omitted] [ABSTRACT FROM AUTHOR]

Liriope spicata Lour., a species listed in the catalogue of 'Medicinal and Edible Homologous Species', is traditionally used for the treatment of fatigue, restlessness, insomnia and constipation. This study is aimed to evaluate the sedative and hypnotic effect of the saponins from a natural plant L. spicata Lour. in vivo. The total saponin (LSTS) and purified saponin (LSPS) were extracted from L. spicata , followed by a thorough analysis of their major components using the HPLC-MS. Subsequently, the therapeutic efficacy of LSTS and LSPS was evaluated by the improvement of anxiety and depression behaviors of the PCPA-induced mice. LSTS and LSPS exhibited similar saponin compositions but differ in their composition ratios, with liriopesides-type saponins accounting for a larger proportion in LSTS. Studies demonstrated that both LSTS and LSPS can extend sleep duration and immobility time, while reducing sleep latency in PCPA-induced mice. However, there was no significant difference in weight change among the various mice groups. Elisa results indicated that the LSTS and LSPS could decrease levels of NE, DA, IL-6, and elevate the levels of 5-HT, NO, PGD2 and TNF-α in mice plasma. LSTS enhanced the expression of neurotransmitter receptors, while LSPS exhibited a more pronounced effect in regulating the expression of inflammatory factors. In conclusion, the saponins derived from L. spicata might hold promise as ingredients for developing health foods with sedative and hypnotic effects, potentially related to the modulation of serotonergic and GABA A ergic neuron expression, as well as immunomodulatory process. L. spicata is a health drink and functional food that consumed in China for many years, which is considered to have function with nourishing Yin, clearing away heartburn, calming the nerves. Our results showed the saponins LSTS and LSPS administration could significantly increase the sleep duration time and immobility time, and decrease the sleep latency of the PCPA induced depression mice. LSTS and LSPS could decrease the NE, DA, IL-6 amount, and increase the 5-HT, NO, PGD2 and TNF-α level in mice plasma. LSTS could significantly improve the expression of neurotransmitters receptors (5HT-1A, 5HT-2A, GABAAα2, GABAAα3 and GABAAα5), and the LSPS showed better effect of regulating the inflammatory factors expression. This work proved that the major component saponins could relieve the spirit of PCPA induced mice, indicating that the saponins from L. spicata are potential functional food with spirit-quieting effect. [Display omitted] [ABSTRACT FROM AUTHOR]

Bufei Huoxue capsule (BHC) as a classic Chinese patent medicine formula, has the efficacy of tonifying the lungs and activating the blood. It has been extensively used in China for the treatment of chronic obstructive pulmonary disease (COPD) clinically. However, its mechanism is still unclear, which hampers the applications of BHC in treating COPD. The purpose of the present study was to demonstrate the protective efficacy and mechanism of BHC on COPD model rats by integrating serum metabolomics analysis and network pharmacology study. A COPD rat model was established by cigarette fumigation combined with lipopolysaccharide (LPS) airway drip for 90 consecutive days. After oral administration for 30 days, the rats were placed in the body tracing box of the EMKA Small Animal Noninvasive Lung Function Test System to determine lung function related indexes. Histopathological alteration was observed by H&E staining and Masson staining. The serum levels of inflammatory cytokine , matrix metalloprotein 9, and laminin were determined by ELISA kits. Oxidative stress levels were tested by biochemical methods. UHPLC-Q-TOF/MS analysis of serum metabolomics and network pharmacology were performed to reveal the bioactive metabolites, key components and pathways for BHC treating COPD. WB and ELISA kits were used to verify the effects of BHC on key pathway. BHC could improve lung function, immunity, lung histopathological changes and collagen deposition in COPD model rats. It also could significantly reduce inflammatory response in vivo, regulate oxidative stress level, reduce laminin content, and regulate protease-antiprotease balance. Metabolomics analysis found 46 biomarkers of COPD, of which BHC significantly improved the levels of 23 differential metabolites including arachidonic acid, leukotriene B4 and prostaglandin E2. Combined with the results of network pharmacology, the components of BHC, such as calycosin, oxypaeoniflora, (S)-bavachin and neobavaisoflavone could play therapeutic roles through the arachidonic acid pathway. In addition, the results of WB and ELISA indicated that BHC could suppress the expressions of COX2 and 5-LOX in lung tissues and inhibit the generation of AA and its metabolites in serum samples. Regulation of arachidonic acid metabolic pathway may be the crucial mechanism for BHC treating COPD. In summary, the studies indicated that BHC exhibited the protective effect on COPD model rats by anti-inflammatory and anti-oxidative properties through arachidonic acid metabolism pathway. This study provided beneficial support for the applications of BHC in treating COPD. [Display omitted] • BHC exhibits the protective effect on COPD model rats. • Anti-Inflammatory and anti-oxidant properties are exhibited by BHC. • BHC alleviates COPD by arachidonic acid metabolism pathway. [ABSTRACT FROM AUTHOR]

"Snow-white waterlily" (Nymphaea candida) dried flower possesses various efficacy in Uighur medicine such as reducing fever and nourishing the liver, anti-inflammatory and cough relieving, moistening the throat and quenching thirst. Polyphenols are characteristic component of N. candida as well as its quality markers, and the purpose of this study was to conduct investigations into anti-inflammatory, antitussive, antipyretic, and analgesic activities of the polyphenol-enriched fraction from N. candida (NCTP) in order to validate the traditional efficacy of this plant. The polyphenols in NCTP were analyzed by HPLC, and an acute oral toxicity study was conducted for NCTP. The anti-inflammatory activities of NCTP were evaluated using xylene induced ear edema, capillary permeability, cotton pellet granuloma, and carrageenan-induced rat paw edema, of which multiple biochemical indices were measured in carrageenan-induced rat paw edema such as prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2),5-lipoxygenase (5-LOX), interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) activities; the analgesic activities were investigated using acetic acid writhing, hot plate test, and formalin test; the anti-tussive and antipyretic effects were tested by ammonia induced cough in mice and yeast-induced fever respectively. NCTP with LD50 of 5222 mg/kg was low toxicity and safety. NCTP (200 mg/kg) could significantly reduce ear swelling and capillary permeability by 30.63% and 31.37%, respectively. NCTP revealed 15.76% inhibiting activities in cotton pellet granuloma in mice at a dosage of 200 mg/kg. Furthermore, NCTP (50, 100, and 200 mg/kg) substantially decreased carrageenin-induced paw edema in rats between 1 and 5 h, and NCTP could decrease PGE2, 5-LOX, COX-2 levels as well as IL-6, IL-1β, TNF-α activities compared with the control group; NCTP could decrease MDA contents in carrageenin-induced rise, and increase SOD and GSH activities. Furthermore, the dose-dependent inhibition effect of NCTP on pain was revealed in the hot plate experiment. In addition to reducing the amount of writhes brought on by acetic acid, NCTP (50, 100, and 200 mg/kg) significantly inhibited pain latency against both stages of the formalin test. Moreover, NCTP (50, 100, 200 mg/kg) showed the better antitussive activities in mice in a dose-dependent manner. In the yeast-induced pyrexia test, dosages of 50, 100, and 200 mg/kg resulted in a statistically significant drop in rectal temperature. The experimental results proved the analgesic, anti-inflammatory, anti-tussive and antipyretic activities of the polyphenol-enriched fraction from N. candida , and supported the traditional use of this plant as well. [Display omitted] [ABSTRACT FROM AUTHOR]

Shen Bai formula (SBF) is a proven effective traditional Chinese medicine for treating viral myocarditis (VMC) sequelae in clinic, and myocardial injury is the pathological basis of VMC sequelae. However, the pharmacological action and mechanism of SBF have not been systematically elucidated. In present research, the doxorubicin-induced myocardial injury rat model was used to evaluate the efficacy of SBF, and energy metabolism and metabolomics approaches were applied to elucidate the effects of SBF on myocardial injury. Through energy metabolism measurement system and UPLC-Q-TOF-MS/MS oriented blood metabolomics, directly reflected the therapeutic effect of SBF at a macro level, and identified biomarkers of myocardial injury in microcosmic, revealing its metabolomic mechanism. Results showed that SBF significantly improved the electrocardiogram (ECG), heart rate (HR), extent of myocardial tissue lesion, and ratio of heart and spleen. In addition, the serum levels of AST, CK, LDH, α-HBDH, cTnI, BNP, and MDA decreased, whereas SOD and ATP activity and content increased. Moreover, SBF increased locomotor activity and basic daily metabolism in rats with myocardial injury, restoring their usual level of energy metabolism. A total of 45 potential metabolomic biomarkers were identified. Among them, 44 biomarkers were significantly recalled by SBF, including representative biomarkers arachidonic acid (AA), 12-HETE, prostaglandin J 2 (PGJ 2), 15-deoxy-Δ-12,14-PGJ 2 , 15-keto-PGE 2 , 15(S)-HPETE, 15(S)-HETE, 8,11,14-eicosatrienoic acid and 9(S)-HODE, which involved AA metabolism, biosynthesis of unsaturated fatty acids and linoleic acid metabolism. We successfully replicated a myocardial injury rat model with the intraperitoneal injection of doxorubicin, and elucidated the mechanism of SBF in treating myocardial injury. This key mechanism may be achieved by targeting action on COX, Alox, CYP, and 15-PGDH to increase or decrease the level of myocardial injury biomarker, and then emphatically interven in AA metabolism, biosynthesis of unsaturated fatty acids and linoleic acid metabolism, and participate in regulating purine metabolism, sphingolipid metabolism, primary bile acid biosynthesis, and steroid hormone synthesis. [Display omitted] • Combine macro energy metabolism with micro serum metabolomics methods to systematically evaluate the efficacy of SBF. • Regulation of arachidonic acid and linoleic acid metabolism are the key pathways of SBF in treating myocardial injury. • COX, Alox, CYP, and 15-PGDH are the key enzymes in the treatment of myocardial injury with SBF. [ABSTRACT FROM AUTHOR]

