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Anti-inflammatory and antitumoural effects of Uncaria guianensis bark
... ex Schult.) DC., commonly known as "unha-de-gato" (cat's claw), have been used in traditional medicine to treat inflammatory diseases [19,20]. ...
... The anti-inflammatory activities of Uncaria spp. have been previously demonstrated [19,20,33], thereby justifying the study of extracts and pure compounds derived from U. guianensis with the aim of improving the clinical manifestations of endometriosis. The chemical profiles of aqueous extracts of U. guianensis established herein were similar to those reported by Sandoval et al. [20] and characterized by low concentrations of pentacyclic oxindole alkaloids and high concentrations of phenolic compounds. ...
... Furthermore, treatment of EEE and LEE cells with U. guianensis extracts ABE, ALE, and ARE (alone or in combination with rutin) did not increase cell death, different from our previous observations with U. tomentosa. The anti-inflammatory properties of the active principles of Uncaria species have been tested previously on macrophages and tumor cells [19,20] but not on endometriotic cells, and this may explain the conflicting results presented herein. ...
There is increasing interest in the potential of natural compounds to treat diseases, such as endometriosis, a gynecological disorder that affects 10-15% of women of reproductive age, and it is related to severe pelvic pain and infertility. We have evaluated the in vitro effects of rutin and the aqueous bark, roots, and leaf extracts (ABE, ARE, and ALE, respectively) and isolated components of Uncaria guianensis on stromal cells from eutopic endometrium and lesions of patients with endometriosis. Two-and three-dimensional cultures were used to assess the cell death and production of reactive oxygen species (ROS), cytokines and growth factors of cells following exposure to these natural products. The applied treatments did not reduce cellular viability, but ROS production did increase. In addition, significant increases in the levels of interleukin (IL)-15, IL-17A, IL-4, IL-6, tumor necrosis factor-α, and vascular endothelium growth factor were observed when 2D-cells from endometrium of patients with endometriosis were treated with ABE, while exposure to ALE induced significant increases in epidermal growth factor in lesion cells.
... Contiene un grupo de alcaloiodes conocidos como uncarinas [49], además se ha determinado la presencia de polifenoles [49] y esteroles como el β-sitosterol y estigmasterol [50]. Se reportan estudios de su actividad antimicrobiana [50], antiinflamatoria [49][50][51][52], e inmunoestimulante [51]. ...
... Contiene un grupo de alcaloiodes conocidos como uncarinas [49], además se ha determinado la presencia de polifenoles [49] y esteroles como el β-sitosterol y estigmasterol [50]. Se reportan estudios de su actividad antimicrobiana [50], antiinflamatoria [49][50][51][52], e inmunoestimulante [51]. ...
Ecuador es un país privilegiado por su riqueza en organismos vivos íntimamente relacionados con su alta biodiversidad. En los últimos 20 años, las universidades públicas y privadas, así como los institutos de investigación, han invertido en la formación de sus docentes-investigadores como en tecnología de última generación relacionada con este tema. Este texto refleja los avances en la producción científica que se han generado en el país. Tres capítulos son revisiones exhaustivas del uso tradicional y el potencial de las plantas medicinales en problemas de salud y aplicaciones puntuales. Un capítulo analiza las plantas medicinales y sus metabolitos en una determinada área biogeográfica del Ecuador. Una revisión se centra en el aceite esencial de una especie nativa de elevado potencial bio-económico como la Psidium guajava. Dos estudios experimentales confirman la riqueza fitoquímica y el potencial medicinal de especies de nuestra biodiversidad como la Persea americana y Chuquiraga jussiuei. Y finalmente, un capítulo analiza la importancia del control en los productos naturales procesados con base en su calidad microbiológica y la relación con las correctas prácticas de manufactura. Este texto confirma que Ecuador tiene mucho que mostrar al mundo de la ciencia.
... [4][5][6] In vitro and clinical studies have corroborated the traditional use of U. guianensis as anti-inflammatory and antioxidant. [7][8][9] Other biological activities, such as antitumor [9,10] and antimicrobial, [11] have also been found. Previous chemical studies of U. guianensis revealed the presence of indole and oxindole alkaloids, [12,13] proanthocyanidins, [7] flavonols, [14] triterpenoid glycosides, [15] and steroids. ...
... [4][5][6] In vitro and clinical studies have corroborated the traditional use of U. guianensis as anti-inflammatory and antioxidant. [7][8][9] Other biological activities, such as antitumor [9,10] and antimicrobial, [11] have also been found. Previous chemical studies of U. guianensis revealed the presence of indole and oxindole alkaloids, [12,13] proanthocyanidins, [7] flavonols, [14] triterpenoid glycosides, [15] and steroids. ...
A simple and low-cost solid-phase extraction methodology for isolating the bioactive flavonoid kaempferitrin from a defatted fraction of the Uncaria guianensis leaf ethanol extract was developed using the kaempferitrin retention behavior in reversed-phase-high-performance liquid chromatography as well as thin-layer chromatography coupled to ImageJ software (Bethesda, USA) for densitometric analyses. In addition, the method enabled the isolation of less-complex mixtures for the further separation of minor constituents. The target compound was successfully isolated from 1 to 5 mg of the fraction per 500 mg C18 cartridge using 6 mL of 15% acetonitrile at 60% relative recovery and 99% purity.
... Overall, UGH elicited better results than UGA, which can be explained by different extraction methods, which, in turn, may produce extracts with different compositions. Indeed, fractions of extracts of U. guianensis with different polarities had different effects (Urdanibia et al., 2013). In addition, results showed that concentrations of chlorogenic acid and mitraphylline were higher in UGH, compared to UGA. ...
Uncaria guianensis (Aubl.) J. F. Gmel. (“cat’s claw”, Rubiaceae) is a plant with potential to treat asthma because of its anti-inflammatory and antioxidant activities. The aim of this study was to evaluate the effects of two extracts of U. guianensis in an animal model of allergic asthma. Balb/c mice were sensitized twice with ovalbumin intraperitoneally one week apart, then challenged with intranasal ovalbumin for three days. Animals were treated with aqueous or hydroethanolic extracts (100 mg/kg) for three days, simultaneously with ovalbumin challenges. Control mice received saline solution on the same days. In vivo bronchial hyper responsiveness, airway and lung inflammation, IgE levels, and total antioxidant capacity were measured. Treatment with the hydroethanolic extract significantly reduced total cell and eosinophil counts in bronchoalveolar lavage, and in vivo bronchial hyper responsiveness. Moreover, U. guianensis hydroethanolic extract significantly reduced interleukin 13 levels in lung homogenate. Total antioxidant capacity and IgE serum levels were not affected with the extract administration. Of note, treatment with the aqueous extract did not elicit significant effects on asthma-like characteristics. Only the hydroethanolic extract of U. guianensis reduced lung inflammation and bronchial hyper responsiveness in asthmatic mice
... DC. and Uncaria guianensis (Aublet) Gmell. These species are popularly known as "cat's claw" and have attracted attention for their value in medicine, displaying a wide range of pharmacological activities, such as anticancer 15 , anti-inflammatory 16,17 and immunomodulation effects 18 . In spite of many pharmacological studies, little work has been reported about the biosynthetic aspects of these compounds; only one 14 C-feeding experiment has reported the elucidation of the oxindole alkaloid biosynthesis in Mitragyna parvifolia (Roxb.) ...
