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Context: Ranunculus ternatus Thunb (Ranunculaceae), (RTT) is used clinically for the treatment of tuberculosis or as tumour adjuvant therapy, but its potential effect on diabetic nephropathy (DN) has not been studied., Objective: To investigate the effect of RTT extract in renal fibrosis of DN., Materials and Methods: C57BL/6 mice were randomly divided into four groups ( n  = 12). Diabetes mellitus (DM) mice were induced by streptozotocin (STZ, 55 mg/kg/day) for five consecutive days and treated by RTT extract (2 g/kg). Afterward, blood glucose, HE and Masson staining were assayed. The expression levels of Vimentin, ɑ-SMA, TNF-ɑ, NF-κB p-p65, NF-κB p65, SMYD2, H3K36me3, H3K4me3 were determined by western blots. Firbronectin was respectively assayed by western blot and immunofluorescent staining., Results: RTT extract significantly ameliorated renal injury and renal fibrosis in the renal tissue of STZ-induced diabetic mice as demonstrated by the decreased expression level of Fibronectin (65%), Vimentin and α-SMA (75% & 53%). In addition, the levels of TNF-α (57%), NF-κB p-p65 and NF-κB p65 (35% & 25%) were elevated in the DN mice. Importantly, these were alleviated after RTT extract treatment. Moreover, we observed that the protein levels of SMYD2 (30%), H3K36me3 and H3K4me3 (53% & 75%) were reduced in DN mice after treatment with RTT extract., Discussion and Conclusions: RTT extract mediates antifibrotic effects and anti-inflammatory responses in STZ-induced DN mainly through suppressing SMYD2 activation and H3K36me3 and H3K4me3 protein expression. RTT extract might have therapeutic potential against high glucose-induced nephropathy.

Leishmaniasis and schistosomiasis are neglected tropical diseases (NTDs) infecting the world's poorest populations. Effectiveness of the current antileishmanial and antischistosomal therapies are significantly declining, which calls for an urgent need of new effective and safe drugs. In Ethiopia fresh leaves of Ranunculus multifidus Forsk. are traditionally used for the treatment of various ailments including leishmaniasis and eradication of intestinal worms. In the current study, anemonin isolated from the fresh leaves of R. multifidus was assessed for its in vitro antileishmanial and antischistosomal activities. Anemonin was isolated from the hydro-distilled extract of the leaves of R. multifidus . Antileishmanial activity was assessed on clinical isolates of the promastigote and amastigote forms of Leishmania aethiopica and L. donovani clinical isolates. Resazurin reduction assay was used to determine antipromastigote activity, while macrophages were employed for antiamastigote and cytotoxicity assays. Antischistosomal assays were performed against adult Schistosoma mansoni and newly transformed schistosomules (NTS). Anemonin displayed significant antileishmanial activity with IC 50 values of 1.33 nM and 1.58 nM against promastigotes and 1.24 nM and 1.91 nM against amastigotes of L. aethiopica and L. donovani , respectively. It also showed moderate activity against adult S. mansoni and NTS (49% activity against adult S. mansoni at 10 µM and 41% activity against NTS at 1 µM). The results obtained in this investigation indicate that anemonin has the potential to be used as a template for designing novel antileishmanial and antischistosomal pharmacophores.