Ethnopharmacological Importance: Uncaria tomentosa Willd. DC., is used in the Amazonian region of South America, wherein ethnic groups use the plant to treat diseases, including gastric disorders. However, despite its widespread popular use, this species has yet to be assessed for its anti-ulcer effects., Aim of the Study: In this study, we aimed to evaluate the in vivo gastroprotective and gastric healing activities of an aqueous extract of the bark of Uncaria tomentosa (AEUt) and sought to gain an understanding of the pharmacological mechanisms underlying these biological effects., Materials and Methods: To verify the gastroprotective properties rats were treated with AEUt (30, 60, or 120 mg/kg) prior to inducing gastric ulceration with ethanol or piroxicam. Additionally, the involvement of nitric oxide, non-protein sulfhydryl compounds (NP-SH), α-2 adrenergic receptors, and prostaglandins was investigated. Furthermore, a pylorus ligature model was employed to investigate the antisecretory activity of AEUt. The gastric healing effects of AEUt (60 mg/kg) were examined in rats in which ulceration had been induced with 80% acetic acid, whereas the quality of healing was evaluated in mice with interleukin-induced recurrent ulcers. We also evaluated the in vivo thickness of the gastric wall using ultrasonography. Moreover, the levels of reduced glutathione (GSH) and malondialdehyde (MDA) were evaluated in ulcerated mucosa, and we determined the activities of the enzymes myeloperoxidase (MPO), N-acetyl-β-D-glycosaminidase, superoxide dismutase, catalase, and glutathione S-transferase. In addition, we assessed the effects of AEUt on cell viability and subjected the AEUt to phytochemical analyses., Results: Administration of the AEUt (60 or 120 mg/kg) prevented ethanol- and piroxicam-induced ulceration, which was also confirmed histologically. Moreover, we observed that pre-treatment with NEM and indomethacin abolished the gastroprotective effects of AEUt, thereby indicating the involvement of NP-SH and prostaglandins in these protective effects. In addition, we found that the administration of AEUt had no appreciable effects on the volume, acidity, or peptic activity of gastric juice. Furthermore, the AEUt (60 mg/kg) accelerated the gastric healing of acetic acid-induced ulcers by 46.2% and ultrasonographic findings revealed a reduction in the gastric wall thickness in this group. The gastric healing effect of AEUt was also accompanied by a reduction in MPO activity. The AEUt (60 mg/kg) also minimized ulcer recurrence in mice exposed to IL-1β and was associated with the maintenance of GSH levels and a reduction in MDA contents. We deduce that the biological effects of AEUt could be associated with the activities of polyphenols and the alkaloids isomitraphylline and mitraphylline, identified as predominant constituents of the AEUt. Furthermore, we found no evidence to indicate that AEUt would have any cytotoxic effects., Conclusion: Collectively, our findings provide compelling evidence indicating the therapeutic efficacy of U. tomentosa. Our data indicate that compounds in AEUt confer gastroprotection and that this preventive effect of AEUt was accompanied by gastric healing and a reduction in gastric ulcer recurrence. Moreover, we provide evidence to indicate that the gastroprotective and gastric healing effects involve the antioxidant system and anti-inflammatory responses that contribute to preserving the gastric mucosa., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Abstract Ethnopharmacology relevance Sparassis crispa , also known as cauliflower mushroom, has been used historically in traditional Asian medicine. It possesses various biological activities, such as immunopotentiation, anti-diabetes, anti-cancer, and anti-inflammatory effects. Recently, we isolated the non-aqueous fraction from methanol extract of S. crispa (SCF4) by using water-organic solvent mixtures and high-performance liquid chromatography (HPLC). In the present study, we identified the anti-inflammatory activity and action mechanism of SCF4 in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophage cells. Materials and methods The chloroform layer isolated from S. crispa methanol extract was separated into seven fractions using preparative HPLC. The fractions were then applied to NO assay to identify the fraction with the best anti-inflammatory activity. The inflammation inhibitory effect and underlying mechanism of SCF4 in LPS-stimulated RAW264.7 cells were assessed using WST-1 assay, enzyme-linked immunosorbent assay (ELISA), ROS assay, and Western blot analysis. Results SCF4 significantly suppressed LPS-induced production of pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandin E 2 (PGE 2), and pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)− 6, and IL-1β, without cytotoxicity. In addition, SCF4 downregulated not only the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), but also the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) stimulated by LPS. SCF4 also blocked the nuclear translocation of NF-κB via reduction of inhibitor of κB alpha (IκBα) degradation. Furthermore, SCF4 inhibited the phosphorylation of transforming growth factor beta-activated kinase 1 (TAK1), an important upstream factor of NF-κB and MAPK signaling mediated through toll-like receptor (TLR). Conclusions These findings demonstrate for the first time the correlation between the anti-inflammatory activity of SCF4 and TLR-mediated NF-κB and MAPK signaling pathways in LPS-stimulated RAW264.7 macrophage cells, suggesting that the non-aqueous extract of S. crispa could be applied as a promising natural product for the prevention and treatment of inflammatory diseases. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Paralleling the increasing incidence of gastrointestinal disorders world-wide, therapeutic investigations of nutraceuticals to promote gastrointestinal health are gaining popularity. Although anecdotally well-known for its gut health promoting potential, sparse scientific evidence supports this action of Aspalathus linearis (Burm.f.) R. Dahlgren - or rooibos - at the gastrointestinal epithelial level. Traditionally, rooibos is considered to exert antispasmodic, anti-inflammatory, and anti-nociceptive effects in the gut. However, the direct effect on intestinal epithelium is unknown. Thus, to assess the validity of anecdotal claims, two larval zebrafish models were utilized to evaluate effects of rooibos on intestinal health. Firstly, a larval zebrafish model of gastrointestinal inflammation (2-day TNBS-exposure) was employed. Co-administration of 6α-methylprednisolone served as an internal treatment control. Assessments included live imaging techniques and post-mortem immunofluorescent staining of epithelial tight junction proteins. In addition, whole body H 2 O 2 and prostaglandin E2 assays were performed. Secondly, a gastrointestinal motility assay was performed, with known pro- and anti-kinetic mediators to assess the effect of rooibos to alter functional outcome in vivo. Aqueous and ethanol extracts of green rooibos rescued TNBS-induced reductions in neutral red stained length of larval mid-intestines. Subsequent experiments confirmed the rescue capacity of the aqueous green rooibos extract regarding whole body oxidative and inflammatory status. Concerning tight junction proteins, only the aqueous green rooibos extract – and not prednisolone – normalized both zona occludens-1 and occludin expression levels when compared the TNBS group. In terms of gastrointestinal motility, the aqueous green rooibos extract significantly reduced the extent of gut motility dysregulation achieved by kinetic modulators. Data indicates the potential of a 2 mg/ml aqueous extract of green rooibos to improve gastrointestinal integrity and functionality in vivo , suggesting beneficial effects of rooibos may already occur at the level of the gut. This provides some evidence to support indigenous knowledge. [Display omitted] • Green rooibos extract rescued TNBS-induced loss of intestinal epithelial viability. • Only aqueous green rooibos normalized ZO-1 and occludin expression levels. • Green rooibos reduced the extent of gut motility dysregulation. [ABSTRACT FROM AUTHOR]

Terminalia argentea Mart. (Combretaceae) is a deciduous tree commonly found in Brazil, Bolivia, and Paraguay. It occurs in all regions of Brazil and is widespread in the Amazon, Cerrado, Pantanal, Atlantic Rain Forest, and Caatinga Biomes. In the traditional medicine of Brazil, people widely use tea or decoction of its leaf materials for treating gastritis, ulcers, wound healing, and inflammation. The current study aims to evaluate the gastroprotective and ulcer-healing activities of the hydroethanolic extract of T. argentea leaves (HETa) and investigate the underlying mechanisms of action through in vivo and in vitro experiments. We extracted the leaves of T. argentea with a 70% hydroethanolic solution (HETa) and performed phytochemical analysis using high-performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MSn). We researched the antiulcer activity using in vivo and in vitro experiments, administering three doses (2, 10, and 50 mg/kg) and different concentrations of 1, 5, and 20 μg/mL, respectively. We verified the acute antiulcer activity using chemical models (acidified ethanol (EtOH/HCl) and indomethacin (IND)) and physiological models (water-immersion stress (WRS)). To induce chronic ulcers, used acetic acid and treated the animals for seven days. To investigate the mechanism of action, conducted assays of antioxidant activity, measured the dosage of inflammatory cytokines, quantified mucus, treated with inhibitors (IND, L-NAME, glibenclamide, and yohimbine), performed histopathological analysis, and measured gastric acid secretion. Furthermore, we performed in vitro experiments on murine macrophage cell lines (RAW 264-7 cells) to quantify nitrite/nitrate and cytokine production and on V79-4 cells to verify cell proliferation/migration. We conducted HPLC and ESI-MSn analyses to obtain a fingerprint of the chemical composition of the HETa, revealing the presence of phenolics (caffeoyl ellagic acid), flavonoids (rutin, quercetin xyloside, quercetin rhamnoside, quercetin glucoside, quercetin galloyl xyloside, quercetin), and tannins (terminalin), respectively. The three doses of HETa reduced acute and chronic ulcers in different models. The mechanism of action involves increasing mucus production and angiogenesis, and it partially involves prostaglandins, nitric oxide, K+ATP channels, and α 2 -adrenergic receptors. HETa also exhibited antioxidant potential, reducing myeloperoxidase (MPO) activity, and increasing glutathione (GSH) levels. Moreover, it demonstrated anti-inflammatory action by reducing nitrite/nitrate levels and pro-inflammatory cytokine concentrations in vivo , and it increased in vitro proliferation/migration of fibroblasts. The study shows that HETa presents a potent preventive and curative antiulcer effect in different ulcer models, supporting the popular use of homemade preparations of T. argentea leaves. The preventive and gastric healing ulcer activity of HETa involves multiple targets, including increasing the gastric mucus barrier, antioxidant defenses, and anti-inflammatory effects on gastric mucosa repair. Phytochemical analysis identified the presence of phenolic compounds, flavonoids, and tannins in HETa, and the antiulcer activity may be attributable to the combined effect of these constituents. [Display omitted] • HETa demonstrated potent gastroprotective and ulcer healing activity in experimental models. • HETa presented multitarget anti-ulcer action mechanism. • These results corroborate with the traditional use of T. argentea leaves for gastric ulcers. • HPLC and ESI-MSn analyses revealed the presence of phenolics, flavonoids and tannins in HETa. • HETa can be considered a new and promising anti-ulcer phytotherapeutic agent. [ABSTRACT FROM AUTHOR]

Hosta plantaginea (Lam.) Aschers flower is a famous Mongolian folk medicine in China and has a therapeutic effect on acute pharyngitis (AP). However, the effect and potential mechanism of H. plantaginea flower on AP have not been fully elucidated. The present work aimed to evaluate the effects and mechanisms of the crude extract of H. plantaginea flowers (HP) and its four fractions of petroleum ether fraction (HPA), ethyl acetate fraction (HPB), n-butanol fraction (HPC), and water residue (HPD) against AP in rats. A 15% ammonia-induced AP rat model in rats was established. Therapeutic effects of HP and HPA∼D in model rats were evaluated based on body weight, histopathological analysis, and inflammatory parameters, including tumor necrosis factor α (TNF-α), prostaglandin E2 (PGE2), interleukin 1β (IL-1β), and IL-6. The protein expression of nuclear factor kappa-B p65 (NF-κB p65), inhibitor of NF-κB alpha (IκBα), c-Jun N-terminal kinases (JNK), mitogen-activated protein kinase (MAPK) p38, extracellular signal-regulated kinase (Erk), just another kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt) were detected by a Western blotting assay. HP, HPB, and HPC treatments markedly alleviated AP in rats by increasing body weight and improving pathological damages in pharyngeal tissues. In addition, HP, HPB, and HPC treatments significantly inhibited inflammation, including decreasing the levels of TNF-α, PGE2, IL-1β, and IL-6, and suppressing phosphorylated protein expression of p65, IκBα, JNK, p38, Erk, JAK1, STAT3, PI3K, and Akt in pharyngeal tissues of rats. Collectively, HP, HPB, and HPC can attenuate pharynx injury in rats by suppressing inflammation via inhibition of NF-κB, MAPKs, JAK-STAT, and PI3K-Akt pathways, which supports the traditional use of H. plantaginea flowers. [Display omitted] • For the first time, the anti-AP effect and mechanism of Hosta plantaginea were explored in-depth. • Hosta plantaginea flower showed a significant anti-AP effect in rats. • HPB and HPC were the main active fractions of H. plantaginea flower. • HPB and HPC fractions showed anti-AP effects through inhibition of NF-κB, MAPKs, JAK-STAT, and PI3K-Akt pathways. [ABSTRACT FROM AUTHOR]