Spiro-oxindole scaffolds have been studied due to their promising therapeutic potential. In the Amazon rainforest there are two important Uncaria species known as “cat’s claw”, which biosynthesize spirocyclic oxindole alkaloids; Uncaria tomentosa (Willd. ex Schult.) DC. and Uncaria guianensis (Aublet) Gmell. We carried out a precursor-directed biosynthesis approach with U. guianensis and successfully obtained oxindole alkaloid analogues with molecular mass corresponding to the addition of a methyl or fluorine group on the oxindole ring using tryptamine analogue precursors. Two of these novel oxindole alkaloid analogues (3b-7-methyl-isomitraphylline and 3c-6-fluoro-isomitraphylline) were isolated and characterized by NMR spectroscopy and ESI-QTOF-MS/MS. Having established a substrate feeding protocol for these plantlets, the biosynthetic route for mitraphylline (1), rhynchophylline (2), isomitraphylline (3) and isorhynchophylline (4) was also investigated using 13C-precursors (1-13C-D-glucose, 2-13C-tryptophan, 1-13C-DL-glyceraldehyde, and methyl-13C-D-methionine).
... In addition, Uncaria preparations may possess immunomodulatory and chemopreventive properties besides direct cytotoxic activity. The former assumption is supported by the involvement of anti-inflammatory processes rather than cytotoxic events in the antitumor activity of a hydroethanolic U. guianensis stembark extract in 4 T1 mammary tumor-bearing BALB/c mice [161]. The latter supposition stems from the changes in expression patterns of critical proto-oncogenes and tumor suppressor genes in DMBA-treated CBA/Ca mice following administration of Claw of Dragon tea (CoD™ tea), a mixture of the stembarks from U. guianensis, U. tomentosa, and the trumpet-tree Tabebuia avellanedae Lorentz ex Griseb. ...
Despite much progress in our understanding of the essence of cancer, remarkable advances in methods for early diagnosis, the expanding array of antineoplastic drugs and treatment modalities, as well as important refinements in their use, this disease is among the leading causes of morbidity and mortality in many parts of the world. In fact, the next decade is anticipated to bring over 20 million new cases per year globally, about half of whom will die from their disease. This indicates a need for better strategies to deal with cancer. One way to go forward is to draw lessons from ancient ethnopharmacological wisdom and to evaluate the plant biodiversity for compounds with potential antineoplastic activity. This approach has already yielded many breakthrough cytotoxic drugs such as vincristine, etoposide, paclitaxel, and irinotecan. The Republic of Suriname (South America), renowned for its pristine and highly biodiverse rain forests as well as its ethnic, cultural, and ethnopharmaco-logical diversity, could also contribute to these developments. This chapter addresses the cancer problem throughout the world and in Suriname, extensively deals with nine plants used for treating cancer in the country, and concludes with their prospects in anticancer drug discovery and development programs.
... [6][7][8] These researches focus more on the use of available natural resources and further investigate different mechanisms leading to cancer which could be the possible targets in suppressing its emergence. [9][10][11] Plants play a significant role in the prevention and treatment of diseases and can even prevent and minimize the adverse effects of conventional treatments. 12 They can be source of chemical compounds of biological and pharmacological importance. ...
Introduction: Broussonetia luzonica (Moraceae) Blanco is an edible and endemic plant in the Philippines. Other species of the plant are used traditionally in Chinese medicine to treat impotency and eye disorders and was proven to have anticancer potential. To date, there are no published scientific evidences yet to prove the cytotoxicity against hepatocellular carcinoma cell lines (HepG2) of B. luzonica. Furthermore, the bioactive compounds of the ethyl acetate leaf extract were determined. Methods: Bioactive compounds were determined using Gas Chromatography-Mass Spectrometry (GC-MS). To determine the IC50, the percentage Hepg2 Cell inhibition of the extract at 200 μg/mL, 100 μg/mL, 50 μg/Ml, 25 μg/mL And 12.5 μg/ mL concentrations against (HepG2) was evaluated using 3-(4,5-Dimethylthiazol- 2yl)-2,5-Diphenyltetrazolium Bromide (MTT) Assay. Results: GC-MS revealed the top three major bioactive compounds of ethyl acetate leaf extract based on quantity (%). These are 1,2,3-propanetriol, monoacetate (21.21%), phytol (20.28%) and squalene (6.85%). MTT assay showed that ethyl acetate extract at different concentrations exhibited marked inhibition of the HepG2. The concentration of the extracts that will inhibit 50% of the cancer cell lines (IC50) was also determined. The assay revealed that compared to positive control (doxorubicin) with IC50 5.068 μg/mL, Ethyl Acetate Extract statistically exhibited greater cytotoxic effect against HepG2 Cell Lines With IC50 1.118 μg/mL (P=0.001). Conclusion: The presence of several bioactive compounds in ethyl acetate extract from the leaves of B. luzonica confirms the importance of the plant in treatment of diseases. Furthermore, the extract manifested more potent cytotoxic activity than the positive control, indicating promising chemotherapeutic potential of the plant.
... Macrophage expression of IκB degradation was completely inhibited, while NF-κB activation was inhibited by 70%. UG subfraction also decreased serum NO, TNFα, paw oedema induced by carrageenan and mammary tumour growth by 91% [80]. ...
It is estimated that there are as many as 1400 plant species currently used in traditional Peruvian medicine; however, only a few have undergone scientific investigation. In this paper, we make a review of the botanical, chemical, pharmacological and clinical propierties of the most investigated Peruvian medicinal plants. The plant species selected for this review are: Smallanthus sonchifolius (yacon), Croton lechleri (sangre de grado), Uncaria tomentosa/U. guianensis (una de gato), Lepidium meyenii (maca), Physalis peruviana (aguaymanto), Minthostachys mollis (muna), Notholaena nivea (cuti-cuti), Maytenus macrocarpa (chuchuhuasi), Dracontium loretense (jergon sacha), Gentianella nitida (hercampuri), Plukenetia volubilis (sacha inchi) and Zea mays (maiz morado). For each of these plants, information about their traditional uses and current commercialization is also included.
... Accumulating evidence indicates that NO and PGE 2 are important mediators of inflammation, such as autoimmune diseases and neurodegenerative disease [25][26][27][28][29][30]. The generation of excessive NO and PGE2 in response to various inflammatory stimuli contributes to the development of chronic inflammatory diseases [31][32][33][34]. For these reasons, the suppression of NO production may possibly be a promising strategy against inflammatory diseases. ...
Inflammation is a response of body tissues to injury and infection. Compounds that can inhibit inflammation have been shown
to have potential therapeutic clinical application. Gambogenic acid (GEA) has potent antitumor and anti-inflammatory activities.
Herein, the molecular mechanisms of GEA's anti-inflammatory effect were investigated in lipopolysaccharide (LPS)-stimulated
macrophage cells. The results showed that pretreatment with GEA could markedly inhibit interleukin (IL)-1α, IL-1β, tumor necrosis
factor-α, IFN-β, IL-12b, and IL-23a production in a dose-dependent manner in LPS-induced model. Furthermore, this drug significantly
reduced the release of nitric oxide (NO), and impaired the protein level of inducible NO synthase and the cyclooxygenase 2.