Ethnopharmacological Relevance: The members of the genus Ranunculus have counter-irritating properties and thus, they are traditionally used for treating anti-inflammatory disorders and other skin conditions. Ranunculus macrophyllus Desf. is a wild medicinal plant growing in Algeria and traditionally used to treat some cutaneous skin disorders., Aim: The aim of this study was to characterize the composition of the ethyl acetate and n-butanol extracts from Ranunculus macrophyllus Desf. as well as to elucidate and to compare their effect against acute skin inflammation. Moreover, both the antioxidant activity and the acute toxicity of the plant extracts were also studied., Materials and Methods: Spectrophotometric and chromatographic methods were employed to identify and quantify phenolic compounds and triterpenoids from R. macrophyllus Desf. fractions. The antioxidant activity was estimated using the phosphomolebdenum, DPPH, reducing power and β-carotene bleaching assays. The ethyl acetate and n-butanol extracts were screened for their anti-inflammatory activities using ex-vivo membrane stabilizing assays and in-vivo acute skin inflammation model., Results: Ethyl acetate fraction showed the highest amounts of total phenolic compounds (413 ± 4 μg GAE/mg extract) and triterpenoids (70.4 ± 1.8 μg UAE/mg extract). Rutin, hesperidin, myricetin and kaempferol were the major compounds identified in the different fractions. Ethyl acetate fraction exhibited strong DPPH • radical scavenging ability (IC 50 1.6 ± 0.2 μg/mL), high total antioxidant capacity (447 ± 7 μg AAE/mg extract) and reducing power (514 ± 8 μg AAE/mg extract). Ethyl acetate fraction inhibited (73.4 ± 0.3) % of linoleic acid peroxidation. Ethyl acetate and n-butanol fractions did not have any visible toxicity at 2000 mg/kg and presented excellent membrane stabilizing ability. The inhibition of xylene induced ear inflammation was (38 ± 4) % and (46 ± 1) % for RM-B and RM-EA, respectively., Conclusions: The high content of both phenolic compounds and triterpenoids combined with the remarkable anti-inflammatory effect and antioxidant activity of ethyl acetate and n-butanol extracts from R. macrophyllus Desf. support the wide spread use of this traditional plant on some skin disorders (inflammatory skin disorders)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ranunculus scleratus Linn. is used in folk medicine to treat hypertension. This study was aimed at providing validation to its traditional use and to explore underlying mechanisms of action. Effects of hydro-ethanolic crude extract of the plant and its fractions on blood pressure was evaluated using direct surgical method in normotensive and in fructose induced hypertensive rats. Various doses of crude extract, RSC, (5, 10, 20, 30mg/kg) and all fractions (3, 5, 10, 20mg/kg) were studied. Results suggested that aqueous fraction of R. scleratus (RSA) produced most pronounced effects at 10mg/kg in normotensive and at 20mg/kg in hypertensive animals. Underlying mechanisms, using various pharmacological antagonists were also elucidated. Results suggested the involvement of muscarinic receptor, angiotensin converting enzyme (ACE) inhibition, ganglionic block and nitric oxide (NO) release in presenting hypotensive response.

(1) Background: Ranunculus bulumei is a flowering plant that belongs to the Ranunculus species. Several Ranunculus species, such as R. aquatilis and R. muricatus , have traditionally been used to treat fever and rheumatism throughout Asia, suggesting that plants belonging to the Ranunculus species may have anti-inflammatory effects. To our knowledge, the pharmacological activity of R. bulumei has not been reported. Therefore, in this study, we aim to assess the anti-inflammatory activity of a methanol extract that was derived from R. bulumei (Rb-ME) in macrophage-mediated inflammatory responses and to identify the molecular mechanism that underlies any anti-inflammatory action. (2) Methods: The anti-inflammatory efficacy of Rb-ME was evaluated while using in vitro and in vivo experiments. The RAW264.7 cells and peritoneal macrophages were stimulated by lipopolysaccharide (LPS). In addition, LPS-induced peritonitis and HCl/EtOH-triggered gastritis models were produced. A nitric oxide (NO) assay, real-time PCR, luciferase reporter gene assay, western blot analysis, plasmid overexpression strategy, and in vitro kinase assay were used to determine the molecular mechanisms and target molecules of Rb-ME. The phytochemical active ingredients of Rb-ME were also identified by high performance liquid chromatograph (HPLC). (3) Results: Rb-ME reduced the production of NO and mRNA expression of iNOS, COX-2, IL-1β, and IL-6 without cytotoxicity. The protein secretion of TNF-α and IL-6 was also decreased by Rb-ME. HPLC analysis indicates that quercetin, luteolin, and kaempferol are the main active ingredients in the anti-inflammatory efficacy of Rb-ME. Rb-ME also blocked MyD88-induced NF-κB promoter activity and nuclear translocation of NF-κB subunits (p65 and p50). Moreover, Rb-ME reduced the phosphorylation of IκBα, Akt, p85, Src, and Syk, which are NF-κB upstream signaling molecules in LPS-activated RAW264.7 cells. According to the in vitro kinase assay, Rb-ME directly inhibits Syk kinase activity. The oral administration of Rb-ME alleviated inflammatory responses and the levels of p-IκBα in mice with LPS-induced peritonitis and HCl/EtOH-induced gastritis. (4) Conclusions Rb-ME has anti-inflammatory capacity by suppressing NF-κB signaling and it has been found to target Src and Syk in the NF-κB pathway. Based on this efficacy, Rb-ME could be developed as an anti-inflammatory herbal medicine.