Liver cancer is a worldwide malignant tumor, and currently lacks effective treatments. Clinical studies have shown that epimedium (YYH) has therapeutic effects on liver cancer, and some of its prenylflavonoids have demonstrated anti-liver cancer activity through multiple mechanisms. However, there is still a need for systematic research to uncover the key pharmacodynamic material basis and mechanism of YYH. This study aimed to screen the anti-cancer material basis of YYH via integrating spectrum-effect analysis with serum pharmacochemistry, and explore the multi-target mechanisms of YYH against liver cancer by combining network pharmacology with metabolomics. The anti-cancer effect of the extract of YYH (E-YYH) was first evaluated in mice with xenotransplantation H22 tumor cells burden and cultured hepatic cells. Then, the interaction between E-YYH compounds and the cytotoxic effects was revealed through spectrum-effect relationship analysis. And the cytotoxic effects of screened compounds were verified in hepatic cells. Next, UHPLC-Q-TOF-MS/MS was employed to identify the absorbed components of E-YYH in rat plasma to distinguish anti-cancer components. Subsequently, network pharmacology based on anti-cancer materials and metabolomics were used to discover the potential anti-tumor mechanisms of YYH. Key targets and biomarkers were identified and pathway enrichment analysis was performed. The anti-cancer effect of E-YYH was verified through in vitro and in vivo experiments. Six anti-cancer compounds in plasma (icariin, baohuoside Ⅰ, epimedin C, 2″-O-rhamnosyl icariside Ⅱ, epimedin B and sagittatoside B) were screened out by spectrum-effect analysis. Forty-five liver-cancer-related targets were connected with these compounds. Among these targets, PTGS2, TNF, NOS3 and PPARG were considered to be the potential key targets preliminarily verified by molecular docking. Meanwhile, PI3K/AKT signaling pathway and arachidonic acid metabolism were found to be associated with E-YYH's efficacy in network pharmacology and metabolomics analysis. Our research revealed the characteristics of multi-component, multi-target and multi-pathway mechanism of E-YYH. This study also provided an experimental basis and scientific evidence for the clinical application and rational development of YYH. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Celosia argentea L. (Amaranthaceae), popularly known as "crista de galo", is used in folk medicine due to its diuretic and hypotensive effects. However, there are no reports in the literature regarding its pharmacological effects on the cardiovascular system as well as no data proving the safety of this species. Aim To perform a detailed ethnopharmacological investigation of the ethanol soluble fraction from C. argentea (ESCA) using male and female Wistar rats. Material and methods Firstly, a morpho-anatomical characterization was performed to determine the quality control parameters for the identification of the species under investigation. Then, the ethanol extract was obtained and chemically characterized by LC-DAD-MS. Furthermore, an oral acute toxicity study was performed in female Wistar rats. Finally, the possible diuretic and hypotensive effects of three different doses of ESCA (30, 100 and 300 mg/kg) were evaluated in male Wistar rats. Besides, the vasodilatory response of ESCA in mesenteric vascular beds (MVBs) and its involvement with nitric oxide/cGMP and prostaglandin/cAMP pathways as well as potassium channels were evaluated. Results The main secondary metabolites present in ESCA were phenolic compounds, megastigmanes and triterpenoid saponins. ESCA caused no toxic effects in female rats nor increased urinary excretion in male rats after acute administration. However, ESCA significantly increased the renal elimination of potassium and chloride, especially at the end of 24 h after administration. Intermediary dose (100 mg/kg) of ESCA was able to promote significant acute hypotension and bradycardia. Moreover, its cardiovascular effects appear to be involved with the voltage-dependent K+ channels activation in MVBs. Conclusion This study has brought new scientific evidence of preclinical efficacy of C. argentea as a hypotensive agent in normotensive rats. Apparently, these effects are involved with the activation of the voltage-sensitive K+ channels contributing to the reduction of peripheral vascular resistance and cardiac output. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance The danshen (the root of Salvia miltiorrhiza Bge.)-shanzha (the fruit of Crataegus pinnatifida Bge. var. major N.E.Br.) (DS) herb combination is a commonly used traditional Chinese medicine with cardiovascular disease (CVD) treatment potential. Materials and methods In this study, we investigated the anti-atherosclerotic effects and mechanisms of DS by the integration of network pharmacology and polypharmacology. Eight main components were selected for target fishing by PharmMapper. Results The network pharmacological study indicated that DS may target 41 proteins and 16 pathways associated with inflammation, lipid metabolism and endothelial protection, which indicates that DS probably adjusts these processes as part of its anti-atherosclerotic activities. Furthermore, this hypothesis was verified by polypharmacology using an atherosclerotic model. Histopathological examination showed that DS inhibited pathological changes in the arteries of atherosclerotic rats and reduced the intima-media thickness (IMT). DS significantly reduced the levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein-cholesterol (LDL-C) and increased the high-density lipoprotein-cholesterol (HDL-C) level in the blood. DS also decreased the concentrations of interleukin (IL)-1β and IL-18, indicating anti-inflammation activity. In addition, DS increased the serum levels of nitric oxide (NO) and 6-keto-prostaglandin F 1α (6-keto-PGF 1α) and decreased the serum levels of endothelin (ET) and thromboxane B 2 (TXB 2), indicating an endothelial protective effect. Conclusions In conclusion, DS has an anti-atherosclerotic ability to lower lipid concentrations and to protect endothelial function, and it also has anti-inflammatory activity. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Polyalthia is one of the largest and notable genera in Annonaceae family. Polyalthia species have been widely used in folklore medicine for the treatment of rheumatic fever, gastrointestinal ulcer and generalized body pain. Numerous in vitro and in vivo studies on Polyalthia Species have also corroborated the significant anti-inflammatory potential of its extracts and secondary metabolites. Aim of the study This review is an attempt to assess the anti-inflammatory activity of Polyalthia species by giving critical appraisal and establishing evidences of their traditional uses. Moreover this review will highlight the lead compounds for future drug development that can serve as a potential anti-inflammatory drug with comparative efficacy and minimum side effects. Materials and methods An extensive literature review, focusing the anti-inflammatory potential of Polyalthia species was conducted using the following databases:PubMed, ScienceDirect, SpringerLink, Ovid, Scopus and ProQuest, as well as the locally available books, journals and relevant documents. The reference lists of retrieved papers were also searched for additional studies. Results The Polyalthia species have shown significant anti-inflammatory activity through various mechanism of action. The most significant anti-inflammatory mechanism includes the inhibition of nuclear factor kappa B (NF-κB), prostaglandins (PGs), pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS). The data suggests that hydroxycleroda-3,13-dien-15,16-olide and 16-oxocleroda-3,13-dien-15-oic acid, quercetin, rutin, spinasterol, α-spinasterol, goniothalamin and (−)−5-hydroxygoniothalamin are the most potent anti-inflammatory compounds from Polyalthia species with comparable IC 50 with positive controls. Conclusions Numerous pharmacological studies have supported the use of Polyalthia species against pain, rheumatic fever, haemorrhages and inflammation in traditional medicine. Flavonoids, diterpenoids, sterols and styrylpyrones from genus Polyalthia are the most significant class of compounds with potent anti-inflammatory activity. Secondary metabolites from these classes should be brought into further research to fill the gaps of knowledge in pharmacokinetics, pharmacodynamics, bioavailability, and toxicity in order to convert the pre-clinical results into clinical data for further investigation. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Ilex pubescens Hook. et Arn (MDQ), a traditional Chinese herb, is used in the treatment of cardiovascular diseases. However, the mechanisms underlying the preventive effect of MDQ on blood stasis remain unclear. Aim of the study In this study, serum metabolomics integrated with a biochemical assay strategy were established to evaluate the preventive effect and mechanism of action of MDQ on rats with acute blood stasis. Materials and methods Forty-nine rats were divided into seven groups: the control group, model group, aspirin treatment group (30 mg/kg), clopidogrel treatment group (8 mg/kg) and three MDQ treatment groups (250, 500 and 1000 mg/kg). A hybrid quadrupole time of flight mass spectrometry (QTOF/MS) coupled to ultra-high-performance liquid chromatography (UPLC) was applied for profiling the serum metabolites. The multivariate data analysis techniques using unsupervised principal component analysis (PCA) and supervised orthogonal projections to latent structures discriminant analysis (OPLS-DA) were used for pattern recognition and distinguishing variabilities among groups. Results MDQ protected the rats against blood stasis, as evidenced by the restoration of the anti-platelet aggregation activity, fibrinogen concentration, prothrombin time, thrombin time, activated partial thromboplastin time, endothelial nitric oxide synthase, endothelin, thromboxane B 2 and 6-keto-prostaglandin F1 α. The combination of PCA and OPLS-DA revealed deviations in eighteen differential biomarkers in serum. The identified biomarkers were primarily engaged in the metabolic pathways including arachidonic acid metabolism, glycerophospholipid metabolism, phospholipid biosynthesis and bile acid biosynthesis. The levels of eleven biomarkers showed significant alterations and a tendency to be restored to normal values in MDQ-treated blood stasis rats. Moreover, a correlation network diagram was constructed to show the serum biomarkers perturbed by MDQ. Conclusions These results suggested that MDQ had preventive effects on blood stasis in rats via arachidonic acid metabolism and glycerophospholipid metabolism. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Luehea divaricata Mart. (Malvaceae) is an important medicinal species that is widely used as a diuretic in the Brazilian Pantanal region. An ethanolic supernatant that was obtained from an infusion of leaves of this species (ESLD) was recently shown to exert hypotensive and diuretic activity. Nevertheless, the secondary metabolites that are responsible for this activity and the molecular mechanisms of pharmacological action remain unknown. Aim We performed a detailed study to identify possible active metabolites that are present in different ESLD fractions and investigated their effects on renal and peripheral arteriolar tone. We further evaluated their interrelations with sustained diuretic and hypotensive actions. Materials and methods The ESLD was first obtained from L. divaricata leaves, and liquid-liquid fractionation was performed. The fractions were analyzed by liquid chromatography-mass spectrometry. An ethyl acetate fraction (AceFr), n -butanolic fraction (ButFr), and aqueous fraction (AqueFr) were then orally administered in male Wistar rats in a single dose or daily for 7 days. The doses were previously defined based on the yield that was obtained from each fraction. Hydrochlorothiazide was used as a positive control. Blood pressure, heart rate, urinary volume, pH, density, and urinary sodium, potassium, chloride, and calcium levels were measured. Serum levels of nitrite, thiobarbituric acid reactive species, nitrotyrosine, aldosterone, vasopressin, and plasma angiotensin converting enzyme activity were also measured. Finally, the direct effects of the ButFr on renal and mesenteric arteriolar tone and the role of nitric oxide and prostaglandins in the renal and hemodynamic effects were investigated. Results Of the fractions that were tested, only the ButFr exerted significant diuretic and saluretic effects. The AceFr and ButFr also had acute hypotensive effects, but only the ButFr maintained its response after 7 days of treatment. Prolonged treatment with the ButFr increased serum nitrite levels and significantly reduced oxidative and nitrosative markers of stress. Additionally, the ButFr caused a vasodilatory response in the renal and mesenteric arteriolar beds through the release of nitric oxide and prostaglandins. Finally, the diuretic and hypotensive effects of the ButFr were completely blocked by pretreatment with N ω-nitro- L -arginine methyl ester and indomethacin, thus demonstrating the direct involvement of nitric oxide and prostaglandins in these effects. Conclusion The ButFr that was obtained from Luehea divaricata exerted sustained diuretic and hypotensive effects. These effects were apparently attributable to the release of nitric oxide and prostaglandins, which reduce renal and peripheral arteriolar tone and lead to an increase in the glomerular filtration rate and a reduction of global peripheral resistance. These findings suggest that the ButFr may be a potential complementary therapy for several conditions in which diuretic and hypotensive effects are required. [ABSTRACT FROM AUTHOR]