The finding also showed that the effect of GEA may be related to the suppression of the nuclear factor-κB (NF-κB) and mitogen-activated
protein kinase (MAPK) signaling pathway. These results indicate that GEA could suppress LPS-simulated inflammatory response
partially by attenuating NO synthesis and NF-κB and MAPK activation, suggesting that it may become a potent therapeutic agent
for the treatment of inflammatory diseases.
... Fazio AL et al., en macrófagos peritoneales de ratones C57/BL6, portadores de melanoma B16/BL6, demostró que la UT inhibía IL-6 y NO pero no TNF-a (20) . Urdanibia et al., encontraron un efecto antinflamatorio y antitumoral en otra especie de Uncaria, la U. guianensis, al observar la inhibición del crecimiento del tumor mamario (4T1) relacionado probablemente con la disminución de mediadores inflamatorios como TNF-a e IL-6 a través de la inhibición de la vía NFkB (21) . En este estudio reportamos la actividad antitumoral in vitro de un extracto hidroalcohólico de UT así como también un efecto inmunomodulador sobre DC y las citoquinas IL-12, Th1, Th2, Th17 a partir de PBMC humanos. ...
Unlabelled:
Objetives. This study aimed to research the in vitro immunomodulatory effects of an Uncaria tomentosa hydroalcoholic extract standardized (5.03%, pentacyclic oxindole alkaloids) (UT-POA) on the immunophenotype of dendritic cells (DC) subsets, Th1, Th2, Th17 and IL-12 cytokines from patients with stage II breast cancer (BCII) and healthy women (H).
Materials and methods:
Blood of 11 H and 7 BCII was obtained, PBMC were isolated and cultured for 2h with/without various concentrations of UT-POA and stimulated or not with LPS for 24h. PBMC were labeled with specific antibodies for DC and in the supernatant we measured Th1/Th2/Th17 cytokines, both by flow cytometry. Furthermore IL-12 was measured by ELISA.
Results:
UT-POA did not alter DC or accessory molecules expression in BCII. However, H exhibited a decrease in the percentage of mDC (myeloid DC) and an increase in HLA-DR and CD86 expression at 1000 μg/mL. IL-12 secretion was modified only in the H group, increasing p70 subunit and decreasing p40 subunit. UT-POA increased Th1 (IFN-γ and IL-2), Th2 (IL-4) and Th17 (IL-17) secretion in both groups.
Conclusions:
UT-POA increased the production of cytokines related with anti-tumoral response at concentrations of 500-1000 μg/mL. This positive effect should be evaluated not only systemically but also in the tumor microenvironment in further studies. UT-POA may be a useful phytochemical in chemoprevention and in the alternative use in cancer therapies.
... Fazio AL et al., en macrófagos peritoneales de ratones C57/BL6, portadores de melanoma B16/BL6, demostró que la UT inhibía IL-6 y NO pero no TNF-a (20) . Urdanibia et al., encontraron un efecto antinflamatorio y antitumoral en otra especie de Uncaria, la U. guianensis, al observar la inhibición del crecimiento del tumor mamario (4T1) relacionado probablemente con la disminución de mediadores inflamatorios como TNF-a e IL-6 a través de la inhibición de la vía NFkB (21) . En este estudio reportamos la actividad antitumoral in vitro de un extracto hidroalcohólico de UT así como también un efecto inmunomodulador sobre DC y las citoquinas IL-12, Th1, Th2, Th17 a partir de PBMC humanos. ...
Objetivos. Evaluar el efecto inmunomodulador del extracto estandarizado (5,03%, alcaloides oxindólicos pentacíclicos) de Uncaria tomentosa (UT-POA) sobre el inmunofenotipo de células dendríticas (DC) y IL-12/Th1/Th2/Th17 en pacientes con cáncer de mama estadio II (BCII) y mujeres sanas (H). Materiales y métodos. Se obtuvó sangre de 11 H y 7 BCII, se aislaron y cultivaron PBMC por 2 h con/sin distintas concentraciones de UT-POA y se estimularon o no con LPS por 24 h. Las PBMC fueron marcadas con anticuerpos específicos para DC y en el sobrenadante se midió las citoquinas Th1/Th2/Th17, ambos por citometría de flujo. Además, se midió IL-12 por ELISA. Resultados. UT-POA no alteró a las DC o la expresión de moléculas accesorias en BCII. Sin embargo, en H mostró una disminución en el porcentaje de DC mieloides (mDC) con incremento de HLA-DR y CD86 a 1000 μg/mL. La secreción de IL-12 fue modificada solo en H, incrementando la subunidad p70 y disminuyendo la p40. UT-POA incremento Th1 (IFN-γ y IL-2), Th2 (IL-4) y Th17 (IL-17) en BCII y H. Conclusiones. UT-POA incrementa la producción de citoquinas relacionadas con la respuesta antitumoral a concentraciones entre el rango de 500-1000 μg/mL. Este efecto positivo debería ser evaluado no solo sistemicamente sino también en el microambiente tumoral. La UT-POA puede ser un fitoquímico útil en la quimioprevención y en el uso alternativo con terapias contra el cáncer
... Consider the case of Uncaria spp. as a specific example. Although both anti-inflammatory and anticancer activities have been reported for this plant (Heitzman et al., 2005), results from our laboratory suggest that the antitumoural activity of Uncaria may be due to a great degree to its anti-inflammatory properties (Caballero et al., 2005;Fazio et al., 2008;Urdanibia et al., 2013). Although cytotoxic compounds have been identified, we do not believe that they are present at a high enough concentration in Uncaria extracts to explain the anticancer effect. ...
... via enhancing body immunity by elevating serum IL-2 and TNF-α levels [117]. Moreover, reduced pro-tumorigenic inflammatory processes, possibly mediated through NF-κB and related to Uncaria guianensis (Aublet), a medicinal plant from the jungles of South and Central America, has been reported [118]. ...
Currently, the main treatments available for cancer include surgery, biological therapy, radiation and chemotherapy. However, these treatments have strong secondary effects on patients, which can prohibit their use. Therefore, the search for alternative treatments is a current challenge for scientists. Several studies have identified compounds from plants that exhibit biological properties compatible with the desired activity of anti-neoplastic drugs. Natural products are thought to be more compatible with the human body and cause fewer side effects. Furthermore, substances present in fruits, vegetables and herbal essential oils have demonstrated important antiproliferative activity, inducing cell and genomic changes favorable for cancer prevention and therapy. Taking into account that the molecular mechanisms by which natural compounds function to prevent cancer are not fully understood and that molecular targets can be important tools for evaluating their effectiveness, this chapter aims to present and discuss potential active compounds as possible anti-cancer agents.
... Consider the case of Uncaria spp. as a specific example. Although both anti-inflammatory and anticancer activities have been reported for this plant (Heitzman et al., 2005), results from our laboratory suggest that the antitumoural activity of Uncaria may be due to a great degree to its anti-inflammatory properties (Caballero et al., 2005;Fazio et al., 2008;Urdanibia et al., 2013). Although cytotoxic compounds have been identified, we do not believe that they are present at a high enough concentration in Uncaria extracts to explain the anticancer effect. ...