Ranunculus muricatus Linn. (RML) have been traditionally used for the treatment of various cardiovascular disorders. The aim of present study was to evaluate their cardiovascular effects in isolated perfused rabbit heart. The methanolic extract of RML was prepared by cold maceration process. The methanolic extract of RML (1 ng to 10 mg) was used to determine the percentage change in force of contraction (FC), heart rate (HR) and perfusion pressure (PP) by using Langendorff's Perfused Heart Apparatus. The PP, FC and HR of isolated rabbit heart were measured by power lab data acquisition system. Moreover, phytochemical analysis and acute toxicity study were also performed. The methanolic extract at the doses from I ng to 10 mg exhibited a significant increase in perfusion pressure and force of contraction. Moreover, the crude extract of RML revealed a significant increase in heart rate at doses from 1 ng to μg. The maximum rise in all the thee parameters was observed at 1 μg and 1 ng, respectively In another study, the melhanoliC extract was tested in the presence of propranolol and verapamil on isolated perfused rabbit heart. The study shown that the increase in HR and FC produced by the plant extracts was significantly reduced in the presence of propranolol whereas PP remained significantly raised even in the presence of propranolol. However, in the presence of verapamil, this increased PP was significantly reversed to a decrease while a significant positive inotropic and chronotropic effects were observed. It is concluded that the cardiotonic activity of methanolic extract of RML might be due certain cardio active chemical compounds. Further studies are needed to isolate these pharmacologically active phytochemical constituents and elucidate their exact mechanism of action.

Ranunculus muricatus is commonly known as spiny fruit buttercup and is used in the treatment of intermittent fevers, gout and asthma. Qualitative analysis of phytochemicals of Ranunculus muricatus indicated the presence of saponins, tannins, phenols, flavonoids and alkaloids. Saponins were present in high amount as compared with other chemicals. Inorganic and heavy metals constituents were determined. Heavy metals estimation in the sample showed that iron was present in high amount followed by zinc even then the concentration of these metals is below acceptable limit. The physical parameters, antioxidant and antimicrobial activities of the extracts were determined. Acetone extract fraction showed optimal antioxidant activity as compared to ethanol and chloroform fractions of the candidate plant. The antimicrobial and antifungal activities of the crude extract and extract fractions were determined by well agar diffusion method. Highest zone of inhibitions were observed for crude extract followed by acetone extract fraction against Micrococcus luteus. Antifungal activities were high for crude extracts against Candida Albican. Findings of this study show that Ranunculus muricatus has a good medicinal impact.

Background: Ranunculus arvensis L. (R. arvensis) has long been used to treat a variety of medical conditions such as arthritis, asthma, hay fever, rheumatism, psoriasis, gut diseases and rheumatic pain. Here, we screened R. arvensis for antioxidant activity, phytochemical and high performance liquid chromatography (HPLC) analyses., Methods: The chloroform, chloroform:methanol, methanol, methanol:acetone, acetone, methanol:water and water extracts of R. arvensis were examined for DPPH (1, 1-diphenyl-2-picrylhydrazyl) free radical scavenging assay, hydrogen peroxide scavenging assay, phosphomolybdenum assay, reducing power assay, flavonoid content, phenolic content and high performance liquid chromatography analysis., Results: Significant antioxidant activity was displayed by methanol extract (IC 50 34.71 ± 0.02) in DPPH free radical scavenging assay. Total flavonoids and phenolics ranged 0.96-6.0 mg/g of extract calculated as rutin equivalent and 0.48-1.43 mg/g of extract calculated as gallic acid equivalent respectively. Significant value of rutin and caffeic acid was observed via high performance liquid chromatography., Conclusions: These results showed that extracts of R. arvensis exhibited significant antioxidant activities. Moreover, R. arvensis is a rich source of rutin, flavonoids and phenolics.