Ethnopharmacology relevance Based on basic theories of Chinese medicine, Yi-Qi-Yang-Yin-Hua-Tan-Qu-Yu (YQYYHTQY) recipe was constituted by eleven kinds of Chinese herbs and effective in treatment of type 2 diabetes (T2DM). But the therapy target was unclear. Objective In this study, we used the serum proteome labeled by iTRAQ to find therapy target of YQYYHTQY recipe on T2DM. Materials and methods The rat model was induced by high-fat diet (HFD) and streptozotocin (STZ, 30 mg/kg). Drugs were administered to rats once daily for 14 days. Related laboratory parameters were observed. Serum proteome were compared between T2DM and YQYYHTQY group using the iTRAQ labeling quantitative proteomics technique. Functional differential proteins were analysis by STRING software. Target proteins were confirmed by ELISA kits. Results Hyperglycemia, hyperinsulinemia, insulin resistance, decrease of glucose transporter, depilation, less activity, flock together, depression, ecchymosis of tongue and tail appearance, the typical diabetic patients “a little more than three” symptoms, as well as the decrease of grip strength, serum cyclic adenosine monophosphate (cAMP)/ cyclic guanosine monophosphate (cGMP) ratio, serum high density lipoprotein-cholesterol (HDL-C) and the increase of serum triglyceride (TG), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), thromboxane B 2 (TXB 2 )/ 6-keto prostaglandin F1α (6-keto PGF1α) ratio, endothelin-1 (ET-1) levels were found in T2DM group. After drugs treatment, all the above indexes almost were improved in different degrees and effect of YQYYHTQY recipe was superior to pioglitazone hydrochloride. In addition, there were 23 differential proteins, 5 up-regulated and 18 down-regulated proteins. Of them, there were 4 proteins related with diabetes, blood and behavior. Cell division control protein 42 homolog (CDC42) and Ras homolog gene family member A (RhoA) were the therapy targets of YQYYHTQY recipe on T2DM. Conclusions YQYYHTQY recipe showed therapy effect on T2DM. CDC42 and RhoA proteins were the therapy targets of YQYYHTQY recipe. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Nowadays, bronchial asthma is still a severe disease threatening human health, and it is incumbent upon us to seek effective therapeutic drugs. Mahuang decoction (MHD), a classic famous Chinese prescription, has been used for thousands of years to prevent phlegm from forming, stop coughing and relieve asthma, but the relevant mechanism has not been thoroughly clarified. This study aims to investigate the anti-airway inflammation effect of MHD and the possible molecular mechanism underlying IL21/STAT3 signaling pathway, so as to provide guidance for the treatment of MHD on bronchial asthma. Materials and methods Specific pathogen free SD rats were randomly divided into 6 groups: normal control group, model group, positive group (Compound methoxyphenamine), MHD-treated groups at doses of 10 ml/kg, 5 ml/kg and 2.5 ml/kg, 10 rats in each group. Except for the normal control group, rats in other groups were sensitized with ovalbumin via introperitoneal injection and challenged with ovalbumin inhalation to trigger asthma model. At 24 h after the last excitation, bronchoalveolar lavage fluid (BALF) of every rat was drawn and the number of inflammatory cells was analyzed using cell counting method. ELISA method was performed to determine the concentrations of TXB 2 , 6-keto-PGF 1α , MMP-9, TIMP-1, IL-2, IL-4, IL-5 and TNF-α in rat serum. The protein expressions of IL-21, IL-21R, STAT3 and p-STAT3 in murine pulmonary tissues were assessed with western blotting analysis. Results Compared with the control group, the airway wall and airway smooth muscle of murine pulmonary tissues significantly thickened and massive inflammatory cells infiltration occurred around the bronchus in the model group, and the cell counts of WBC and EOS in BALF were also apparently increased, which indicated the rat asthma model was successfully established. MHD or Compound methoxyphenamine not only alleviated the pulmonary inflammatory pathological damages, but also down- regulated the numbers of WBC and EOS in BALF. What's more, the levels of TXB 2 , MMP-9, TIMP-1, ILs-(2, 4, 5) and TNF-α in rat serum were lessened by the treatment of MHD. In western blotting analysis, treatment with 10 ml/kg or 5 ml/kg MHD markedly declined the increased protein expressions of IL-21, IL-21R, STAT3 and p-STAT3 in lung tissues of asthmatic rats to normal level. Conclusion MHD intervention demonstrated a strong inhibitory action on the secretion of inflammatory mediators as well as the inflammatory cell infiltration in pulmonary tissues of asthmatic rats, and also depressed the protein expressions of IL-21, IL-21R, STAT3 and p-STAT3 in pulmonary tissues. MHD effectively mitigates airway inflammation and regulates the IL-21/STAT3 signaling pathway in rat asthma model. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Compound Muniziqi granule (CMG) is usually used as a traditional Uighur medicine to treat acne, chloasma, skin inflammation, primary dysmenorrhea (PDM), and menopausal syndrome. However, there are no sufficient data to support the clinic uses of CMG in PDM. Aim of the study This work aims to examine the effect of CMG as a treatment for PDM and reveal its possible therapeutic mechanism. Materials and methods In vivo and in vitro mouse PDM models were utilized in this study. The mouse uterine contraction was induced by oxytocin after progynova or estradiol benzoate pretreatment. CMG, alkaloid extracts from seeds of Peganum harmala (AEP), and 10% and 95% ethanol extracts from seeds of Nigella glandulifera (EEN10 and EEN95) were given to mice in three doses by gavage. The writhing times within 30 min after oxytocin treatment were recorded to evaluate the analgesic effect, and the glutathione peroxidase (GSH-Px), malondialdehyde (MDA), 6-keto-prostaglandin F 1α (6-k-PGF 1α ), prostaglandin F 2α (PGF 2α ), thromboxane B2 (TXB 2 ), and nitric oxide (NO) levels in uterine tissues and PGF 2α and MDA in serum were determined. The effects (contractile curve) of CMG, AEP, EEN10, and EEN95 on uterus contraction induced by oxytocin in isolated mouse uterus were recorded. Results In contrast to the control group, CMG, AEP, N10, and N95 could display analgesic activities dose dependently by reducing the writhing response of the PDM model mice. CMG, AEP, EEN10, and EEN95 could also remarkably decrease the level of PGF 2α , 6-k-PGF 1α , TXB 2 , NO and MDA in uterine tissues and PGF 2α and MDA in serum, whereas the activity of GSH-Px in uterine tissues was increased. Furthermore, CMG, AEP, EEN10, and EEN95 could significantly inhibit the frequency and amplitude of isolated uterus induced by oxytocin in a concentration-dependent manner. Conclusions CMG exhibited a significant protective effect on experimental PDM. The mechanisms are probably associated with abating lipid peroxidation and over-inflammatory reaction, and alleviating the contraction of isolated mouse uterus. The seeds of P. harmala and N. glandulifera in the CMG may play an important role in exerting protective effects on PDM. This study provides pre-clinic proof to the use of CMG in clinical practice of PDM. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The leaves and roots of Cissampelos sympodialis (Menispermaceae) are used by indian tribes and in folk medicine to treat genitourinary infections, inflammation, asthma and gastrointestinal disorders. Material and methods The standardized ethanolic extract (Cs-EtOHE) and alkaloids total fraction (Cs-TAF) obtained from aerial parts of C. sympodialis were evaluated in several models of acute gastric ulcers. The antisecretory and/or neutralizing mechanisms of the gastric acid secretion, cytoprotective, antioxidant and immunoregulatory mechanisms were also evaluated. Results Cs-EtOHE and Cs-TAF presented a reduction in gastric mucosa lesions against ethanol, NSAIDs, hypothermic restraint-stress and gastric juice containment induced ulcer models. This activity is related to alkaloids present in the extract, and involves the participation of sulfhydryl compounds, nitric oxide, K ATP channels, prostaglandins, decreased levels of IL-1β and TNF-α and increased levels of GSH and IL-10. Conclusion The data indicate gastroprotective activity, due to the participation of the cytoprotective, antioxidant and immunoregulatory mechanisms. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Moslae Herba (MH) is broadly used as an antiviral, antipyretic and anticoagulant drug which effectively treats respiratory diseases including cough, asthma, throat, cold and flu. Aim of this study The excessive inflammation of the lungs is the hallmark of severe influenza A virus (IAV) infection, while platelet aggregation and its subsequent microvascular thrombosis can exacerbate IAV-induced lung injury. Thus, inhibition of platelet aggregation can be a potential target for IAV treatment. Previous studies focus on the flavonoids from MH and their anti-inflammatory activities, but the anticoagulant compounds and potential molecular mechanism of MH remains unclear. This study was to isolate and characterize diketopiperazines (DKPs) from MH and to explore the underlying anticoagulant mechanism on IAV infection models. Materials and methods EtOAc sub-extract separated from MH ethanolic extract was subjected to fractionation through column chromatography. The chemical structures of pure compounds were characterized by the spectral analysis. Antiviral activities of DKPs were assayed in IAV-infected Madin-Darby canine kidney (MDCK) cells and mice. Anticoagulant effects of DKPs were investigated on adenosine 5′-diphosphate (ADP)-induced acute pulmonary embolism and IAV-induced lung injury in vivo , as well as the inhibition on platelet activating factor (PAF), arachidonic acid (AA) and ADP-induced platelet aggregation in vitro . The serum levels of thromboxane B 2 (TXB 2 ) and 6-keto-PGF 1α were detected by ELISA. The expressions of key proteins in CD41-mediated PI3K/AKT pathways were determined by western blotting analysis. Results Six DKPs were, for the first time, isolated from MH and identified as cyclo(Tyr-Leu) ( 1 ), cyclo(Phe-Phe) ( 2 ), cyclo(Phe-Tyr) ( 3 ), cyclo(Ala-Ile) ( 4 ), cyclo(Ala-Leu) ( 5 ) and Bz-Phe-Phe-OMe ( 6 ). Among these DKPs, cyclo(Ala-Ile) and Bz-Phe-Phe-OMe possessed low cytotoxicities and significant inhibition against cytopathic effects induced by IAV (H1N1 and H3N2) replication in MDCK cells. Furthermore, cyclo(Ala-Ile) and Bz-Phe-Phe-OMe significantly alleviated IAV-induced platelet activation and lung inflammation in mice. They could reduce the expression of CD41 and the phosphorylation of PI3K and AKT in PLTs of IAV-infected mice. Conclusion These results suggested that cyclo(Ala-Ile) and Bz-Phe-Phe-OMe isolated from MH have antiviral and anticoagulant effects against IAV-induced PLT aggregation and lung inflammation via regulating CD41/PI3K/AKT pathway, and could be used as the potential agents for IAV treatment. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Aconiti Lateralis Radix Preparata (AR) is the most frequently used herb to generate heat and treat symptoms associated with coldness in Asia. Aims of the study The hypothalamus is one of the master regulators to maintain constant core body temperature. Chronic exposure to cold stress disturbs homeostatic regulation, gradually resulting in hypothalamic inflammation. This study investigate the effects of AR, on the chronic intermittent cold (CIC)-induced release of pro-inflammatory signaling molecules in the mouse hypothalamus. Materials and methods Aconiti Lateralis Radix Preparata extract (ARE) were solubilized in distilled water and diluted with saline before administration. Male ICR mice (7 weeks old, 30–32 g) were divided randomly into 6 groups: (1) control, (2) cold stress, (3) ARE 30, (4) ARE 100, (5) ARE 300, and (6) ARE 1000 mg/kg groups. Groups (2)-(6) were exposed to CIC stress once a day for 14 days. CIC stress was achieved by exposing the mice to 4 °C and 60 ± 10% humidity for 120 min once a day. Rectal temperature was measured after terminating cold stress. Cortisol levels were measured from serum. Hypothalamus tissue was used for western blot analysis, and IL-9, IL-13, PGE1, and PGE2 levels were assessed. Results ARE treatment prevented the CIC-induced decrease in rectal temperature and increase in serum cortisol level. ARE-treated CIC-exposed mice demonstrated decrease in nuclear c-Fos levels dose-dependently compared to CIC-exposed mice. Nuclear NF-kB expression showed significant increase in CIC-exposed mice. ARE treatment significantly blunted the increase in nuclear NF-kB expression. CIC-exposed mice had significantly increased levels of both IL-9 and IL-13. Treatment with ARE suppressed the elevated IL-9 and IL-13 levels. Between control and CIC-exposed mice PGE1 levels showed no difference. However ARE (1000 mg/kg)-treated CIC-exposed mice had a significant increase in PGE1 level compared to CIC-exposed mice. PGE2 levels were significantly higher in CIC-exposed mice compared to control mice. ARE treatment significantly attenuated the increase in PGE2 levels. Conclusions Our findings suggest CIC stress disturbs the anti-inflammatory effect of cortisol and maintenance of the body temperature. Thus AR contributes to suppress the activated proinflammatory factors, IL-9, IL-13, and PGE-2, and to increase the heat production. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Ginger ( Zingiber officinale Roscoe) is a well known anti-inflammatory drug in the Egyptian, Indian and Chinese folk medicines, yet its mechanism of action is unclear. Aim of the study To explore its mechanism of action and to correlate it to its biophytochemicals. Materials and methods Various extracts viz. water, 50%, 70%, 80%, and 90% ethanol were prepared from ginger rhizomes. Fractionation of the aqueous extract (AE) was accomplished using Diaion HP-20. In vitro anti-inflammatory activity of the different extracts and isolated compounds was evaluated using protein denaturation inhibition, membrane stabilization, protease inhibition, and anti-lipoxygenase assays. In vivo anti-inflammatory activity of AE was estimated using carrageenan-induced rat paw edema in rats at doses 25, 50, 100 and 200 mg/kg b.wt. Results All the tested extracts showed significant ( p < 0.1) in vitro anti-inflammatory activities. The strongest anti-lipoxygenase activity was observed for AE that was more significant than that of diclofenac (58% and 52%, respectively) at the same concentration (125 μg/ml). Purification of AE led to the isolation of 6-poradol (G1) , 6-shogaol (G2) ; methyl 6- gingerol (G3) , 5-gingerol (G4) , 6-gingerol ( G5) , 8-gingerol (G6) , 10-gingerol (G7) , and 1-dehydro-6-gingerol ( G8 ). G1 , G2 and G8 exhibited potent activity in all the studied assays, while G4 and G5 exhibited moderate activity. In vivo administration of AE ameliorated rat paw edema in a dose-dependent manner. AE (at 200 mg/kg) showed significant reduction in production of PGE2, TNF-α, IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated upon activation, normal T-cell expressed and secreted (RANTES), myeloperoxidase (MPO) activity by 60%, 57%, 60%, 41%, 32% and 67%, respectively. AE at 100 and 200 mg/kg was equipotent to indomethacin in reduction of NO x level and in increasing the total antioxidant capacity (TAC). Histopathological examination revealed very few inflammatory cells infiltration and edema after administration of AE (200 mg/kg) prior to carrageenan. Conclusions Ginger anti-inflammatory activity is mediated by inhibiting macrophage and neutrophils activation as well as negatively affecting monocyte and leukocyte migration. This was evidenced by the dose-dependent decrease in pro-inflammatory cytokines and chemokines and replenishment the total antioxidant capacity. [ABSTRACT FROM AUTHOR]

