N-Methylneolitsine as a new and potent acetylcholinesterase inhibitor of Cissampelos pareira Linn. aerial parts: bioassay-guided isolation and quantitative densitometric analysis.

The rising geriatric population is expected to increase the demand for drugs treating neurodegenerative diseases. The present work is aimed to discover acetylcholinesterase (AChE) inhibitors from Cissampelos pareira Linn. aerial parts (Family: Menispermaceae). Bioassay-guided isolation, AChE inhibition study and estimation of the therapeutic marker in different parts of raw herbs were conducted. The structure of the compound (1) was elucidated as N-methylneolitsine by using NMR (1D and 2D) and ESI-MS/MS spectral data, which is a new natural analogue of neolitsine. It showed good AChE inhibition with an IC50 value of 12.32 µg/mL. It was densitometrically estimated to be 0.074 - 0.33% in aerial parts of C. pareira, collected from various locations. The alkaloid reported here could be potentially useful for the treatment of various neurodegenerative diseases and the aerial part of C. pareira could be used as a promising ingredient for various preparations treating neurodegenerative diseases.

Bisbenzylisoquinolines from Cissampelos pareira L. as antimalarial agents: Molecular docking, pharmacokinetics analysis, and molecular dynamic simulation studies.

Malaria is a major global health issue due to the emergence of resistance to most of the available antimalarial drugs. There is an urgent need to discover new antimalarials to tackle the resistance issue. The present study aims to explore the antimalarial potential of chemical constituents reported from Cissampelos pareira L., a medicinal plant traditionally known for treating malaria. Phytochemically, benzylisoquinolines and bisbenzylisoquinolines are the major classes of alkaloids reported from this plant. In silico molecular docking revealed prominent interactions of bisbenzylisoquinolines such as hayatinine and curine with Pfdihydrofolate reductase (-6.983 Kcal/mol and -6.237 Kcal/mol), PfcGMP-dependent protein kinase (-6.652 Kcal/mol and -7.158 Kcal/mol), and Pfprolyl-tRNA synthetase (-7.569 Kcal/mol and -7.122 Kcal/mol). The binding affinity of hayatinine and curine with identified antimalarial targets was further evaluated using MD-simulation analysis. Among the identified antimalarial targets, the RMSD, RMSF, the radius of gyration, and PCA indicated the formation of stable complexes of hayatinine and curine with Pfprolyl-tRNA synthetase. The outcomes of in silico investigation putatively suggested that bisbenzylisoquinolines may act on the translation of the Plasmodium parasite to exhibit antimalarial potency.

Anti-SARS-CoV-2 potential of Cissampelos pareira L. identified by connectivity map-based analysis and in vitro studies.

BACKGROUND: Viral infections have a history of abrupt and severe eruptions through the years in the form of pandemics. And yet, definitive therapies or preventive measures are not present. Herbal medicines have been a source of various antiviral compounds such as Oseltamivir, extracted using shikimic acid from star anise (Illicium verum) and Acyclovir from Carissa edulis are FDA (Food and Drug Administration) approved antiviral drugs. In this study, we dissect the anti-coronavirus infection activity of Cissampelos pareira L (Cipa) extract using an integrative approach. METHODS: We analysed the signature similarities between predicted antiviral agents and Cipa using the connectivity map ( https://clue.io/ ). Next, we tested the anti-SARS-COV-2 activity of Cipa in vitro. Molecular docking analyses of constituents of with key targets of SARS-CoV2 protein viz. spike protein, RNA­dependent RNA­polymerase (RdRp) and 3C­like proteinase. was also performed. A three-way comparative analysis of Cipa transcriptome, COVID-19 BALF transcriptome and CMAP signatures of small compounds was also performed. RESULTS: Several predicted antivirals showed a high positive connectivity score with Cipa such as apcidin, emetine, homoharringtonine etc. We also observed 98% inhibition of SARS-COV-2 replication in infected Vero cell cultures with the whole extract. Some of its prominent pure constituents e.g. pareirarine, cissamine, magnoflorine exhibited 40-80% inhibition. Comparison of genes between BALF and Cipa showed an enrichment of biological processes like transcription regulation and response to lipids, to be downregulated in Cipa while being upregulated in COVID-19. CMAP also showed that Triciribine, torin-1 and VU-0365114-2 had positive connectivity with BALF 1 and 2, and negative connectivity with Cipa. Amongst all the tested compounds, Magnoflorine and Salutaridine exhibited the most potent and consistent strong in silico binding profiles with SARS-CoV2 therapeutic targets.