Los conocimientos tradicionales de las mujeres ribereñas amazónicas sobre las plantas son extremadamente diversos, representando un rico acervo de saberes empíricos transmitidos a lo largo de generaciones. Estos conocimientos son fundamentales para su subsistencia, siendo utilizados de diversas formas en la vida cotidiana, como en la alimentación, medicina, artesanía, prácticas rituales y construcción. Con base en este contexto, el presente trabajo tuvo como propósito investigar el etnoconocimiento de las mujeres sobre las plantas de las comunidades ribereñas de Porto Novo y Cajutuba, ubicadas en Belterra, Pará. La investigación se llevó a cabo en cinco etapas distintas, permitiendo un enfoque amplio y profundo del tema en cuestión. 1) Presentación de la investigación a las lideresas comunitarias, donde estas firmaron el Término de Anuencia Previa. 2) Entrevistas semiestructuradas con 20 mujeres para recopilar datos de etnoconocimiento de plantas. 3) Identificación taxonómica de las plantas medicinales. 4) Cálculo de las variables Etnobotánicas, frecuencia relativa de cita (FRC) y valor de uso (UV). 5) Creación de un Atlas Etnobotánico. En la investigación, las mujeres reportaron un total de 125 especies de plantas, distribuidas en 52 familias botánicas, siendo Lamiaceae, Arecaceae, Solanaceae, Myrtaceae, Euphorbiaceae y Fabaceae las más representativas. El UV evidenció 1,1 para Citrus sp. (alimenticia), 1 para Lippia alba (medicinal), 0,05 para Alpinia zerumbet (baño), 0,6 para Ruta graveolens (rezo) y 0,06 para Adenium obesum (ornamental). Al registrar y comprender el vínculo cultural entre las mujeres ribereñas y las plantas a su alrededor, se espera enriquecer el conocimiento científico sobre la biodiversidad regional, así como contribuir al respeto y la conservación de estas prácticas ancestrales tan significativas para la identidad y el sustento de estas comunidades.
Ecuador es un país privilegiado por su riqueza en organismos vivos íntimamente relacionados con su alta biodiversidad. En los últimos 20 años, las universidades públicas y privadas, así como los institutos de investigación, han invertido en la formación de sus docentes-investigadores como en tecnología de última generación relacionada con este tema. Este texto refleja los avances en la producción científica que se han generado en el país. Tres capítulos son revisiones exhaustivas del uso tradicional y el potencial de las plantas medicinales en problemas de salud y aplicaciones puntuales. Un capítulo analiza las plantas medicinales y sus metabolitos en una determinada área biogeográfica del Ecuador. Una revisión se centra en el aceite esencial de una especie nativa de elevado potencial bio-económico como la Psidium guajava. Dos estudios experimentales confirman la riqueza fitoquímica y el potencial medicinal de especies de nuestra biodiversidad como la Persea americana y Chuquiraga jussiuei. Y finalmente, un capítulo analiza la importancia del control en los productos naturales procesados con base en su calidad microbiológica y la relación con las correctas prácticas de manufactura. Este texto confirma que Ecuador tiene mucho que mostrar al mundo de la ciencia.
Las enfermedades del sistema respiratorio sin lugar a duda se en-cuentran entre aquellas que presentan la mayor morbilidad a nivel nacional y mundial. Anualmente se gastan ingentes cantidades de dinero en fárma-cos como: antitusígenos, expectorantes, antivirales, antibióticos, antiinfla-matorios y antipiréticos; para mitigar enfermedades y síntomas derivados de afecciones respiratorias ampliamente difundidas entre la población. Los diversos pueblos y nacionalidades que habitan el Ecuador emplean una gran cantidad de plantas medicinales tanto nativas como introducidas como parte de tratamientos alternativos en enfermedades respiratorias. La presente revisión analiza aquellas especies empleadas de forma tradicional, y verifica en las de mayor uso, su sustento científico evaluando la infor-mación química y de actividad biológica que puede ser encontrada en la literatura científica, contribuyendo de esta manera a incrementar el cono-cimiento de los productos naturales que son usados en nuestro país.Las enfermedades del sistema respiratorio inciden con frecuencia en la salud de las personas, siendo extremadamente comunes a lo largo de la vida. La actual pandemia de la Covid-19 muestra la fragilidad de nuestras sociedades ante los patógenos respiratorios, sin embargo, es necesario en-tender que esta no es la primera o la última vez en que la humanidad deberá enfrentarse a una crisis de esta naturaleza [1,2]. A pesar de la compleja situación que vivimos debemos entender que hemos estado expuestos a virus y bacterias con la capacidad de provocar enfermedades respiratorias prácticamente desde nuestra aparición como especie, lo que nos ha llevado a buscar fuentes de curación ya sean de orígenes natural o sintético.El mayor porcentaje de las enfermedades respiratorias como la in-fluenza o las infecciones bacterianas son toleradas por la población sin in-convenientes y solo se manifiestan como peligrosas en personas de avanza-da edad, en el Ecuador sin embargo constituyen la tercera causa de emer-gencia hospitalaria con cerca a un 30 %, siendo más frecuente en niños de hasta 11 años, esto según el boletín del ECEH del 2019, antes del inicio de la pandemia [3]. Un interesante estudio del 2020 realizado en un sector de la ciudad de Quito en medio de la crisis de la Covid-19, muestra que un 88,1 % de la población ha padecido enfermedades respiratorias superiores, un 5,4 % enfermedades respiratorias inferiores y un 4,9 % Covid-19 [4].
Los productos naturales, mucho antes de la aparición de los medica-mentos de síntesis, han sido empleados para tratar enfermedades respiratorias o para mitigar síntomas relacionados a estas como la tos y la inflamación [5-9]. Una gran parte del uso de los productos naturales se basa en el saber ancestral que en el caso del Ecuador al tener varios pueblos y nacionalidades se vuelve fundamental. La otra fortaleza con la que se cuenta es la elevada biodiversidad en los diferentes nichos ecológicos, donde muchas especies vegetales todavía no cuentan con estudios de respaldo en los campos químico y farmacológico.El siguiente trabajo tiene como finalidad un reconocimiento de las plantas usadas en el país para enfermedades y síntomas respiratorios, una revisión de los tipos de tratamientos empleados y finalmente una indaga-ción en literatura científica de aquellas especies de mayor interés farmacéu-tico y bioeconómico.
Esta obra constituiu-se a partir de um processo colaborativo entre professores, estudantes e pesquisadores que se destacaram e qualificaram as discussões no espaço formativo que tange a produção animal. Resulta, também, de movimentos interinstitucionais e de ações de incentivo à pesquisa que congregam pesquisadores das mais diversas áreas da Zootecnia e de diferentes Instituições de Educação Superior públicas e privadas de abrangência nacional e internacional. Tem como objetivo integrar ações interinstitucionais nacionais e internacionais com redes de pesquisa que tenham a finalidade de fomentar a formação continuada dos profissionais da educação, por meio da produção e socialização de conhecimentos das diversas áreas de pesquisas e práticas contemporâneas relacionadas a Zootecnia. Agradecemos aos autores pelo empenho, disponibilidade e dedicação para o desenvolvimento e conclusão dessa obra. Esperamos também que esta obra sirva de instrumento didático-pedagógico para estudantes, professores dos diversos níveis de ensino em seus trabalhos e demais interessados pela temática.