The combined prescription of two classical decoctions (Ma-Xing-Shi-Gan decoction with Xiao-Chai-Hu decoction), named as San-Yang-He-Zhi (SYHZ) decoction, has been widely used for the treatment of influenza virus (IFV) infections for decades. This study aimed to evaluate the anti-influenza effect of SYHZ decoction and explore the underlying mechanism. The ingredients of SYHZ decoction were analyzed by mass spectrometry. An animal model of IFV infection was established by challenging C57BL/6J mice with PR8 virus. Three groups of mice were infected with lethal or non-lethal doses of IFV, then followed by oral administration of phosphate-buffered saline (PBS), or SYHZ, or oseltamir; blank control mice (without IFV infection) were treated with PBS. Survival rate, Lung index, colon length, body weight loss and IFV viral load were measured 7 days post infection; histology and electron-microscopy examinations of lung tissue were performed; cytokine and chemokine levels in lung and serum were measured; and the intestinal metagenome, the cecum metabolome, and the lung transcriptome were analyzed. SYHZ treatment significantly improved survival rate compared with PBS (40% vs 0%); improved lung index, colon length, and body weight loss; and alleviated lung histological damage and viral load. SYHZ-treated mice had significantly lower levels of IL-1β, TNF-α, IL-6, CCL2, CXCL10 in lung and serum, and increased levels of multiple bioactive components in cecum. Pro-inflammatory cytokines, Toll- and NOD-like receptors, pro-apoptosis molecules, and lung-injury-related proteins were downregulated in SYHZ mice, whereas surfactant protein and mucin were upregulated. The NOD-like receptor pathway, Toll-like receptor pathway, and NF-κB pathway were downregulated by SYHZ treatment. SYHZ decoction alleviated IFV infection in a mouse model. Multiple bioactive ingredients of SYHZ may inhibit replication of IFV and suppress excessive immune response. [Display omitted] • The SYHZ decoction significantly improves survival rate of IFV-infected mice and attenuate their lung injury. • The SYHZ decoction can reduce viral load of the lung and inhibit excessive inflammatory response in the IFV-infected mice. • The SYHZ reduces viral load, which probably involves multiple machnisms triggered by its multiple ingredients as follows: baicalin inhibits virus replication by suppressing autophagy pathway, saikosaponin A downregulates NF-κB pathway and blocks caspase-3-dependent virus ribonucleoprotein nuclear export. • The SYHZ inhibits excessive inflammatory response, which also probably contributes to synergistic effect of its multiple ingredients as follows: wogonin inhibits COX-2 to reduce production of prostaglandin, and downregulates NF-κB pathway to reduce the release of IL-1β, IL-6, TNF-α etc; Kynurenine inhibits differentiation of Th0 to Th17 to reduce the releases of IL-17. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Native Americans used plants from the genus Echinacea to treat a variety of different inflammatory conditions including swollen gums, sore throats, skin inflammation, and gastrointestinal disorders. Today, various Echinacea spp . preparations are used primarily to treat upper respiratory infections. Aim of the study The goal of this study was to evaluate the effects of an ethanolic E. purpurea (L) Moench root extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide (A15) on mast cells, which are important mediators of allergic and inflammatory responses. Inhibition of mast cell activation may help explain the traditional use of Echinacea . Materials and methods A15 was evaluated for its effects on degranulation, calcium influx, cytokine and lipid mediator production using bone marrow derived mast cells (BMMCs) and the transformed rat basophilic leukemia mast cell line RBL-2H3. Methods included enzymatic assays, fluorimetry, ELISAs, and microscopy. A root extract of E. purpurea, and low and high alkylamide-containing fractions prepared from this extract, were also tested for effects on mast cell function. Finally, we tested A15 for effects on calcium responses in RAW 264.7 macrophage and Jurkat T cell lines. Results A15 inhibited ß-hexosaminidase release from BMMCs and RBL-2H3 cells after treatment with the calcium ionophore A23187 by 83.5% and 48.4% at 100 µM, respectively. Inhibition also occurred following stimulation with IgE anti-DNP/DNP-HSA. In addition, A15 inhibited 47% of histamine release from A23187-treated RBL-2H3 cells. A15 prevented the rapid rise in intracellular calcium following FcεRI crosslinking and A23187 treatment suggesting it acts on the signals controlling granule release. An E. purpurea root extract and a fraction with high alkylamide content derived from this extract also displayed these activities while fractions with little to no detectable amounts of alkylamide did not. A15 mediated inhibition of calcium influx was not limited to mast cells as A23187-stimulated calcium influx was blocked in both RAW 264.7 and Jurkat cell lines with 60.2% and 43.6% inhibition at 1 min post-stimulation, respectively. A15 also inhibited the release of TNF-α, and PGE 2 to a lesser degree, following A23187 stimulation indicating its broad activity on mast cell mediator production. Conclusions These findings suggest that Echinacea extracts and alkylamides may be useful for treating allergic and inflammatory responses mediated by mast cells. More broadly, since calcium is a critical second messenger, the inhibitory effects of alkylamides on calcium uptake would be predicted to dampen a variety of pathological responses, suggesting new uses for this plant and its constituents. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Danhong Injection (DHI), a Chinese medical product extracted from Radix et Rhizoma Salviae Miltiorrhizae ( Salvia miltiorrhiza Bge., Labiatae, Danshen in Chinese) and Flos Carthami ( Carthamus tinctorius L., Compositae, Honghua in Chinese), has been reported to have effects on inflammatory, anti-fibrinolytic properties, antithrombotic and decrease blood-lipid. It is extensively used for the clinical treatment of cardiovascular disease. This study aimed to investigate the effects of DHI on blood-lipid levels and platelet aggregation rate in hyperlipidemia rats. Materials and methods Rats were randomly divided into 6 groups: normal control (NC), model control (MC), DHI-treated control at doses of 1.0 mL/kg, 2.0 mL/kg, 4.0 mL/kg, respectively, and Simvastatin positive control at dose of 2.0 mg/kg. All DHI treated groups were intraperitoneally injected for 7 days. The effects of DHI on serum triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were evaluated. And platelet activating factor (PAF), platelet membrane glycoprotein IIb/IIIa (GP IIb/IIIa) and 6-keto-prostaglandin F1а (6-K-PGF1а) were determined by enzyme-linked immunosorbent assay (ELISA). Moreover, the expression of prostaglandin I-2 (PGI 2 ), prostaglandin E-2 (PGE 2 ) and thromboxane A2 (TXA 2 ) in liver was determined by real-time PCR. Results Compared with the MC group, the rats treated with DHI had significantly reduced TC, TG, LDL-C, FIB, GP IIb/IIIa and platelet aggregation. Meanwhile, the thrombin time (TT), activated partial thrombin time (APTT), prothrombin time (PT), 6-K-PGF1а was significantly increased. Expression of PGI 2 and PGE 2 mRNA was significantly increased, whereas the TXA 2 was significantly reduced. Conclusions This study demonstrated that the blood lipid and platelet aggregation has a regulatory effect after DHI treatment. The insights gained from this study will improve understanding of the mechanisms involved in the effect of DHI on hyperlipidemia and the pharmacological rationale for the use of DHI in diseases caused by formation of thrombosis and lipid metabolic disorders. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Periploca forrestii Schltr. is a classical traditional Chinese medicine (TCM) called Heilonggu (HLG) in China. According to the theory of TCM, it possesses the efficacy of eliminating wind and removing dampness. In clinical practice, it is commonly used for the treatment of rheumatoid arthritis. The present work aimed to evaluate the anti-rheumatism activity of HLG ethanol extract and reveal the underlying molecular mechanism by employing an animal model of collagen-induced rheumatoid arthritis (CIA) in rats. Materials and methods The CIA was induced in male Sprague–Dawley rats by intradermal injection of bovine collagen-II in complete Freund's adjuvant (CFA) at the base of tail. The rats received oral administration of HLG (200 and 400 mg/kg) from day 1, with the treatment lasting for 28 days. A variety of indicators were measured for evaluation of anti-rheumatism effect, including paw swelling, arthritis scores, and histopathological changes. Furthermore, the serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and prostaglandin E2 (PGE2), as well as cyclooxygenase-2 (COX-2), nuclear factor NF-κB p65 and Src kinase in joint synovial tissues were detected to explore the possible mechanisms. Results The administration of HLG significantly restored type II collagen-induced arthritis in rats as evidenced by decrease in paw swelling and inflammatory factors in serum. Meanwhile, this treatment also notably reduced NF-κB p65 and COX-2 expression. Surprisingly, the activity of Src kinase was also inhibited demonstrated by downregulation of phosphorylated Src. Conclusion Our results revealed that HLG possessed observable therapeutic action on collagen-induced arthritis by inhibiting the activation of Src and nuclear translocation of NF-κB in rats. HLG may serve as a potential candidate for the management of patients with RA. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Gomphrena celosioides (Amaranthaceae) is a native medicinal plant found in Mato Grosso do Sul State that is used for treating urinary tract and kidney stones. This study aimed to evaluate the diuretic effects of ethanolic extract from G. celosioides (EEGC) on acute and extended diuresis to provide a pharmacological basis for its use in traditional medicine. Aim of the study To evaluate the diuretic and natriuretic activity of EEGC and its mechanism of action in an animal model. Materials and methods EEGC (30, 100 and 300 mg/kg) was orally administered in male Wistar rats, and urinary excretion was measured at intervals of up to 8 h after administration. To evaluate participation of the nitric oxide (NO), prostaglandin and bradykinin pathways in its effect, respective inhibitors were also administered together with effectives doses of EEGC and compared with control groups. A 7-day model with daily administration and urine measurement was also carried out. Results Oral administration of doses of 100 and 300 significantly increased urine output after 8 h compared to the control group. It was observed this effect is dependent on the NO, prostaglandin and bradykinin pathways because their inhibitors reduced the diuretic effects of EEGC. Moreover, after 7 days of treatment, the effect was sustained and a decrease in serum aldosterone was observed in the extract group. Conclusion According to the results, G. celosioides extract showed diuretic and natriuretic effects associated with more than one mechanism of action. Considering that all diuretic drugs are currently available for the treatment of volume and electrolyte disturbances, especially hypertensive status, the present results may have clinical relevance and open new possibilities for the development of new natural diuretics from G. celosioides . [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The stem bark of Dilodendron bipinnatum Radlk. (Sapindaceae), a tree native to Pantanal of Mato Grosso, Brazil, popularly known as “mulher-pobre” (poor woman), has been historically used by the locals, after decoction and maceration, for the treatment of inflammatory conditions. We have recently shown that these preparations indeed possess anti-inflammatory properties, which are mediated by the inhibition of cell migration and the modulation of Th1 and Th2 cytokines. The NO pathway was not affected. Aim of the present study The aim of the present study was to further investigate the mechanisms responsible for the anti-inflammatory properties of the hydroethanolic extract of the stem bark of Dilodendron bipinnatum (HE Db ). Materials and methods HEDb was obtained by maceration of the stem bark of D. bipinnatum as previously described. The corresponding effects on a macrophage-like cell line, RAW 264.7, were investigated. The apoptosis of RAW 264.7 upon treatment with LPS, HEDb and N-acetyl- L -cysteine (NAC) was assessed by flow cytometry, using an Annexin V-PE kit. The production of inflammatory cytokines (TNF-α, IL-1β and IL-10) and PGE 2 were evaluated by ELISA, after cell challenge with LPS. The intracellular redox state and changes in mitochondrial membrane potential were also assessed by flow cytometry, using DCFH-DA and JC-1 as probes. The protein expression levels of MAPK p-p38, p-ERK, p-JNK, MKP-1 and COX-2 were analysed by western blotting. Nuclear translocation of NF-қB was assessed by immunofluorescence microscopy. The quantified results are presented as a nuclear:cytoplasmic ratio. Results LPS, HEDb and NAC did not appear to decrease the number of viable cells in comparison to control treatment. HEDb attenuated the production of pro-inflammatory cytokines (IL-1β and TNF-α) and PGE 2 induced by LPS but did not affect IL-10. The production of ROS was also inhibited by HEDb (1, 5 or 20 µg/mL), even at the lowest concentration; at 20 µg/mL, HEDb was more effective than NAC, which was used as a positive control (74.1% and 66.2% inhibition of LPS's effect, respectively). LPS induced an increase in ΔΨm (19.2%, p<0.001), while HEDb inhibited the change in ΔΨm (7.7% at 20 µg/mL, p<0.001). The results of western blotting showed that HEDb inhibited the expression of MAPK p-p38, p-JNK and COX-2, while the expression of MKP-1 was increased. p-ERK was not affected. LPS promoted the nuclear translocation of NF-қB p65 (67%, p<0.01) in RAW 264.7 cells, in comparison to baseline (33%). Pre-treatment with HEDb inhibited this translocation of NF-κB p65 (58% at 20 µg/mL, p<0.001). Conclusion: HEDb has a potent anti-inflammatory activity and acts on multiple targets and biological pathways of potential therapeutic relevance. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Rhizoma Smilacis Glabrae (RSG) is traditionally used to treat gynecological disease, which is simply recorded in Chinese Pharmacopoeia. However, whether it has effect on upper genital tract inflammation (UGTI) is unclear. Aim of the study To evaluate the pharmacological effect of RSG on UGTI in rats and analyze its phytochemistry characteristics. Materials and methods The substances in RSG extract was qualified by LC-Q-TOF-MS method, and 11 substances were further quantified. The RSG extract, at dose of 241, 482 (clinical dose) and 964 mg/kg/day, was orally administered to UGTI rats whose upper genital tracts were multi-infected with pathogens. Infiltrations of neutrophil and lymphocyte and productions of IL-1β, IL-6, CXCL-1, MCP-1, RANTES, PGE2, COX-2, NF-κB p65 and IκB-α in upper genital tract were examined to evaluate the effects of RSG and its potential mechanism. Results A total of 77 substances were detected in RSG extract, with 50 substances putatively identified, most of which were flavonoids, phenolic acids and phenylpropanoids. The quantification analysis showed flavonoid had a relative high amount. In pharmacological study, RSG extract suppressed infiltrations of inflammatory cells, reduced over-productions of factors involved in inflammation and pelvic pain. A potential mechanism of these effects was blocking NF-κB signal pathway. Conclusions The RSG extract exhibited anti-inflammatory effect on UGTI, with a potential mechanism of blocking the activation of NF-κB signal pathway. The effect may be involved in the presence of substances, such as flavonoids and phenolic acids. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Wild chrysanthemum ( Chrysanthemum indicum ) is one of well-known medicinal plants traditionally used in Korea and China. As a variant of wild chrysanthemum, white wild chrysanthemum ( Chrysanthemum indicum var. albescens) is also ethnopharmacologically applied to treat various symptoms such as inflammatory diseases. Aim of study Although the anti-inflammatory activity of Chrysanthemum indicum has been reported, the anti-inflammatory activity and underlying molecular mechanism of white wild chrysanthemum are poorly understood. Materials and methods The effects of Chrysanthemum indicum var. albescens methanol extract (Civ-ME) on the production of inflammatory mediators, expression of pro-inflammatory genes, cell viability, and the activities of intracellular signaling molecules and transcription factors were investigated in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Results Civ-ME suppressed the production of both nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) without cytotoxicity in LPS-stimulated RAW264.7 cells. Civ-ME was found to reduce the mRNA levels of inflammatory genes such as inducible NO synthase (iNOS) and tumor necrosis factor (TNF)-α and reduced NF-κB-mediated transcriptional activation. Civ-ME inhibited the nuclear translocation of NF-κB (p65 and p50), and its upstream signaling composed of IκBα and IKKα/β. An NF-κB luciferase reporter gene assay and an in vitro kinase assay confirmed that AKT1 and AKT2 might be direct pharmacological targets of Civ-ME. In addition, luteolin was identified by HPLC analysis as the main active pharmacological components of Civ-ME. Conclusion Civ-ME exerts an anti-inflammatory effect by targeting AKT1 and AKT2 in the NF-κB signaling pathway in macrophage-mediated inflammatory responses. [ABSTRACT FROM AUTHOR]