Transcriptome analysis and connectivity mapping of Cissampelos pareira L. provides molecular links of ESR1 modulation to viral inhibition.

Bioactive fractions obtained from medicinal plants which have been used for the treatment of multiple diseases could exert their effects by targeting common pathways. Prior knowledge of their usage could allow us to identify novel molecular links. In this study, we explored the molecular basis of action of one such herbal formulation Cissampelos pareira L. (Cipa), used for the treatment of female hormone disorders and fever. Transcriptomic studies on MCF7 cell lines treated with Cipa extract carried out using Affymetrix arrays revealed a downregulation of signatures of estrogen response potentially modulated through estrogen receptor α (ERα). Molecular docking analysis identified 38 Cipa constituents that potentially bind (ΔG < - 7.5) with ERα at the same site as estrogen. The expression signatures in the connectivity map ( https://clue.io/; ) revealed high positive scores with translation inhibitors such as emetine (score: 99.61) and knockdown signatures of genes linked to the antiviral response such as ribosomal protein RPL7 (score: 99.92), which is a reported ERα coactivator. Further, gene knockdown experiments revealed that Cipa exhibits antiviral activity in dengue infected MCF7 cells potentially modulated through estrogen receptor 1. This approach reveals a novel pathway involving the ESR1-RPL7 axis which could be a potential target in dengue viral infection.

Phytochemical Constituents and Biological Activities of Plants from the Genus Cissampelos.

Cissampelos is a significant genus comprising of approximately 21 species of the medicinal plants (Menispermaceae). The plants of this genus are used in traditional medicine for the treatment of various ailments such as asthma, arthritis, dysentery, hyperglycemia, cardiopathy, hypertension and other related problems. These plants are rich in bioactive dibenzylisoquinoline and aborphine as well as small amounts of other ingredients. In recent years, the chemical constituents and pharmacological activities of Cissampelos genus have been paid more and more attention due to their diversity. Herein, we compile the chemical constituents and biological activities on this genus, and summarize the 13 C-NMR data of the main bioactive ingredients. All information comes from scientific databases such as Google Scholar, PubMed, Sci-Finder, ScienceDirect, Web of Science and CNKI. It provides valuable data for the future research and development of Cissampelos genus.

Cissampelos pareira L.: A review of its traditional uses, phytochemistry, and pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Cissampelos pareira, a well-known medicinal climber-plant of the Menispermaceae family, has been extensively used in the traditional medicinal system since the ancient time for the treatment of numerous diseases such as ulcer, wound, rheumatism, fever, asthma, cholera, diarrhoea, inflammation, snakebite, malaria, rabies, and also recommended for blood purification. AIM OF THE REVIEW: The main purpose of this review is to provide updated information on ethnopharmacology, phytochemistry, chromatographic and spectroscopic analysis, pharmacology, and toxicology of C. pareira along with the possible future research. This information will help to provide a foundation for plant-based drug discovery in the near future. MATERIAL AND METHODS: The online databases such as Scifinder, Web of Science, PubMed, and Google Scholar were used to collect electronically available literature data on C. pareira. Ayurveda text is searched for the traditional uses of this plant in India. The published books are also searched for the information on this plant. Our search was based on traditional uses, botany, phytochemistry, and pharmacological potential by using "Cissampelos pareira" as the keyword. RESULTS: To date, approximately 54 phytomolecules have been isolated and characterized from C. pareira including mainly isoquinoline alkaloids along with few flavonoids, flavonoid glycosides, and fatty acids. The crude extracts of C. pareira have shown various pharmacological activities such as antipyretic, anti-inflammatory, antiarthritic, antiulcer, antidiabetic, anticancer, antifertility, antimicrobial, antioxidant, antivenom, antimalarial, and immunomodulatory, etc. The chemical fingerprinting of C. pareira carried out using HPTLC, HPLC, UPLC, LC-MS, and GC-MS, revealed the presence of alkaloids (isoquinoline alkaloids), fatty acids, and flavonoid glycosides. Moreover, the toxicological assessment of C. pareira has been moderately investigated, which requires further comprehensive studies. CONCLUSION: Comprehensive literature survey reveals that till date, remarkable growth has been made on phytochemistry and pharmacology of C. pareira reflecting the great medicinal potential of this plant. Although some of the traditional uses have been well clarified and documented by modern pharmacological analysis, the correlation between its pharmacological activities and particular phytoconstituents still needs to be validated. Furthermore, there is partial data available on most of the pharmacological studies, along with incomplete toxicological screening. Future research needs to pay more attention to pharmacological studies of C. pareira via pre-clinical and clinical trials. Additionally, scientific validation of traditional knowledge of C. pareira is vital for ensuring safety, efficacy, and mechanism of action before clinical uses.