Uncaria tomentosa (UT) extracts have been shown to have promising anti-tumor activity. We hypothesized that its incorporation into nanostructured systems could improve the anticancer properties. Here, poly-e-caprolactone (PCL) and poly-d,l-lactide-co-glycolide (PLGA) were employed to generate nanoparticles loaded with UT extract in a single emulsion solvent evaporation method. The nanoparticles were characterized by particle size, zeta potential, morphology and entrapment efficiency along with stability and release profiles. The nanoparticles presented entrapment efficiencies above 60% and a mean diameter below 300nm. UT-PCL nanoparticles presented higher entrapment efficiency and mean particle size as well as a slow release rate. The UT-PLGA nanoparticles showed higher drug loading. Two prostate cancer cell-lines, LNCaP and DU145 that were derived from metastatic sites, served as model systems to assess cytotoxicity and anti-cancer activity. In vitro, both formulations reduced the viability of DU145 and LNCaP cells. Yet, the UT-PLGA nanoparticles showed higher cytotoxicity towards DU145 cells while the UTPCL against LNCaP cells. The results confirm that the incorporation of UT into nanoparticles could enhance its anti-cancer activities that can offer a viable alternative for the treatment of prostrate canner and highlights the potential of nanostructured systems to provide a promising methodology to enhance the activity of natural extracts.
The jungles of Central and South America contain two predominant species of cat’s claw (Uña de Gato), Uncaria tomentosa (Willd. ex Schult.) DC. and Uncaria guianensis (Aubl.) J.F. Gmell, which are used in traditional medicine mainly for their anti-inflammatory properties. However, a wealth of compounds have been isolated from these two vines of the Rubiaceae family, including alkaloids, flavonoids and terpenoids, showing a wide range of activities: anti-inflammatory, anti-oxidative, hypotensor, antiviral, smooth muscle relaxant, antispasmodic, gastrointestinal mucosa protector, antiarrhythmic, anticonvulsant, analgesic, anti-leishmaniosis, cytostatic, cytotoxic, hypoglycaemizing, anticholestatic, antihistaminic, hepatoprotective, diuretic, antiulcer, immunostimulating and sedative effects. Some of these activities have been confirmed in both in vitro and in vivo models.
Several useful anticancer drugs have been derived from plants. The growth and metastasis of tumours in the mouse may be used to study plant extracts with therapeutic potential. In the present study we investigated the possible effects of aqueous extracts of three Amazonian plants ( Uncaria tomentosa [UT], Petiveria alliacea [PA] and Phyllantus niruri [PN]) on the growth and metastasis of B16/BL6 melanoma cells in the C57BL/6 mouse, and on the serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and serum amyloid P component (SAP). None of the three extracts inhibited the growth of the B16/BL6 cells in vitro, or of two other tumor cell lines, HT-29 and Caco-2. Serum levels of IL-6 and SAP, and the TNF-α serum response to LPS rose in the animals inoculated i.v. with melanoma cells. Only UT, when injected i.p. every other day for 14 days, was able to significantly reduce lung metastases after an i.v. inoculation of melanoma cells or to delay the appearance and growth of solid tumors after s.c. inoculation. In addition, only UT was able to reduce the serum response of the two proinflammatory cytokines, TNF-α and IL-6. No effect on SAP levels was observed. UT merits further study as an anticancer agent.
The present work intended to study the antitumoral and antioxidant effects of Uncaria tomentosa (UT) hydroalcoholic extract in the Walker-256 cancer model.
Walker-256 cells were subcutaneously inoculated in the pelvic limb of male Wistar rats. Daily gavage with UT extract (10, 50 or 100 mg kg(-1), Groups UT) or saline solution (Control, Group C) was subsequently initiated, until 14 days afterwards. For some parameters, a group of healthy rats (Baseline, Group B) was added. At the end of treatment the following parameters were evaluated: (a) tumor volume and mass; (b) plasmatic concentration of urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT) and lactate dehydrogenase (LDH); (c) hepatic and tumoral activity of catalase (CAT) and superoxide dismutase (SOD), as well as the rate of lipid peroxidation (LPO) and gluthatione (GSH); and (d) hepatic glutathione-S-transferase (GST) activity. The reactivity of UT extract with the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) was assessed in parallel.
UT hydroalcoholic extract successfully reduced the tumor growth. In addition, treatment with UT reduced the activity of AST, which had been increased as a result of tumor inoculation, thus attempting to return it to normal levels. UT did not reverse the increase of LDH and GGT plasma levels, although all doses were remarkably effective in reducing urea plasma levels. An important in vitro free radical-scavenging activity was detected at various concentrations of UT extract (1-300 microg mL(-1)). Treatment also resulted in increased CAT activity in liver, while decreasing it in tumor tissue. SOD activity was reduced in liver as well as in tumor, compared to Group C. No statistical significance concerning ALT, GST, LPO or GSH were observed.
This data represent an in vivo demonstration of both antitumoral and antioxidant effects of UT hydroalcoholic extract. The antineoplastic activity may result, partially at least, from the ability of UT to regulate redox and metabolism homeostasis.
The use of plant extracts to alleviate inflammatory diseases is centuries old and continues to this day. This review assesses the current understanding of the use of such plants and natural products isolated from them in terms of their action against the ubiquitous transcription factor, nuclear factor kappa B (NF-κB). As an activator of many pro-inflammatory cytokines and inflammatory processes the modulation of the NF-κB transduction pathway is a principal target to alleviate the symptoms of such diseases as arthritis, inflammatory bowel disease and asthma. Two pathways of NF-κB activation will first be summarised, leading to the Ikk (IkB kinase) complex, that subsequently initiates phosphorylation of the NF-κB inhibitory protein (IkB). Natural products and some extracts are reviewed and assessed for their activity and potency as NF-κB inhibitors. A large number of compounds are currently known as NF-κB modulators and include the isoprenoids, most notably kaurene diterpenoids and members of the sesquiterpene lactones class, several phenolics including curcumin and flavonoids such as silybin. Additional data on cellular toxicity are also highlighted as an exclusion principle for pursuing such compounds in clinical development. In addition, where enough data exists some conclusions on structure-activity relationship are provided.
This study aimed to compare the anti-neoplastic effects of an Uncaria tomentosa (UT) brute hydroethanolic (BHE) extract with those of two fractions derived from it. These fractions are choroformic (CHCl(3)) and n-butanolic (BuOH), rich in pentacyclic oxindole alkaloids (POA) and antioxidant substances, respectively. The cancer model was the subcutaneous inoculation of Walker-256 tumour cells in the pelvic limb of male Wistar rat. Subsequently to the inoculation, gavage with BHE extract (50 mg.kg(-1)) or its fractions (as per the yield of the fractioning process) or vehicle (Control) was performed during 14 days. Baseline values, corresponding to individuals without tumour or treatment with UT, were also included. After treatment, tumour volume and mass, plasma biochemistry, oxidative stress in liver and tumour, TNF-α level in liver and tumour homogenates, and survival rates were analysed. Both the BHE extract and its BuOH fraction successfully reduced tumour weight and volume, and modulated anti-oxidant systems. The hepatic TNF-α level indicated a greater effect from the BHE extract as compared to its BuOH fraction. Importantly, both the BHE extract and its BuOH fraction increased the survival time of the tumour-bearing animals. Inversely, the CHCl(3) fraction was ineffective. These data represent an in vivo demonstration of the importance of the modulation of oxidative stress as part of the anti-neoplastic activity of UT, as well as constitute evidence of the lack of activity of isolated POAs in the primary tumour of this tumour lineage. These effects are possibly resulting from a synergic combination of substances, most of them with antioxidant properties.