Adverse reactions to traditional Chinese medicine injections involve pseudo-allergic reactions (PARs). However, in clinical practice, "immediate allergic reactions" and PARs in response to these injections are not often differentiated. This study aimed to clarify the type of reactions produced by Shengmai injections (SMI) and elucidate the possible mechanism. A mouse model was used to evaluate vascular permeability. Metabolomic and arachidonic acid metabolite (AAM) analyses were performed using UPLC-MS/MS, and the p38 MAPK/cPLA2 pathway was detected by western blotting. The first exposure to intravenous SMI rapidly and dose-dependently induced edema and exudative reactions in the ears and lungs. These reactions were not IgE-dependent and were likely to be PARs. Metabolomic analysis showed that endogenous substances were perturbed in SMI-treated mice, in which the arachidonic acid (AA) metabolic pathway was the most affected. SMI substantially increased the levels of AAMs in lung, including prostaglandins (PGs), leukotrienes (LTs), and hydroxy-eicosatetraenoic acids (HETEs). The p38 MAPK/cPLA2 signaling pathway was activated after a single SMI dose. Inhibitors of cyclooxygenase-2 and 5-lipoxygenase enzymes reduced exudation and inflammation in the ears and lungs of mice. Production of inflammatory factors that increase vascular permeability may result in SMI-induced PARs, and p38 MAPK/cPLA2 signaling pathway and downstream AA metabolic pathway are involved in the reactions. [Display omitted] • SMI-induced PARs involve a direct inflammatory response without IgE. • AAMs were involved in SMI-induced PARs. • SMI can activate the p38MAPK/cPLA2 signaling pathway. • AA inhibitors Nimesulide and zileuton inhibit AAMs production. [ABSTRACT FROM AUTHOR]

Egletes viscosa (L.) (macela) is a native wild herb that can be found in different states of northeastern Brazil. The infusions of its flower buds are traditionally used for the treatment of gastrointestinal disorders. E. viscosa possesses two chemotypes (named A and B), distinguishable by the composition of the essential oil from the flower buds. Although there are previous studies of the gastroprotective effect of the isolated constituents of E. viscosa , its infusions have not been investigated yet. The present study aimed to evaluate and compare the chemical composition and the gastroprotective effect of flower bud infusions of E. viscosa from chemotype A (EVCA) and chemotype B (EVCB). Sixteen infusions were brewed with flower buds according to the traditional preparation mode and were analyzed through a UPLC-QTOF-MS/MS based metabolomic approach for determination of their metabolic fingerprints and quantification of bioactive compounds. Afterward, these data were analyzed by chemometric methods (OPLS-DA) for discrimination of the two chemotypes. Additionally, infusions of EVCA and EVCB (50, 100 and 200 mg/kg, p.o.) were evaluated on gastric ulcers induced by absolute ethanol (96%, 0.2 mL, p.o.) in mice. To elucidate the gastroprotective mechanisms, the effect of EVCA and EVCB on gastric acid secretion and gastric wall mucus was determined and the role of TRPV1 channels, prostaglandins, nitric oxide and K ATP channels were assessed. Moreover, the oxidative stress-related parameters and the histological aspects of the stomach tissue were analyzed. The chemotypes can be discriminated from each other using UPLC-QTOF-MS/MS chemical fingerprints. Both chemotypes presented similar chemical compositions, consisting basically of caffeic acid derivatives, flavonoids and diterpenes. The quantification of bioactive compounds demonstrated that chemotype A possesses more ternatin, tanabalin and centipedic than chemotype B. EVCA and EVCB (50, 100 and 200 mg/kg, p.o.) significantly decreased the severity of ethanol-induced gastric lesions, as shown by a reduction in histological alterations and leucocyte infiltration in gastric tissue. The gastroprotective mechanism of both infusions involves an antioxidant effect, maintenance of gastric mucus and reduction gastric secretion. Stimulation of endogenous prostaglandins and nitric oxide release, activation of TRPV1 channels, and K ATP channels are also involved in the gastroprotection of the infusions. The gastroprotective effect of EVCA and EVCB was equivalent and mediated through antioxidant and antisecretory actions, including the activation of TRPV1 receptors, stimulation of endogenous prostaglandins and nitric oxide, and opening of K ATP channels. The presence of caffeic acid derivatives, flavonoids and diterpenes in both infusions is involved in mediating this protective effect. Our findings support the traditional use of infusions of E. viscosa for gastric disorders regardless of the chemotype. [Display omitted] • E. viscosa infusions protect against ethanol-induced gastric lesions in mice. • E. viscosa infusions have antioxidant, antisecretory, and cytoprotective actions. • NO, TRPV1and K ATP channels participate in the infusions' gastroprotection action. • Infusions of the two chemotypes of E. viscosa have similar chemical compositions. • Ternatin, tanabalin, and centipedic acid are present in both E. viscosa infusions. [ABSTRACT FROM AUTHOR]

Fridericia chica (Bonpl.) L.G. Lohmann (Bignoniaceae), is a climber native to Brazil, found in all Brazilian biomes. It is mostly known in Brazil as "carajiru," and home medicines made from the leaves have been used to cure disorders including stomach ulcers and other gastrointestinal disorders. The objective of the study was to investigate the F. chica hydroethanolic extract of leaves (HEFc) preventative and curative antiulcer gastrointestinal efficacy as well as the mechanisms of action using in vivo rodent models. F. chica was collected in the municipality of Juína, Mato Grosso, and its leaves were used to prepare the extract by maceration technique (70% hydroethanol in the 1:10 ratio, w/v) to obtain the HEFc. The chromatographic analysis of HEFc was carried out by High Performance Liquid Chromatography-Photo Diode Array-Electrospray Ionization-Mass Spectrometry (HPLC-PDA-ESI-MS)- LCQ Fleet™ system. To determine the potential antiulcer potential of HEFc (1, 5 and 20 mg/kg, p.o.), the gastroprotective activity was assessed in various animal models of stomach ulcers caused by acidified ethanol, water constraint stress, indomethacin, (acute), and acid acetic (chronic). Additionally, the prokinetic properties of the HEFC were assessed in mice. The gastroprotective underlying mechanisms were evaluated by the histopathological analysis and determination of gastric secretion (volume, free and total acidity), gastric barrier mucus, activation of PGs, NO, K + ATP channels, α 2 -adrenoceptor, antioxidant activity (GSH, MPO and MDA), NO and mucosal cytokines (TNF-α, IL-1β, and IL-10) levels. The chemical composition of HEFc was analyzed and apigenin, scutellarin, and carajurone were identified. HEFc (1, 5 and 20 mg/kg) showed effect against acute ulcers induced by HCl/EtOH with a reduction in the ulcerated area of 64.41% (p < 0.001), 54.23% (p < 0.01), 38.71% (p < 0.01), respectively. In the indomethacin experiment, there was no change in the doses tested, whereas in the water immersion restraint stress ulcer there was a reduction of lesions at doses of 1, 5, and 20 mg/kg by 80.34% (p < 0.001), 68.46% (p < 0.01) and 52.04% (p < 0.01). HEFc increased the mucus production at doses of 1 and 20 mg/kg in 28.14% (p < 0.05) and 38.36% (p < 0.01), respectively. In the pyloric ligation-induced model of gastric ulceration, the HEFc decreased the total acidity in all doses by 54.23%, 65.08%, and 44.40% (p < 0.05) and gastric secretory volume in 38.47% at dose of 1 mg/kg (p < 0,05) and increased the free acidity at the dose of 5 mg/kg by 11.86% (p < 0.05). The administration of EHFc (1 mg/kg) showed a gastroprotective effect possibly by stimulating the release of prostaglandins and activating K+ ATP channels and α 2- adrenoreceptors. Also, the gastroprotective effect of HEFc involved an increase in CAT and GSH activities, and a reduction in MPO activity and MDA levels. In the chronic gastric ulcer model, the HEFc (1, 5 and 20 mg/kg) decreased the ulcerated area significantly (p < 0.001) at all doses by 71.37%, 91.00%, and 93.46%, respectively. In the histological analysis, HEFc promoted the healing of gastric lesions by stimulating the formation of granulation tissue and consequently epithelialization. On the other hand, regarding the effect of HEFc on gastric emptying and intestinal transit, it was observed that the extract did not alter gastric emptying, but there was an increase in intestinal transit at the dose of 1 mg/kg (p < 0.01). These outcomes confirmed the advantages of Fridericia chica leaves for the treatment of stomach ulcers, which are well-known. HEFc was discovered to have antiulcer characteristics through multitarget pathways, which might be related to an increase in stomach defense mechanisms and a decrease in defensive factor. HEFc can be regarded as a potential new antiulcer herbal remedy because of its antiulcer properties, which may be attributed to the mixture of flavonoids, apigenin, scutellarin and carajurone. [Display omitted] • HEFc chemical profile was analyzed and apigenin, scutellarin, and carajurone were identified. • HEFc attenuated gastric ulceration in models of acute and chronic gastric ulcers. • HEFc presented antiulcer activity acting via multi-targets related to gastric ulcer. • Results support the folkloric usage of home remedies prepared from the leaves F. chica to treat gastric ulcer disorders. • HEFc can be considered as a promising new antiulcer herbal medicine. [ABSTRACT FROM AUTHOR]

Tylophora yunnanensis Schltr (TYS) is widely distributed in Yunnan, Guizhou, and other places in China. It is commonly used by folks to treat hepatitis and other liver-related diseases; however, its mechanism of action is still unclear. This study aimed to determine the effects of TYS on regulating gut microbiota and its metabolites in non-alcoholic steatohepatitis (NASH) rats by inhibiting the activation of NOD-like receptor protein3 (NLRP3). An HFD-induced rat model was established to investigate if the intragastric administration of TYS could mediate gut microbiota and their metabolites to ultimately improve the symptoms of NASH. The improving effects of TYS on NASH rats were assessed by measuring their body weight, lipid levels, histopathology, and inflammatory factor levels in the rat models. The regulatory effects of TYS on NLRP3 in the NASH rats were analyzed using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), which determined the levels of NLRP3-related factors. The changes in the composition of the gut microbiota of NASH rats were analyzed using 16S rRNA gene sequencing technology. Meanwhile, the Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for the non-targeted analysis of metabolites in the cecum contents. The results showed that TYS could improve NASH by decreasing the body weight and levels of lipid, AST, ALT, LPS, FFA, VLDL, IL-1β, IL-6, TNF-α, TGF-β, NLRP3, ASC, and Caspase-1 in the NASH rats. The analysis of gut microbiota showed that TYS could improve the diversity and abundance of gut microbiota and alter their composition by decreasing the Firmicutes/Bacteroidetes (F/B) ratio and relative abundances of Lachnospiraceae, Christensenellaceae, Blautia, etc. while increasing those of Muribaculaceae, Rumiaococcus, Ruminococcaceae, etc. The analysis of metabolites in the cecum contents suggested that the arachidonic acid metabolism, bile secretion, serotonergic synapse, Fc epsilon RI signaling pathway, etc. were regulated by TYS. The metabolites enriched in these pathways mainly included chenodeoxycholic acid, prostaglandin D2, TXB2, 9-OxoODE, and 13(S)-HOTrE. These findings suggested that TYS could alleviate the NASH symptoms by decreasing the body weight, regulating the lipid levels, reducing the inflammatory response, and inhibiting the expression levels of NLRP3, ASC, and Caspase-1 in the NASH rats. The changes in the composition of gut microbiota and their metabolic disorder were closely related to the activation of NLRP3. TYS could significantly inhibit the activation of NLRP3 and regulate the composition of gut microbiota and the disorder of metabolites during NASH modeling. [Display omitted] [ABSTRACT FROM AUTHOR]

Caesalpinia coriaria (Jacq.) Willd is widely used as a traditional medinal plant in Mexico for protective and healing purposes and the treatment of gastrointestinal diseases. To investigate the gastroprotective effect of extract of Caesalpinia coriaria pods against ethanol-induced and indomethacin-induced gastric lesion models, its anti-inflammatory and antioxidative activities, and its main compounds through LC-MS analysis. Male Wistar rats were orally administered a methanol extract obtained from the pods of C. coriaria at doses of 10, 30, 100, and 300 mg/kg prior to inducing gastric lesions with ethanol or indomethacin. Gastric mucosal lesions were evaluated by macroscopic and histopathological alterations. Determination of prostaglandin E 2 (PGE 2), alpha tumor necrosis factor (TNF-α), leukotriene B 4 (LTB 4), nitrites/nitrates, superoxide dismutase (SOD), and H 2 S gastric levels were investigated. Its main compounds of the active extract through LC-MS analysis. Phenolic compounds were identified as major components of methanol extract. LC-MS analysis identified 15 constituents, and the significant compounds were gallic acid, 3- O -galloylquinic acid, digalloylglucose, tetragalloylglucose, valoneic acid dilactone, pentagalloylglucose, digalloylshikimic acid, and ellagic acid. Pretreatment with the extract at doses of 100 and 300 mg/kg significantly reduced gastric ulcer lesions in both models. Compared with the reference drugs (omeprazole or ranitidine, respectively), no significant difference was found (p < 0.05). The extract's gastroprotective effect was accompanied by significant decreases in leukocyte recruitment, and gastric levels of TNF-α and LTB 4 by two to fourfold (p < 0.05). Also, gastric levels of PGE 2 gastric levels were maintained and the antioxidant enzyme activities of SOD and nitrate/nitrite in the gastric tissue were improved (p < 0.05). The LC-MS analysis indicated the presence of hydrolyzable tannins (mainly gallic acid derivatives). The results suggest that the gastroprotective effect of the methanol extract of C. coriaria pods occurs through anti-inflammatory, antioxidant, and NO modulation properties, and gallic acid derivatives may be the main possible compounds responsible for its actions. [Display omitted] [ABSTRACT FROM AUTHOR]