A new pyrrole alkaloid from the roots of Cissampelos pareira.

Phytochemical investigation of the roots of Cissampelos pareira Linn. led to the isolation of one new pyrrole alkaloid, cissampeline (1), together with ten known alkaloids, (-)-curine (2), (-)-cyclanoline (3), (+)-tetrandrine (4), (+)-obaberine (5), (+)-obamegine (6), (-)-oblongine (7), (+)-homoaromoline (8), (-)-nor-N׳-chondrocurine (9), trans-N-feruloyltyramine (10) and (+)-coclaurine (11). Their structures were elucidated by extensive NMR and MS spectroscopic analyses. Interestingly, compound 1 represents the first example of pyrrole alkaloid found in the genus Cissampelos. Moreover, compounds 5-11 were isolated for the first time from this genus. Among them, compound 6 showed the highest anti-acetylcholinesterase activity with an IC50 value of 3.26 µM, whereas compound 8 displayed the most potent cytotoxicity against human colon cancer (HT29) cells with an IC50 value of 7.89 µM.

Antibiotic-Potentiating Activity of Phanostenine Isolated from Cissampelos sympodialis Eichler.

Cissampelos sympodialis Eichler is well studied and investigated for its antiasthmatic properties, but there are no data in the literature describing antibacterial properties of alkaloids isolated from this botanical species. This work reports the isolation and characterization of phanostenine obtained from roots of C. sympodialis and describes for the first time its antimicrobial and antibiotic modulatory properties. Phanostenine was first isolated from Cissampelos sympodialis and its antibacterial activities were determined. Chemical structures of the alkaloid isolate were determined using spectroscopic and chemical analyses. Phanostenine was also tested for its antibacterial activity against standard strains and clinical isolates of Escherichia coli and Staphylococcus aureus. Minimal inhibitory concentration (MIC) was determined in a microdilution assay and for the evaluation of antibiotic resistance-modifying activity. MIC of the antibiotics was determined in the presence or absence of phanostenine at sub-inhibitory concentrations. The evaluation of antibacterial activity by microdilution assay showed activity for all strains with better values against S. aureus ATCC 12692 and E. coli 27 (787.69 mm). The evaluation of aminoglycoside antibiotic resistance-modifying activity showed reduction in the MIC of the aminoglycosides (amikacin, gentamicin and neomycin) when associated with phanostenine, MIC reduction of antibiotics ranging from 21 % to 80 %. The data demonstrated that phanostenine possesses a relevant ability to modify the antibiotic activity in vitro. We can suggest that phanostenine presents itself as a promising tool as an adjuvant for novel antibiotics formulations against bacterial resistance.

Toxicological evaluation in silico and in vivo of secondary metabolites of Cissampelos sympodialis in Mus musculus mice following inhalation.

The ethanolic extract of the leaves of Cissampelos sympodialis showed great pharmacological potential, with inflammatory and immunomodulatory activities, however, it showed some toxicological effects. Therefore, this study aims to verify the toxicological potential of alkaloids of the genus Cissampelos through in silico methodologies, to develop a method in LC-MS/MS verifying the presence of alkaloids in the infusion and to evaluate the toxicity of the infusion of the leaves of C. sympodialis when inhaled by Swiss mice. Results in silico showed that alkaloid 93 presented high toxicological potential along with the products of its metabolism. LC-MS/MS results showed that the infusion of the leaves of this plant contained the alkaloids warifteine and methylwarifteine. Finally, the in vivo toxicological analysis of the C. sympodialis infusion showed results, both in biochemistry, organ weights and histological analysis, that the infusion of C. sympodialis leaves presents a low toxicity.