Uncaria tomentosa (Willd. ex Roem. & Schult.) DC. (Rubiaceae) is widely used by populations living in South America to treat many ailments associated with inflammatory disorders. Mitraphylline was shown to be the major pentacyclic oxindolic alkaloid present in the bark chloroformic extract of this plant. Its activity against cytokines involved in inflammation process was tested in a murine model in vivo.
Mice received mitraphylline once a day for 3 days at 30mg/kg/day by oral route. Then, they were subjected to bacterial lipopolysaccharide (LPS) endotoxin (15mg/kg) and the LPS-induced production of 16 different cytokines was determined by Elisa multiplex. Control group received dexamethasone orally at 2mg/kg/day. Toxicity on K565 cells and murine peritoneal macrophages, in vitro, at doses up to 100μM was monitored by XTT-colorimetric assay.
For the first time mitraphylline was tested in vivo against a large range of cytokines that play a crucial role in inflammation. Mitraphylline inhibited around 50% of the release of interleukins 1α, 1β, 17, and TNF-α. This activity was similar to dexamethasone. It also reduced almost 40% of the production of interleukin 4 (IL-4) while the corticoid did not. Lastly it did not show any toxicity on K565 cells nor murine macrophages at doses up to 100μM.
It has been increasingly recognized that tumor microenvironment plays an important role in carcinogenesis. Inflammatory component is present and contributes to tumor proliferation, angiogenesis, metastasis and resistance to hormonal and chemotherapy. This review highlights the role of inflammation in the tumor metastasis. We focus on the function of proinflammatory factors, particularly cytokines during tumor metastasis. Understanding of the mechanisms by which inflammation contributes to metastasis will lead to innovative approach for treating cancer.
Extracts of the bark of Uncaria tomentosa (Cat is Claw ¿ Uña de Gato) have been used traditionally for their anti-inflammatory and anticancer properties. We investigated the effect of a hydroethanolic extract (UT) of U. tomentosa on a) the viability of primary and tumor cells, b) the inflammatory response (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6] and nitric oxide [NO]) both in vitro and in vivo, c) B16/BL6 melanoma cell growth and metastasis in the C57BL/6 mouse, and d) nuclear factor κB (NF-κB) activity in LPS-stimulated HeLa cells. UT did not show an important cytotoxic effect in vitro at the doses up to 300 μg/ml, but did inhibit tumor growth and metastasis in vivo. UT inhibited TNF-α, IL-6 and NO production in vitro. NF-κB activity was also inhibited. Our studies show that UT merits further study for its effects on processes common to inflammation and cancer.
Cyclooxygenase (COX)-2 expression was immunohistochemically examined in 59 human lung cancers as well as in normal and premalignant lung specimens. In contrast to scattered weak reactivity seen in normal peripheral airway epithelial cells, markedly up-regulated COX-2 expression was detected in about one-third of atypical adenomatous hyperplasias and carcinoma in situ specimens, and a significant increase in COX-2 expression was observed in 70% of invasive adenocarcinoma cases. Interestingly, the proportion of adenocarcinoma cells with marked COX-2 expression was much greater in lymph node metastases than in the corresponding primary tumors. In contrast, small cell carcinomas showed virtually negligible expression, and squamous cell carcinomas showed infrequent and low expression. These findings suggest that an increase in COX-2 expression may be associated with the development of adenocarcinomas and possibly with acquisition of an invasive and metastatic phenotype.
Aim:
The purpose of this investigation was to evaluate the ability of cat's claw, an Amazonian medicinal plant, to treat osteoarthritis of the knee, collect safety and tolerance information and compare the antioxidant, and anti-inflammatory actions of Uncaria guianensis and Uncaria tomentosa in vitro.
Materials and methods:
Forty-five patients with osteoarthritis of the knee were recruited, 30 were treated with freeze-dried U guianensis, and 15 with placebo. Hematological parameters were assessed on entry and exit of the four-week trial. Pain, medical and subject assessment scores and adverse effects were collected at weeks 1, 2 and 4. The antioxidant and anti-inflammatory activity of the cat's claw species was determined by the alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) free radical scavenging method. Inhibition of TNFalpha and prostaglandin E2 (PGE2) production was determined in RAW 264.7 cells by ELISA.
Results:
Cat's claw had no deleterious effects on blood or liver function or other significant side-effects compared to placebo. Pain associated with activity, medical and patient assessment scores were all significantly reduced, with benefits occurring within the first week of therapy. Knee pain at rest or at night, and knee circumference were not significantly reduced by cat's claw during this brief trial. In vitro tests indicated that U guianensis and U. tomentosa were equivalent at quenching DPPH radicals (EC50, 13.6-21.7 microg/ml) as well as inhibiting TNFalpha production. However, the latter action was registered at much lower concentrations (EC50, 10.2-10.9 ng/ml). Cat's claw (10 microg/ml) had no effect on basal PGE2 production, but reduced LPS-induced PGE2 release (P < 0.05), but at higher concentrations than that required for TNFalpha inhibition.
Conclusion:
Cat's claw is an effective treatment for osteoarthritis. The species, U guianensis and U tomentosa are equiactive. They are effective antioxidants, but their anti-inflammatory properties may result from their ability to inhibit TNFalpha and to a lesser extent PGE2 production.
Numerous experimental, epidemiologic, and clinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the highly selective cyclooxygenase (COX)-2 inhibitors, have promise as anticancer agents. NSAIDs restore normal apoptosis in human adenomatous colorectal polyps and in various cancer cell lines that have lost adenomatous polyposis coli gene function. NSAIDs also inhibit angiogenesis in cell culture and rodent models of angiogenesis. Many epidemiologic studies have found that long-term use of NSAIDs is associated with a lower risk of colorectal cancer, adenomatous polyps, and, to some extent, other cancers. Two NSAIDs, sulindac and celecoxib, have been found to inhibit the growth of adenomatous polyps and cause regression of existing polyps in randomized trials of patients with familial adenomatous polyposis (FAP). However, unresolved questions about the safety, efficacy, optimal treatment regimen, and mechanism of action of NSAIDs currently limit their clinical application to the prevention of polyposis in FAP patients. Moreover, the development of safe and effective drugs for chemoprevention is complicated by the potential of even rare, serious toxicity to offset the benefit of treatment, particularly when the drug is administered to healthy people who have low annual risk of developing the disease for which treatment is intended. This review considers generic approaches to improve the balance between benefits and risks associated with the use of NSAIDs in chemoprevention. We critically examine the published experimental, clinical, and epidemiologic literature on NSAIDs and cancer, especially that regarding colorectal cancer, and identify strategies to overcome the various logistic and scientific barriers that impede clinical trials of NSAIDs for cancer prevention. Finally, we suggest research opportunities that may help to accelerate the future clinical application of NSAIDs for cancer prevention or treatment.