Ethno-pharmacological relevance Pattanga is botanically equated as Caesalpinia sappan Linn. (Family: Caesalpiniaceae ) and is used in Ayurveda system of medicine since ages. According to Ayurveda, useful part is Heartwood, which is bitter, astringent and acrid and is useful in vitiated conditions of vata and pitta , burning sensation, wounds, ulcers, leprosy, skin diseases, menorrhagia, leucorrhea, and diabetes. It is used as a major ingredient in Ayurvedic formulations and preparations like Patrangasava, Chandanadya Thalia, and Karpuradyarka . Aim of the study The present study is planned to evaluate the gastroprotective activity of the selected Ayurvedic drug using three different in vivo gastric ulcer models, so as to provide scientific evidence for the Ayurvedic claims. Materials and methods For this study, Wistar albino rats fasted overnight were selected. The hydroalcoholic extract of Caesalpinia sappan heartwood at the dose level 250 and 500 mg/kg body weight was selected and administered orally before necrotizing agents. Antioxidant and antiulcer parameters were evaluated and the stomach samples were subjected for histopathological studies. In addition, PGE2 estimation and protein expressions of COX-1, COX-2 and iNOS were analyzed by Western blot. The plant extract was subjected to LCMS/MS analysis. In addition, Cytoprotective effect in isolated gastric mucosal cells, TUNEL Assay, Acid neutralizing capacity assay, H + /K + ATPase inhibitory assay were performed. Results The ulcer protection was found to be 92%, 86% and 64% against ethanol, NSAID and pylorus ligation induced ulcer respectively. The hydro-alcoholic extract of C. sappan heartwood exhibited cytoprotective effect with 76.82% reduction against indomethacin-induced cytotoxicity at the concentration of 25 µg/ml. C. sappan showed 63.91% inhibition in H + /K + ATPase inhibitory assay at the concentration 500 µg/ml. Conclusions Our results depict that Caesalpinia sappan heartwood possesses gastroprotective activity, possibly mediated through cytoprotection and antioxidant mechanisms. The data obtained in the present study provides scientific support for the traditional use of Caesalpinia sappan in the management of peptic ulcer. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Agastache mexicana has been used in traditional medicine for relief of abdominal pain and treatment of other diseases. Two subspecies have been identified: A. mexicana ssp. mexicana (AMM) and A. mexicana ssp. x olocotziana (AMX) and both are used traditionally without distinction or in combination. Aim of the study To determine the effect of methanol extracts of A. mexicana ssp. mexicana and A. mexicana ssp. x olocotziana on gut motility and their possible mechanism of action. Materials and methods The effect of AMM and AMX methanol extracts were tested on the spontaneous activity in the isolated guinea pig ileum and on tissues pre-contracted with KCl, electrical field stimulation (EFS) or ACh. In addition, the possible mechanism of action of each subspecies on gut motility was analyzed in the presence of hexametonium, indomethacin, L-NAME, verapamil, atropine or pyrylamine. A comparative chromatographic profile of these extracts was also done to indicate the most abundant flavonoids presents in methanol extracts of both subspecies. Results AMM, but not AMX, induced a contractile effect in the guinea pig ileum. This spasmogenic effect was partially inhibited by atropine, antagonist of muscarinic receptors; and pyrilamine, antagonist of H 1 receptors. In contrast, AMX, but not AMM, diminished the contractions induced by KCl, EFS or ACh. The spasmolytic activity of AMX was partially inhibited by hexamethonium, ganglionic blocker; and indomethacin, inhibitor of the synthesis of prostaglandins; but not by L-NAME, inhibitor of nitric oxide synthase. In addition, AMX diminished the maximal contraction induced by CaCl 2 in a calcium-free medium. Chromatographic analyses of these methanol extracts showed the presence of acacetin and tilanin in both. Conclusions These results suggest that in folk medicine only AMX should be used as spasmolytic, and not in combination with AMM as traditionally occurs, due to the spasmogenic effects of the latter. In addition, activation of nicotinic receptors, prostaglandins and calcium channels, but not nitric oxide mechanisms, could be responsible for the spasmolytic activity of AMX. On the other hand, release of ACh and histamine could be involved in the spasmogenic effect induced by AMM. Acacetin and tilanin are present in methanol extracts of both subspecies and both flavonoids were more abundant in AMX than AMM. Our findings contribute to the validation of the traditional use of Agastache mexicana in relieving gastrointestinal disorders, but indicate that the subspecie that should be used for this effect is A. mexicana ssp. xolocotziana . [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Da Chuanxiong Formula (DCXF) which origins from Jin Dynasty is a famous classical 2-herb Chinese medicinal prescription. It is composed of dried rhizomes of Ligusticum chuanxiong (Chuanxiong Rhizoma, CR) and Gastrodia elata (Gastrodiae Rhizoma, GR) at the ratio of 4:1 (w/w). It has been used to treat headache which is caused by wind pathogen and blood stasis for thousands of years in China. Aim of study The present study was performed to investigate the anti-inflammatory effect of DCXF and elucidate its underlying molecular mechanisms using LPS-stimulated RAW 264.7 cells. Materials and methods The anti-inflammatory effect of DCXF was evaluated using LPS-stimulated RAW 264.7 cells. Generation of nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) were measured by the Griess colorimetric method and enzyme-linked immunosorbent assay (ELISA), respectively. The gene expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected by reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, the effect of DCXF on NF-κB activation was measured by western blot assay. Results Treatment with DCXF significantly suppressed the productions of NO and PGE 2 through inhibitions of iNOS and COX-2 expressions in LPS-stimulated RAW 264.7 cells. DCXF significantly decreased IκBα phosphorylation, inhibited p65 expression and reduced p-p65 level. These results suggested the anti-inflammatory effect of DCXF was associated with the reduction of inflammatory mediators through inhibition of NF-κB pathway. Conclusions These results indicated that DCXF inhibited inflammation in LPS-stimulated RAW 264.7 cells through inactivation of NF-κB pathway. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Hibiscus sabdariffa Linn., also known as roselle, is used in folk medicine as an anti-inflammatory agent. Urinary tract infection (UTI) is a common problem in long-term care facilities. However, effects of roselle on UTI and renal inflammation remained to be analyzed. Aim Here we surveyed the effect of roselle drink on the prevention of UTI in long-term care facilities and analyzed the anti-inflammatory potential of roselle on lipopolysaccharide (LPS)-induced renal inflammation in mice. Materials and methods Survey questionnaires and clinical observation were applied to evaluate the use of roselle and the incidence of UTI in long-term care facilities. Mice were administrated roselle orally for 7 consecutive days and then challenged with LPS. Anti-renal inflammatory effects of roselle were analyzed by microarray and immunohistochemical staining. Results Clinical observation showed that taking roselle drink in residents with urinary catheters reduced the incidence of UTI in long-term care facilities. Renal inflammation is a key event of UTI. Roselle suppressed LPS-induced nuclear factor-κB (NF-κB) activation in cells and LPS-induced interleukin-1β production in mice a dose-dependent manner. Immunohistochemical staining showed that roselle inhibited LPS-induced NF-κB activation and inflammatory cell infiltration in kidney. Gene expression profiling further showed that roselle suppressed the expression of pro-inflammatory cytokine genes and enzyme genes involved in the production of prostaglandin and nitric oxide. In addition, NF-κB was the main transcription factor involved in the regulation of roselle-regulated gene expression in kidney. Conclusions This is the first report applying clinical observation-guided transcriptomic study to explore the application and mechanism of roselle on UTI. Our findings suggested that roselle drink ameliorated LPS-induced renal inflammation via downregulation of cytokine network, pro-inflammatory product production, and NF-κB pathway. Moreover, this report suggested the potential benefit of roselle drink on UTI. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Ageratum conyzoides L. is a plant widely used in traditional medicine in tropical and subtropical regions of the world due to its anti-inflammatory, antinociceptive and antibacterial properties. Aim of the study To characterize the standardized extract of polymethoxyflavones (SEPAc) from the plant and evaluate its antinociceptive and anti-inflammatory effects. Materials and methods The SEPAc purified from the ethanol extract of the plant leaves was characterized by high resolution mass spectrometry and the methoxyflavones were quantified by a validated UPLC-PDA method. The antinociceptive and anti-inflammatory activities of the SEPAc were evaluated after oral administration on the acute nocifensive behavior of mice induced by formalin, prostaglandin E2 (PGE2) and proinflammatory cytokines (interleukin-1beta (IL-1β)) and tumor necrosis factor-alpha (TNF-α) in mice. Results Qualitative analyses revealed the presence of seven methoxyflavones in the SEPAc, also a simple UPLC-PDA method was developed and validated for the quantification of 5,6,7,3′,4′,5′-hexametoxyflavone; nobiletin; 5′-methoxynobiletin and eupalestin, major compounds in the extract. The SEPAc exhibited antinociceptive and anti-inflammatory activities in both formalin phases, with significant inhibition of the paw edema formation and significant reduction of the nocifensive response induced by an intraplantar injection of PGE2 and intrathecal injection of interleukin-1β. Conclusions The SEPAc exhibited significant antinociceptive and anti-inflammatory effects. These results provided scientific suggestion of its potential as a source of new medicines to treat inflammatory diseases, such rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Cinnamomum cassia Presl (Lauraceae) can be found southern China and its bark is commonly used for centuries as ingredient in food and cosmetic industry. The twigs of Cinnamomum cassia Presl is popularly used in China to treat inflammatory processes, pain, menstrual disorders, hypertension, fever etc. The aim of this study is to evaluate the antinociceptive and anti-inflammatory properties of the essential oil (EO) from the twigs of Cinnamomum cassia Presl. Material and methods The chemical characterization of the EO was performed by gas chromatography coupled with mass spectrometry (GC-MS). The EO doses of 15, 30, and 60 mg/kg were employed in the biological assays. The antinociceptive effects of the EO were evaluated using the models of acetic acid-induced writhing, oxytocin-induced writhing, and formalin and complete Freund's adjuvant (CFA) -induced overt pain tests. we also investigated the effect of the EO in pain intensity to a mechanical stimulus (mechanical hyperalgesia) after carrageenan by using an electronic version of von Frey filaments. Evaluation of anti-inflammatory activity was based on paw edema induced by carrageenan (300 µg/25 µL/paw) in mice. The levels of cytokines, NO, and PGE2 in paw skin tissue were determined according to instructions. COX-2 and iNOS proteins in paw skin tissue were assessed by Western Blot. Results The EO (15, 30, and 60 mg/kg) reduced the number of abdominal writhings induced by acetic acid with inhibition of 38.0%, 55.4% and 58.7%, respectively. The EO (15, 30, and 60 mg/kg) also reduced the number of abdominal writhings induced by oxytocin with inhibition of 27.3%, 51.7% and 69.0%, respectively. The EO significant inhibited the inflammatory (second phase: 10–30 min) phase of the formalin-induced paw flinching and licking at the doses of 15, 30, and 60 mg/kg. The EO at the tested doses of 15, 30, and 60 mg/kg showed inhibited CFA-induced paw flinching and licking. The EO (15, 30, and 60 mg/kg) also inhibited carrageenan-induced mechanical hyperalgesia and paw edema. It also decreased the levels of cytokines (TNF-α, and IL-1β), NO, and PGE2 in carrageenan-induced mice paw skin tissue. Moreover, Western blot analysis showed that COX-2 and iNOS expressions in paw skin tissue of mice were significantly reduced. Conclusions These results demonstrate that the antinociceptive and anti-inflammatory properties of the EO from the twigs of Cinnamomum cassia Presl, corroborating its use in folk medicine. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Zingiber simaoense Y. Y. Qian belongs to the Zingiberaceae family. Its rhizome has been used in Thai folk medicine to relieve gastric disorders; however, scientific evidence of its pharmacological activities has not yet been revealed. Aim of the study This study was designed to validate the gastroprotective activity and to identify possible mechanisms of gastroprotection of Z. simaoense rhizome ethanol extract (ZSE) in rats. Materials and methods The gastroprotective effect of ZSE was tested using models of gastric ulcers induced by acidified ethanol, indomethacin, and restraint water immersion stress. Models for determination of gastric wall mucus secretion and plasma malondialdehyde levels as well as pylorus ligation were used to explore the mechanisms of action. Results After oral administration by intragastric gavage, ZSE 7.5, 15, and 30 mg/kg or cimetidine 100 mg/kg significantly inhibited the formation of gastric ulcer in all gastric ulcer models. The gastric wall mucus amount was significantly higher than that of the ulcer control group, plasma malondialdehyde levels were normalized, and gastric secretion was partly inhibited by pretreatment with ZSE. Conclusions This study demonstrates the gastroprotective activity of ZSE in rats. The mechanisms of action of ZSE may depend on its ability to maintain the integrity of gastric wall mucus through the protection of gastric mucus, and/or by increasing the gastric mucus synthesis and secretion through prostaglandin synthesis. Moreover, the antioxidant activity of ZSE may also contribute to its mechanism of gastroprotection. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance of the study Diarrhea remains one of the main killers of children aged below five years. Traditional antidiarrheal remedies form a potentially viable source of novel low cost efficacious treatments in low resource settings. There is therefore a pressing need to scientifically evaluate these remedies. Aim of the study This study aimed to investigate the in vivo and in vitro antidiarrheal activity of freeze dried Bidens biternata, a herb used in traditional Ayurvedic medicine in the management of diarrhea. Materials and methods In the castor oil test, twenty (20) adult Sprague-Dawley rats were randomized to a negative control (normal saline, n=5), a positive control (5 mg/kg loperamide, n=5), and two test groups. The low dose test group received 200 mg/kg Bidens biternata extract (n=5) while the high dose test group received 400 mg/kg B. biternata extract (n=5). Castor oil (4 ml/kg) was then administered to the animals one hour after administration of the respective treatments after which the total mass of fecal output excreted after four (4) hours was determined. In the charcoal meal test fifteen (15) Sprague Dawley rats were randomized to a control group (normal saline 5 ml/kg orally, n=5), a positive control group (atropine sulfate 0.1 mg/kg i.p., n=5) and a test group (400 mg/kg B. biternata extract, n=5). Charcoal meal was then administered via oral gavage to each rat thirty (30) minutes after the administration of the various treatments. The distance covered by the charcoal meal from the pylorus was then determined after sacrifice of the animals thirty minutes after the meal. In the enteropooling test twenty (20) Sprague-Dawley rats were randomized to a control group (5% v/v ethanol in normal saline, n=5), a positive control group (5 mg/kg loperamide, n=5) and a test group (400 mg/kg B. biternata extract, n=5). For each group prostaglandin E2 (PGE2) (100 μg/kg) was administered immediately after the treatments. The animals were then sacrificed half an hour later and the volume of the small intestine contents determined. The effects of different concentrations of B. biternata extract (0.5. 1.0, 2.0, 3.0 and 5.0 mg/ml) on jejunal contraction were investigated and a dose-response curve constructed using the experimental data after which The ED50 dose was determined. The effect of tamsulosin (α1 adrenergic blocker), yohimbine (α2 adrenergic blocker), propranolol (β adrenergic blocker) and naloxone (μ opioid blocker) on the contractile activity of the extract were also investigated. The experimental data were expressed as mean±standard error of mean (SEM) and then analyzed using one-way ANOVA followed by Tukey's post hoc test in cases of significance (set at p<0.05). Results The freeze dried extracts of B. biternata had significant antidiarrheal effects in the castor oil induced diarrhea model (p<0.01) with the highest activity being observed at the 400 mg/kg dosage level (1.66±0.81 g vs. 4.54±0.51 g control, p=0.01). B. biternata extract had significant effects on intestinal motility in the charcoal meal test compared to the control group (43.61±4.42% vs. 60.54±3.33%: p<0.05). B. biternata extract had a significant effect on PGE2 induced enteropooling (3.06±0.07 ml vs. 4.74±0.10 ml; p<0.001). The freeze dried extracts of B. biternata had a significant negative effect on the contractility of the isolated rabbit jejunum (p<0.001). The effects of the extract were significantly attenuated by tamsulosin (53.94±4.20% vs. 80.57±4.09%; p<0.01) and naloxone (53.94±4.20% vs. 73.89±7.26%; p<0.05). Yohimbine (p>0.05) and propranolol (p>0.05) however did not have any significant effect on the contractile activity of the extract. Conclusions The freeze dried extract of B. biternata possess significant antidiarrheal activity in both in vitro and in vivo models which appears to be mediated by modulating both the intestinal motility as well as the secretory activity. The results of this study also validate its traditional use as an antidiarrheal remedy. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Cerbera manghas L. (Apocynaceae) is a medicinal plant traditionally used to ameliorate the clinical signs of inflammatory diseases and hypertension. Aim of study Although C. manghas L. has long been used as a traditional remedy for various diseases, the underlying molecular and cellular mechanisms are poorly understood. A detailed investigation of these mechanisms is necessary to demonstrate the ethnopharmaceutical utility of this plant. Materials and Methods The effects of C. manghas methanol extract (Cm-ME) on the production of inflammatory mediators and the expression of proinflammatory cytokines and identification of molecular targets were investigated using lipopolysaccharide (LPS)-treated macrophages in vitro . In addition, the inhibitory effects of Cm-ME orally administered were tested by LPS/ D -galactosamine ( D -GalN)-induced hepatitis and LPS-induced peritonitis mouse models in vivo . Results Cm-ME downregulated the production of prostaglandin (PG)E 2 and the mRNA expression of cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β in LPS-stimulated RAW264.7 cells under non-toxic concentration of Cm-ME. This extract inhibited the nuclear translocation of c-Jun and p-ATF2, the phosphorylation of JNK and p38, and AP-1 activity. Western blot analysis and in vitro kinase assay confirmed that JNK is a direct pharmacological target of Cm-ME action. In addition, Cm-ME significantly ameliorated the clinical signs of LPS/ D -GalN-induced hepatitis and lowered the production of nitric oxide (NO) and the phosphorylation of JNK in LPS-induced peritonitis conditions. Conclusion Cm-ME exerts anti-inflammatory actions on LPS-stimulated macrophages and in mouse models of acute inflammatory disease. These actions are predominantly mediated by targeting JNK in the AP-1 signaling pathway. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Zao-Jiao-Ci (ZJC), as the spine of Chinese Honey locust ( Gleditsia sinensis Lam.), is traditionally used as Chinese medicine to reduce inflammation. Aim of the study The present study aimed to investigate an anti-inflammatory effect of ZJC aqueous extract both in vitro and in vivo , as well as its underlying mechanisms. Materials and methods Anti-inflammatory effect of ZJC aqueous extract was evaluated by using carrageenan-induced paw edema in rats. In addition, the inhibitory effects of ZJC on nitric oxide production, intracellular reactive oxygen species production, pro-inflammatory mediator expression and prostaglandin E 2 (PGE 2 ) production were determined by using LPS-activated RAW 264.7 cells. The anti-oxidant activity of ZJC was assessed using 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid assay. Results ZJC aqueous extract showed significant suppressive effect on paw edema in rats at 100 mg/kg. Moreover, ZJC aqueous extract decreased the expression of cyclooxygenase (COX)-2 and significantly decreased the PGE2, tumor necrosis factor-α, interleukin (IL)-1β and IL-6 production in LPS-activated macrophages in dose-dependent manners. ZJC aqueous extract inhibited the mRNA expression of these inflammatory cytokines as well. Furthermore, ZJC aqueous extract was found as an anti-oxidant and could inhibit ROS production in the LPS-induced cells. Conclusions These findings show the potential of ZJC aqueous extract as a naturally occurring COX-2 inhibitor to reduce inflammation. [ABSTRACT FROM AUTHOR]