Bioactive isoquinoline alkaloids from Cissampelos pareira †.

The phytochemical and biological investigation of Cissampelos pareira leads to the isolation of one new isoquinoline alkaloid (7) along with six known isoquinoline alkaloids, namely, magnoflorine (1), magnocurarine (2), cissamine (3), curine (4), hayatinine (5) and cycleanine (6). Magnoflorine (1) and magnocurarine (2) were isolated for the first time from C. pareira. A new, rapid, simple and sensitive UPLC method was developed for simultaneous quantification of five pure compounds (1-5). Seasonal variation study revealed higher content of these compounds during the rainy season. The chloroform (CPCF) and n-butanol (CPBF) fractions showed cytotoxic efficacy against KB cells. Among pure compounds, hayatinine (5) was found to be most active against KB and A549, while, cycleanine (6) against KB cells.

A preliminary investigation of the effects of labour inducing plant, Cissampelos mucronata, on the outcomes of pregnancy using rat models.

Background: The use of traditional remedies in pregnancy has been associated with bad obstetric outcomes including uterine rupture and foetal distress. These outcomes may ultimately lead to maternal and child mortality or morbidity. Few studies have been done to measure the effects of various herbs in pregnant women or a developing fetus. This study investigated the effects of the commonly used labour inducing plant, Cissampelos mucronata, on pregnancy outcomes using a rat model. Methods: Pregnant female rats were divided into 3 groups of 10 each. The first group was the control. The second group was treated with the aqueous extract of Cissampelos mucronata at mid-pregnancy. The third group was treated with Cissampelos mucronata close to full term. All the groups were left to give birth and outcomes were recorded. Results: Rats treated at mid-term had significantly low number of pups when compared to the control group as well as the close to term treated group (4.1 ± 0.54 vs. 6.4 ± 0.60; 6.2± 0.56). The mid-term treated rats had pups with significantly lower body weight when compared to the control and the close to term treated groups (3.73 ± 0.36g vs. 5.37 ± 0.16g; 4.27 ± 0.1g). The average gestation period was significantly short in the mid-term treated group when compared to the control and the close to term treated groups (18.16 ± 0.50 days vs. 20.40 ± 0.44 days; 20.12 ± 0.37 days). There were no uterus ruptures observed in all study groups 3 days after delivery. Conclusion: Administration of Cissampelos mucronata during pregnancy leads to early induction of labour.

The effects of Cissampelos pareira extract on envenomation induced by Bothropsdiporus snake venom.

ETHNOPHARMACOLOGICAL RELEVANCE: Ophidian accidents are a serious public health problem in Argentina; the Bothrops species is responsible for 97% of these accidents, and in particular, B. diporus is responsible for 80% of them. In the northeast of the country (Corrientes Provinces), Cissampelos pareira L. (Menispermaceae) is commonly used against the venom of B. diporus; its use is described in almost all ethnobotanical literature from countries where the plant grows. AIM OF THE STUDY: In this study, the in vitro and in vivo antivenom activities of C. pareira extracts were evaluated against B. diporus venom, with a particular focus on the local effects associated with envenoming. The seasonal influence on the chemical composition of the active extracts was also studied, in order determine the associated range of variability and its influence on the antivenom activity. MATERIALS AND METHODS: This research was conducted using aerial parts (leaves, flowers, tender stems) and roots of Cissampelos pareira collected from two different phytogeographic regions of Corrientes (Argentina); Paso de la Patria and Lomas de Vallejos. In addition, to perform a seasonal analysis and to evaluate the metabolic stability, material was collected at three different growth stages. In vivo and in vitro anti-snake venom activities were tested, and a bio-guided chromatographic separation was performed in order to determine the active chemicals involved. The fractions obtained were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and the chemical profile of the most active constituent was analyzed by ultra high-performance liquid chromatography coupled to quadrupole/high-resolution mass spectrometry (Q-Orbitrap). (UHPLC-MS). RESULTS: The alcoholic extract was found to be the most active The bio-guided fractionation allowed selection one fraction to be analyzed by UHPLC-MS in order to identify the components responsible for the activities found; this identified five possible flavonoids. CONCLUSIONS: Our studies of the activity of C. pareira against the venom of B. diporus have confirmed that this species possesses inhibitory effects in both in vitro and in vivo models. Moreover, the present data demonstrate that certain flavonoids may mitigate some of the venom-induced local tissue damage.