The use of plant extracts to alleviate inflammatory diseases is centuries old and continues to this day. This review assesses the current understanding of the use of such plants and natural products isolated from them in terms of their action against the ubiquitous transcription factor, nuclear factor kappa B (NF-kappaB). As an activator of many pro-inflammatory cytokines and inflammatory processes the modulation of the NF-kappaB transduction pathway is a principal target to alleviate the symptoms of such diseases as arthritis, inflammatory bowel disease and asthma. Two pathways of NF-kappaB activation will first be summarised, leading to the IKK (IkappaB kinase) complex, that subsequently initiates phosphorylation of the NF-kappaB inhibitory protein (IKB). Natural products and some extracts are reviewed and assessed for their activity and potency as NF-kappaB inhibitors. A large number of compounds are currently known as NF-kappaB modulators and include the isoprenoids, most notably kaurene diterpenoids and members of the sesquiterpene lactones class, several phenolics including curcumin and flavonoids such as silybin. Additional data on cellular toxicity are also highlighted as an exclusion principle for pursuing such compounds in clinical development. In addition, where enough data exists some conclusions on structure-activity relationship are provided.
We assessed in vivo the anti-inflammatory activity of two Cat's claw bark extracts, by comparing a spray-dried hydroalcoholic extract against an aqueous freeze-dried extract, to determine which extract was more effective. We used the carrageenan-induced paw edema model in mice. In addition, to assess the molecular mechanism of action, we determined the inhibition of NF-kappa B through the Electrophoretic Mobility Shift Assay (EMSA) and the effects on cycloxygenase-1 and -2. Results showed that the anti-inflammatory activity was significantly higher using the hydroalcoholic compared with the aqueous extract (P<0.05). The extracts also showed little inhibitory activity on cyclooxygenase-1 and -2. It cannot be excluded that the slight inhibitory activity on DNA binding of NF-kappa B is due to cytotoxic effects.
Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.
From the methanol extract of Bauhinia megalandra fresh leaves, eight flavonoids were isolated and evaluated by rat liver microsomal glucose-6-phosphatase (G-6-Pase) bioassay, which might be a useful methodology for screening antihyperglycaemic substances. All the flavonoids assayed showed an inhibitory effect on the intact microsomal G-6-Pase: quercetin and kaempferol exhibited the lowest effect; astilbin, quercetin 3-O-alpha-rhamnoside, kaempferol 3-O-alpha-rhamnoside and quercetin 3-O-alpha-arabinoside an intermediate effect. The highest inhibitory activity was shown by quercetin 3-O-alpha-(2''-galloyl)rhamnoside and kaempferol 3-O-alpha-(2''galloyl)rhamnoside. None of the flavonoids mentioned above showed an inhibitory effect on the disrupted microsomal G-6-Pase. Quercetin 3-O-alpha-(2''-galloyl)rhamnoside and kaempferol 3-O-alpha-(2''-galloyl)rhamnoside exhibited the lowest IC50 of all the flavonoids assayed. Also, the phlorizin IC50 is reported.
Uncaria guianensis (Aublet) J. F. Gmelin is an herbal medicine from tropical areas of South and Central America. We investigated the anti-inflammatory and anti-allergic properties of an ethanolic extract of U. guianensis leaves, containing alkaloids, flavonoids and phenol carboxylic acids, as revealed by thin layer chromatography (TLC). Oral pre-treatment with U. guianensis inhibited zymosan-induced paw oedema (500 mg/paw) and pleural exudation (100 mg/kg) within 4 h (25-200 mg/kg). U. guianensis (100 mg/kg) inhibited total leukocyte and neutrophil numbers in the pleural cavity 4 h after zymosan stimulation. Pre-treatment with U. guianensis (100 mg/kg, p.o.) inhibited total leukocyte, neutrophil and eosinophil recruitment into the pleural cavity 24 h after LPS (250 ng/cavity, i.t.). Pre-treatment with U. guianensis inhibited paw oedema (25-200 mg/kg) induced by ovalbumin (OVA) within 1 h, and neutrophil and eosinophil recruitment into the mice pleural cavity 24 h after OVA (100 mg/kg). In vitro data revealed that U. guianensis impaired LPS-induced nitric oxide and CXCL8 generation by murine peritoneal macrophages, as well as OVA-induced interleukin-5 synthesis by previously sensitized spleen cells. These results demonstrate that U. guianensis leaves provide effective anti-inflammatory and anti-allergic activities.
Uncaria tomentosa, commonly known as cat's claw, is a medicinal plant native to Peru, which has been used for decades in the treatment of various inflammatory disorders. Uncaria tomentosa can be used as an antioxidant, has anti-apoptotic properties, and can enhance DNA repair, however it is best know for its anti-inflammatory properties. Treatment with Uncaria tomentosa extracts inhibits the production of the pro-inflammatory cytokine, TNF-alpha, which is a critical mediator of the immune response. In this paper, we showed that treatment of THP-1 monocyte-like cells with Uncaria tomentosa extracts inhibited the MAP kinase signaling pathway and altered cytokine expression. Using ELISA assays, we showed that treatment with Uncaria tomentosa extracts augmented LPS-dependent expression of IL-1beta by 2.4-fold, while inhibiting the LPS-dependent expression of TNF-alpha by 5.5-fold. We also showed that treatment of LPS-stimulated THP-1 cells with Uncaria tomentosa extracts blocked ERK1/2 and MEK1/2 phosphorylation in a dose-dependent manner. These data demonstrate that treatment of THP-1 cells with Uncaria tomentosa extracts has opposite effects on IL-1beta and TNF-alpha secretion, and that these changes may involve effects on the MAP kinase pathway.
The sulforhodamine B (SRB) assay is used for cell density determination, based on the measurement of cellular protein content. The method described here has been optimized for the toxicity screening of compounds to adherent cells in a 96-well format. After an incubation period, cell monolayers are fixed with 10% (wt/vol) trichloroacetic acid and stained for 30 min, after which the excess dye is removed by washing repeatedly with 1% (vol/vol) acetic acid. The protein-bound dye is dissolved in 10 mM Tris base solution for OD determination at 510 nm using a microplate reader. The results are linear over a 20-fold range of cell numbers and the sensitivity is comparable to those of fluorometric methods. The method not only allows a large number of samples to be tested within a few days, but also requires only simple equipment and inexpensive reagents. The SRB assay is therefore an efficient and highly cost-effective method for screening.
A low incidence of lung carcinoma has been reported in cases of prolonged use of aspirin. Cyclooxygenase (COX) 2 expression is frequently seen in adenocarcinoma of the lung, but COX-2 expression in atypical adenomatous hyperplasia (AAH), a possible precursor lesion of adenocarcinoma of the lung, is not known. COX-2 expression was immunohistochemically evaluated in a cohort of 20 cuboidal cell hyperplasias (CCH), 81 atypical adenomatous hyperplasias (AAH), 18 bronchioloalveolar carcinomas (BAC), and 88 invasive adenocarcinomas (I-Ad). The relationship between COX-2 expression and clinicopathologic factors and survival was examined. COX-2 overexpression was detected in over 80% of CCH, AAH, BAC, and I-Ad. However, overexpression was diffuse in AAH (71.6%) and BAC (66.7%). No relationship was found between COX-2 expression and clinicopathological factors or survival. COX-2 expression was most frequently detected in AAH. These findings, taken with previous reports that treatment with COX-2 inhibitor suppresses human colon carcinogenesis, suggest that inhibition of COX-2 may reduce the incidence of human adenocarcinoma of the lung.