Pharmocological relevance 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA), is a phloroglucinol compound found naturally in Melicope ptelefolia. Melicope ptelefolia has been used traditionally for centuries as natural remedy for wound infections and inflammatory diseases. Aim of the study Endothelial barrier dysfunction is a pathological hallmark of many diseases and can be caused by lipopolysaccharides (LPS) stimulation. Therefore, this study aims to investigate the possible barrier protective effects of tHGA upon LPS-stimulated inflammatory responses in human umbilical vein endothelial cells (HUVECs). Materials and methods HUVECs were pretreated with tHGA prior to LPS stimulation, where inflammatory parameters including permeability, monocyte adhesion and migration, and release of pro-inflammatory mediators were examined. Additionally, the effect of tHGA on F-actin rearrangement and adhesion protein expression of LPS-stimulated HUVECs was evaluated. Results It was found that pretreatment with tHGA inhibited monocyte adhesion and transendothelial migration, reduced endothelial hyperpermeability and secretion of prostaglandin E 2 (PGE 2 ). Additionally, tHGA inhibited cytoskeletal rearrangement and adhesion protein expression on LPS-stimulated HUVECs. Conclusion As the regulation of endothelial barrier dysfunction can be one of the therapeutic strategies to improve the outcome of inflammation, tHGA may be able to preserve vascular barrier integrity of endothelial cells following LPS-stimulated dysfunction, thereby endorsing its potential usefulness in vascular inflammatory diseases. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Guizhi Fuling formula, a well-known Chinese herbal formula recorded in the Eastern Han Dynasty, is composed of Cinnamomum cassia (L.) J.Presl (Cassia bark), Poria cocos (Schw.) Wolf (Poria), Paeonia suffruticosa andrews (Moutan Cortex), Paeonia lactiflora Pall (Herbaceous peony), and Amygdalus persica L.(Persicae Semen). It has clinical efficacy of activating blood circulation to dissipate blood stasis and is commonly used for the treatment of primary dysmenorrhea. However, its therapeutic mechanism has not been clearly elucidated. The aim of this study is to reveal molecular mechanisms of action using in vivo and in vitro experimental models. Material and methods The ICR mouse uterine contraction was induced by oxytocin exposure following estradiol benzoate pretreatment. Mice were given GZFLC (0.54, 1.08 g/kg) by gavage. The levels of NO, PGF 2α and Ca 2+ in uterine tissue were determined according to instructions. Cyclooxygenase-2 (COX-2) and oxytocin receptor (OTR) proteins in uterine tissue were assessed by Western Blot. Mouse isolated uterus strips were mounted in tissue organ baths containing Locke's solution. The contractile responses were recorded with Power Lab recording system. The effect of GZFLC on spontaneous uterine contraction, and uterine contraction induced by oxytocin, PGF 2α was observed. Myometrial cells were exposed to oxytocin (5 U/L) to induce calcium release, and the effect of GZFLC and its components (PL, PGG, CA) on intracellular Ca 2+ was analyzed with fluorometry imaging. Results In vivo study demonstrated that GZFLC significantly reduced oxytocin-induced writhing responses with a maximal inhibition of 55%. It also decreased the levels of NO, PGF 2α and Ca 2+ in oxytocin-induced mice uterine tissue. Moreover, Western blot analysis showed that COX-2 and OTR expressions in uterine tissue of dysmenorrhea mice were significantly reduced. GZFLC inhibited spontaneous uterus contractions in a dose-dependent manner, and the IC 50 value was 0.99 mg/ml. The IC 50 values of GZFLC on PGF 2α , oxytocin-induced contractions were 1.45 mg/ml, 3.53 mg/ml, respectively. Further in vitro studies indicated that GZFLC and its components (PL, PGG, CA) could restrain intracellular calcium levels in favour of uteri relaxation. Conclusions Both in vivo and in vitro results indicated that GZFLC possessed a significant spasmolytic effect on uterine tetanic contraction. The present study provides in vivo and in vitro experimental evidence to support the use of GZFLC for the clinical treatment of primary dysmenorrheal (PD). [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Euphorbia umbellata ( leitosinha ) is used in southern Brazilian folk medicine to treat gastric problems, as well as for its analgesic and anti-inflammatory properties. Aim of study To evaluate the anti-ulcer effects of methanolic bark fraction (MF) against in vivo and in vitro assays, as well as an antioxidant, antibacterial and chromatographic study of this fraction. Materials and methods In vivo anti-ulcer activity was performed using ethanol and indomethacin models with different MF concentrations (50, 100 or 200 mg/Kg). The stomachs of the animals were applied to histological evaluation, and the serum to evaluate the ABTS •+ radical capture. The 200 mg/Kg dose was used to analyze the mechanisms involved in antiulcerogenic properties of methanolic fraction. The in vitro activity was performed using several different antioxidant assays, in addition to anti- Helicobacter pylori and anti-urease experiments. The chromatographic study was carried out by LC-MS analysis. Results Pharmacological investigation of the MF showed an anti-ulcer potential in ethanol and indomethacin in vivo assays. The material presented a high antioxidant activity for several oxidant in vitro systems (DPPH • , ABTS •+ , O 2 •- , HOCl, TauCl and HRP), as well as an ABTS •+ capture increasing (7.5%) by the treated animals serum (when compared to the negative control). Prostaglandins, nitric oxide/ cyclic guanosine monophosphate pathway and involvement of the protein components of the glutathione complex are some of the mechanisms related with this potential anti-ulcer action. The histological examination of the stomachs of the animals showed that the MF also prevents local action of offensive agents. Chemical analysis using LC-QTOF-MS revealed the presence of ellagic and gallic acid derivatives and flavonols. Conclusion The findings provide scientific basis to the ethnopharmacological purpose of the studied plant and the biological activities of MF of E. umbellata stem bark may be due to the presence of phenolic compounds. [ABSTRACT FROM AUTHOR]