Computational Chemistry Study of Natural Alkaloids and Homemade Databank to Predict Inhibitory Potential Against Key Enzymes in Neurodegenerative Diseases.

Cissampelos sympodialis Eichl is used in folk medicine for the treatment of various inflammatory diseases; several alkaloids have been isolated from this species and some of them have anti-allergic, immunomodulatory and spasmolytic activities. Treatment of rats with the total tertiary alkaloid fraction showed an antidepressant effect. One of the depression causes can be the deficiency of monoamines, which is a factor displayed in patients with Alzheimer's disease. Theoretical studies using in silico methods have aided in the process of drug discovery. From this perspective, we applied ligand-based-virtual associated with structure-based-virtual screening of alkaloids from C. sympodialis Eichl and 101 derivatives proposed by us are promising leads against some important targets (BACE, GSK-3ß and MAO-A). From the ChEMBL database, we selected a diverse set of 724, 1898 and 1934 structures, which had been tested against BACE, GSK-3ß and MAO-A, to create Random Forest (RF) models with good overall prediction rate, over 78%, for cross-validation and test set. Compounds 24 and 47 presented activity against GSK-3ß and MAO-A simultaneously. The natural alkaloids roraimine and simpodialine-ß-N-oxide presented activity against BACE and liriodenine against MAO-A. The top 20 compounds with best docking performance per enzyme were selected and validated through the RF model. All 9 compounds classified as active in RF model for BACE are bisbenzylisoquinoline alkaloids and were present in the top docking scoring, demonstrating a consensus on results. Affinities of bisbenzylisoquinoline alkaloids, including two secondary metabolites (roraimine and simpodialine-ß-N-oxide), with BACE suggest that this skeleton can be used as a model to design new antagonists of this enzyme.

Cissampelos pareira Linn. ameliorates thyroxin-induced cardiac hypertrophy in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Cissampelos pareira extract has been traditionally used in ayruveda as cardiotonic, diuretics and in heart complains but its pharmacological evaluation in thyroxin-induced cardiac hypertrophy has not yet been explored. AIM OF THE STUDY: The aim of this study was to assess the cardioprotective effect of C. pareira root extract in experimentally induced hyperthyroidism in rats. MATERIALS AND METHODS: Male Wistar rats were treated with (i) thyroxin (0.1 mg/kg/day, i.p.) for 30 days, (ii) C. pareira extract (200 mg/kg/day, p.o.) alone for 60 days, (iii) C. pareira extract (100 and 200 mg/kg/day, p.o., respectively) for 30 days then with thyroxin for another 30 days, (iv) thyroxin for 30 days then C. pareira extract (100 and 200 mg/kg/day, p.o., respectively) for another 30 days. At the end of experiment, serum calcineurin, nitric oxide, lactate dehydrogenase, and thiobarbituric acid reactive substance as well as serum and/or myocardial antioxidant enzymes activity were estimated. RESULTS: Hyperthyroid induced cardiotoxicity was characterized by a significant (P<0.001) increase in heart weight/body weight ratio, serum calcineurin, nitric oxide, lactate dehydrogenase and thiobarbituric acid reactive substance levels as well as a significant decrease in serum reduced glutathione, myocardial glutathione peroxidase, glutathione reductase and glutathione-S-transferase levels, which were significantly (P<0.05 and P<0.01) reverted by C. pareira extract treatment. Reversal of histological changes on treatment with C. pareira extract was also supported the biochemical parameters. These results were quite comparable with amlodipine, the standard drug taken in this study. CONCLUSIONS: Treatment with C. pareira extract ameliorates thyroxin-induced oxidative stress and cardiac hypertrophy, probably through amelioration of calcineurin activity and augmentation of antioxidant enzyme activities.

Cissampelos pareira Linn: Natural Source of Potent Antiviral Activity against All Four Dengue Virus Serotypes.