Ethnopharmacological Relevance: In Turkish folk medicine Ranunculus species are used for wound healing and for the treatment of rheumatism. The present study was conducted to evaluate in vivo wound healing and anti-inflammatory properties of Ranunculus pedatus and Ranunculus constantinapolitanus., Material and Methods: In vivo wound healing activity of the extracts prepared from Ranunculus pedatus and Ranunculus constantinapolitanus was evaluated by linear incision and circular excision wound models. Hydroxyproline content of the treated tissues was also assessed. We also studied the anti-inflammatory activity using Whittle method with some modifications., Results: Methanolic extract of Ranunculus pedatus showed significant wound healing effect both in incision (31.4%) and excision (55.74%) wound models. Methanolic extract of both Ranunculus pedatus and Ranunculus constantinapolitanus demonstrated anti-inflammatory activity with the inhibition value of 26.2% and 23.3% respectively, at the dose of 100 mg/kg. Hydroxyproline content of the tissues treated with the methanolic and aqueous extracts of Ranunculus pedatus and methanolic extract of Ranunculus constantinapolitanus were found to be significantly higher than that of the other extracts., Conclusion: The experimental data revealed that Ranunculus pedatus showed significant wound healing and anti-inflammatory effect., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

A rapid method for the analysis of the main components of the total glycosides of Ranunculus japonicus (TGOR) was developed using ultra-performance liquid chromatography with quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS). The separation analysis was performed on a Waters Acquity UPLC system and the accurate mass of molecules and their fragment ions were determined by Q-TOF MS. Twenty compounds, including lactone glycosides, flavonoid glycosides and flavonoid aglycones, were identified and tentatively deduced on the basis of their elemental compositions, MS/MS data and relevant literature. The results demonstrated that lactone glycosides and flavonoids were the main constituents of TGOR. Furthermore, an effective and rapid pattern was established allowing for the comprehensive and systematic characterization of the complex samples.

Background: Medicinal plants represent alternative means for the treatment of several chronic diseases, including inflammation. The genus Ranunculus, a representative of the Ranunculaceae family, has been reported to possess anti-inflammatory, analgesic, antiviral, antibacterial, antiparasitic and antifungal activities, possibly due to the presence of anemonin and other. Different studies have shown the occurrence of unusual fatty acids (FAs) in Ranunculaceae; however, their therapeutic role has not been investigated. The purpose of this study is to characterize potential anti-inflammatory bioactivities in Ranunculus constantinopolitanus D'Urv., traditionally used in Eastern Mediterranean folk medicine., Methods: The aerial part of R. constantinopolitanus was subjected to methanol (MeOH) extraction and solvent fractionation. The bioactive fraction (I.2) was further fractionated using column chromatography, and the biologically active subfraction (Y2+3) was identified using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS). The effects of I.2 and Y2+3 on cell viability were studied in mouse mammary epithelial SCp2 cells using trypan blue exclusion method. To study the anti-inflammatory activities of I.2 and Y2+3, their ability to reduce interleukin (IL)-6 levels was assessed in endotoxin (ET)-stimulated SCp2 cells using enzyme-linked immunosorbent assay (ELISA). In addition, the ability of Y2+3 to reduce cyclooxygenase (COX)-2 expression was studied in IL-1-treated mouse intestinal epithelial Mode-K cells via western blotting. Data were analyzed by one-way analysis of variance (ANOVA), Student-Newman-Keuls (SNK), Tukey HSD, two-sample t-test and Dunnett t-tests for multiple comparisons., Results: The chloroform fraction (I.2) derived from crude MeOH extract of the plant, in addition to Y2+3, a FA mix isolated from this fraction and containing palmitic acid, C18:2 and C18:1 isomers and stearic acid (1:5:8:1 ratio), reduced ET-induced IL-6 levels in SCp2 cells without affecting cell viability or morphology. When compared to fish oil, conjugated linoleic acid (CLA) and to individual FAs as palmitic, linoleic, oleic and stearic acid or to a mix of these FAs (1:5:8:1 ratio), Y2+3 exhibited higher potency in reducing ET-induced IL-6 levels within a shorter period of time. Y2+3 also reduced COX-2 expression in IL-1-treated Mode-K cells., Conclusion: Our studies demonstrate the existence of potential anti-inflammatory bioactivities in R. constantinopolitanus and attribute them to a FA mix in this plant.

Phytochemical investigations on the chloroform and ethyl acetate soluble fractions of the roots of Ranunculus repens led to the isolation of methyl 3,4,5-trihydroxybenzoate 1, R(+)- 4-methoxydalbergione 2 and R(+)-dalbergiophenol 3. The structures of these compounds were established through spectral studies including 1D and 2D NMR experiments and by comparison with literature data. These compounds showed potent inhibitory activity against urease.