BACKGROUND: Dengue, a mosquito-borne viral disease, poses a significant global public health risk. In tropical countries such as India where periodic dengue outbreaks can be correlated to the high prevalence of the mosquito vector, circulation of all four dengue viruses (DENVs) and the high population density, a drug for dengue is being increasingly recognized as an unmet public health need. METHODOLOGY/PRINCIPAL FINDINGS: Using the knowledge of traditional Indian medicine, Ayurveda, we developed a systematic bioassay-guided screening approach to explore the indigenous herbal bio-resource to identify plants with pan-DENV inhibitory activity. Our results show that the alcoholic extract of Cissampelos pariera Linn (Cipa extract) was a potent inhibitor of all four DENVs in cell-based assays, assessed in terms of viral NS1 antigen secretion using ELISA, as well as viral replication, based on plaque assays. Virus yield reduction assays showed that Cipa extract could decrease viral titers by an order of magnitude. The extract conferred statistically significant protection against DENV infection using the AG129 mouse model. A preliminary evaluation of the clinical relevance of Cipa extract showed that it had no adverse effects on platelet counts and RBC viability. In addition to inherent antipyretic activity in Wistar rats, it possessed the ability to down-regulate the production of TNF-α, a cytokine implicated in severe dengue disease. Importantly, it showed no evidence of toxicity in Wistar rats, when administered at doses as high as 2g/Kg body weight for up to 1 week. CONCLUSIONS/SIGNIFICANCE: Our findings above, taken in the context of the human safety of Cipa, based on its use in Indian traditional medicine, warrant further work to explore Cipa as a source for the development of an inexpensive herbal formulation for dengue therapy. This may be of practical relevance to a dengue-endemic resource-poor country such as India.

Cissampelos sympodialis Eichl. (Menispermaceae), a medicinal plant, presents antimotility and antidiarrheal activity in vivo.

BACKGROUND: Cissampelos sympodialis (Menispermaceae), known as "Milona" has a specific verified medicinal use for the treatment of diarrhea and respiratory tract diseases. This work aims to evaluate the antimotility and antidiarrheal activity of crude ethanolic extract (EtOHE-Cs), and the total alkaloid fraction (TAF-Cs) obtained from aerial parts of C. sympodialis. METHODS: Normal intestinal transit and gastric emptying were used to evaluate antimotility activity. Castor oil-induced diarrhea and castor oil-induced enteropooling were used to evaluate antidiarrheal activity. RESULTS: The results indicated that EtOHE-Cs has no antimotility activity, but did demonstrate antidiarrheal activity (at 500 mg/kg), and this activity is related to reduction of intestinal fluid accumulation. The TAF-Cs (at 250 and 500 mg/kg) showed antidiarrheal activity by reducing gastrointestinal motility (gastric emptying and normal intestinal transit). CONCLUSIONS: The antidiarrheal activity of C. sympodialis can be attributed to the chemical compounds already isolated and quantified in this species, mainly alkaloids.

Cytotoxic agents for KB and SiHa cells from n-hexane fraction of Cissampelos pareira and its chemical composition.

Eleven constituents were characterised by gas chromatography-mass spectrometry analysis, and five molecules were isolated using column chromatography. The in vitro study of the extract and isolated molecules against KB and SiHa cell lines revealed oleanolic acid (1) and oleic acid (2) as potent cytotoxic molecules with potential anticancer activity. The IC50 values of n-hexane extract (CPHF), oleanolic acid (1) and oleic acid (2) were >300, 56.08 and 70.7 µg/mL (µM), respectively, against KB cell lines and >300, 47.24 and 80.2 µg/mL (µM), respectively, against SiHa cell lines.

Warifteine, an alkaloid purified from Cissampelos sympodialis, inhibits neutrophil migration in vitro and in vivo.

Cissampelos sympodialis Eichl is a plant from the Northeast and Southeast of Brazil. Its root infusion is popularly used for treatment of inflammatory and allergic diseases. We investigated whether warifteine, its main alkaloid, would have anti-inflammatory effect due to a blockage of neutrophil function. In vivo warifteine treatment inhibited casein-induced neutrophil migration to the peritoneal cavity but did not inhibit neutrophil mobilization from the bone marrow. Analysis of the direct effect of warifteine upon neutrophil adherence and migration in vitro demonstrated that the alkaloid decreased cell adhesion to P and E-selectin-transfected cells. In addition, fLMP-induced neutrophil migration in a transwell system was blocked by warifteine; this effect was mimicked by cAMP mimetic/inducing substances, and warifteine increased intracellular cAMP levels in neutrophils. The production of DNA extracellular traps (NETs) was also blocked by warifteine but there was no alteration on PMA-induced oxidative burst or LPS-stimulated TNF α secretion. Taken together, our data indicate that the alkaloid warifteine is a potent anti-inflammatory substance and that it has an effect on neutrophil migration through a decrease in both cell adhesion and migration.

From arrow poison to herbal medicine--the ethnobotanical, phytochemical and pharmacological significance of Cissampelos (Menispermaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Cissampelos species have a rich history of traditional use, being used for both therapeutic and toxic properties. It is traditionally applied therapeutically in a diverse range of conditions and diseases including asthma, cough, fever, arthritis, obesity, dysentery, snakebite, jaundice and heart, blood pressure and skin-related problems. Conversely, it was traditionally included in preparations of curare applied as arrow poison during hunting to cause death of animals by asphyxiation. This review unites the ethnobotanical knowledge on Cissampelos with the phytochemistry and pharmacological activity which has been explored thus far. In addition, it identifies knowledge gaps and suggests further research opportunities. METHODS: The available electronic literature on the genus Cissampelos was collected using database searches including Scopus, Google Scholar, Pubmed, Web of Science, etc. The searches were limited to peer-reviewed English journals with the exception of books and a few articles in foreign languages which were included. RESULTS: The literature revealed that pharmacological activity including analgesic and antipyretic, anti-inflammatory, anti-allergic, bronchodilator, immunomodulatory, memory-enhancing, antidepressant, neuroprotective, antimicrobial, antimalarial, antiparasitic, anti-ulcer, anticancer, anti-oxidant, cardiovascular, muscle-relaxant, hepatoprotective, antidiabetic, antidiarrhoeal, antifertility, and antivenom activity have been confirmed in vitro and/or in vivo for various Cissampelos species. Cissampelos pareira L. and Cissampelos sympodialis Eichl. are the most explored species of this genus and the smallest number of studies have been conducted on Cissampelos laxiflora Moldenke and Cissampelos tenuipes Engl. Many alkaloids isolated from Cissampelos such as warifteine, methylwarifteine, berberine, hayatin and hayatidin showed promising anti-allergic, immunosuppressive, antidepressant, anticancer, vasodilatory and muscle-relaxant activities. CONCLUSION: The plants of this genus are used in traditional medicine for the treatment of various ailments. These plants are a rich source of bioactive bisbenzylisoquinoline and aporphine alkaloids together with other minor constituents. Although these plants are reputable and revered in various traditional medicine systems, many have not yet been screened chemically or pharmacologically and so there is a vast amount of research still to be conducted to validate their traditional use.

Inhaled Cissampelos sympodialis down-regulates airway allergic reaction by reducing lung CD3+ T cells.

Cissampelos sympodialis Eichl. (Menispermaceae) root infusion is used in Northeast Brazil to treat allergic asthma. We have previously shown that oral use of the plant extract reduces eosinophil infiltration into the lung of ovalbumin (OVA)- sensitized mice. However, drugs taken by inhalation route to treat asthma achieve better outcomes. Thereby, in this study, we evaluated the inhaled C. sympodialis alcoholic extract as a therapeutic treatment in OVA-sensitized BALB/c mice. The parameters which were analyzed consisted of leukocyte recruitment to the airway cavity, tissue remodeling and cell profile. The inhaled extract inhibited mainly eosinophil recruitment to the pleural cavity, bronchoalveolar lavage and peripheral blood. This treatment reduced the OVA-specific IgE serum titer and leukocyte infiltration in the peribronchiolar and pulmonary perivascular areas as well as mucus production. In addition, we also tested isolated alkaloids from the plant extract. The flow cytometric analysis showed that methylwarifteine (MW) and, mainly, the inhaled extract reduced the number of CD3+T cells and eosinophil-like cells. Therefore, inhaled C. sympodialis extract and MW lead to down-regulation of inflammatory cell infiltration with remarkable decrease in the number of T cells in an experimental model of respiratory allergy, suggesting that the plant can be delivered via inhalation route to treat allergic asthma.