Excessive activation of microglial cells has been implicated in various types of neuroinflammation. Suppression of microglial activation would have therapeutic benefits, leading to the alleviation of the progression of neurodegeneration. In this study, the inhibitory effects of rhynchophylline (RIN), a tetracyclic oxindole alkaloid component isolated from Uncaria rhynchophylla (Miq.) Jacks., on the production of pro-inflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated microglia. The results showed that RIN markedly reduced the production of nitric oxide (NO), prostaglandins E(2) (PGE(2) ), monocyte chemoattractant protein (MCP-1), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in LPS-activated microglia. The mRNA expression levels of iNOS and COX-2 were also depressed by RIN in a concentration-dependent manner. Further studies revealed that RIN blocked IκBα phosphorylation and degradation, inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs). In summary, these data suggest that RIN suppresses inflammatory responses of microglia and may act as a potential therapeutic agent for various neurodegenerative diseases involving neuroinflammation. Copyright © 2012 John Wiley & Sons, Ltd.
The activity of Uncaria tomentosa preparations on cancer cells was studied using in vitro and in vivo models. IC (50) values were calculated for preparations with different quantitative and qualitative oxindole alkaloid composition: B/W(37) --bark extracted in water at 37 °C, B/W(b)--bark extracted in boiling water, B/50E(37) --bark extracted in 50% ethanol at 37 °C, B/E(b)--bark extracted in boiling 96% ethanol, B/96E(37) --bark extracted in 96% ethanol at 37 °C and B/SRT--bark extracted in water and dichloromethane. Generally, the results obtained showed a high correlation between the total oxindole alkaloid content (from 0.43% to 50.40% d.m.) and the antiproliferative activity of the preparations (IC(50) from >1000 μg/ml to 23.57 μg/ml). B/96E(37) and B/SRT were the most cytotoxic preparations, whereas the lowest toxicity was observed for B/W(37). B/96E(37) were shown to be active against Lewis lung carcinoma (LL/2) [IC(50) =25.06 μg/ml], cervical carcinoma (KB) [IC(50) =35.69 μg/ml] and colon adenocarcinoma (SW707) [IC(50) =49.06 μg/ml]. B/SRT was especially effective in inhibiting proliferation of cervical carcinoma (KB) [IC(50) =23.57 μg/ml], breast carcinoma (MCF-7) [IC(50) =29.86 μg/ml] and lung carcinoma (A-549) [IC(50) =40.03 μg/ml]. Further animal studies on mice bearing Lewis lung carcinoma showed significant inhibition of tumor growth by B/W(37) administered for 21 days at daily doses of 5 and 0.5 mg (p=0.0009). There were no significant changes in the cell cycles of tumor cells with the exception of cell decrease at the G₂/M phase after the administration of B/96E(37) at a daily dose of 0.5 mg and the G(1)/G(0) cells cycle arrest demonstrated after the B/SRT therapy at a daily-dose of 0.05 mg. All tested preparations were non-toxic and well tolerated.
Excessive production of nitric oxide (NO) and proinflammatory cytokines from activated microglia contributes to human neurodegenerative disorders. Our previous study demonstrated the potent inhibition of lipopolysaccharide (LPS)-induced NO production in rat primary microglial cells by rhynchophylline (RIN) and isorhynchophylline (IRN), a pair of isomeric alkaloids of Uncaria rhynchophylla (Miq.) Jacks. that has been used in China for centuries as a "cognitive enhancer" as well as to treat strokes. We further investigated whether RIN and IRN effectively suppress release of proinflammatory cytokines in LPS-activated microglial cells and the underling molecular mechanism for the inhibition of microglial activation. RIN and IRN concentration-dependently attenuated LPS-induced production of proinflammatory cytokines such as TNF-alpha and IL-1beta as well as NO in mouse N9 microglial cells, with IRN showing more potent inhibition of microglial activation. The western blotting analysis indicated that the potential molecular mechanism for RIN or IRN-mediated attenuation was implicated in suppressions of iNOS protein level, phosphorylation of ERK and p38 MAPKs, and degradation of IkappaBalpha. In addition, the differential regulation of the three signaling pathways by two isomers was shown. Our results suggest that RIN and IRN may be effective therapeutic candidates for use in the treatment of neurodegenerative diseases accompanied by microglial activation.
It has been increasingly recognized that tumor microenvironment plays an important role in carcinogenesis. Inflammatory component is present and contributes to tumor proliferation, angiogenesis, metastasis and resistance to hormonal and chemotherapy. This review highlights the role of inflammation in the tumor metastasis. We focus on the function of proinflammatory factors, particularly cytokines during tumor metastasis. Understanding of the mechanisms by which inflammation contributes to metastasis will lead to innovative approach for treating cancer. How tumor spread remains an enigma and has received great attention in recent years, as metastasis is the major cause of cancer mortality. The complex and highly selective metastatic cascade not only depends on the intrinsic properties of tumor cells but also the microenvironment that they derive from. An inflammatory milieu consisting of infiltrated immune cells and their secretory cytokines, chemokines and growth factors contribute significantly to the invasive and metastatic traits of cancer cells. Here, we review new insights into the molecular pathways that link inflammation in the tumor microenvironment to metastasis.
From the bark of Uncaria guianensis, two new quinovic acid glycosides, quinovic acid 3 beta-O-beta-D-quinovopyranoside and quinovic acid 3 beta-O-beta-D-fucopyranosyl-(27----1)-beta-D-glucopyranosylester, have been isolated, in addition to known quinovic acid 3 beta-O-[beta-D-glucopyranosyl-(1----3)-beta-D-fucopyranosyl]-(27----1)- beta-D-glucopyranosylester and quinovic acid 3 beta-O-beta-D-fucopyranoside. Their structures were elucidated by spectral and chemical studies.
Uncaria tomentosa is a vine commonly known as cat's claw or 'uña de gato' (UG) and is used in traditional Peruvian medicine for the treatment of a wide range of health problems, particularly digestive complaints and arthritis.
The aim of this study was to determine the proposed anti-inflammatory properties of cat's claw. Specifically: (i) does a bark extract of cat's claw protect against oxidant-induced stress in vitro, and (ii) to determine if UG modifies transcriptionally regulated events.
Cell death was determined in two cell lines, RAW 264.7 and HT29 in response to peroxynitrite (PN, 300 microM). Gene expression of inducible nitric oxide synthase (iNOS) in HT29 cells, direct effects on nitric oxide and peroxynitrite levels, and activation of NF-kappaB in RAW 264.7 cells as influenced by UG were assessed. Chronic intestinal inflammation was induced in rats with indomethacin (7.5 mg/kg), with UG administered orally in the drinking water (5 mg/mL).
The administration of UG (100 microg/mL) attenuated (P < 0.05) peroxynitrite-induced apoptosis in HT29 (epithelial) and RAW 264.7 cells (macrophage). Cat's claw inhibited lipopolysaccharide-induced iNOS gene expression, nitrite formation, cell death and inhibited the activation of NF-kappaB. Cat's claw markedly attenuated indomethacin-enteritis as evident by reduced myeloperoxidase activity, morphometric damage and liver metallothionein expression.
Cat's claw protects cells against oxidative stress and negated the activation of NF-kappaB. These studies provide a mechanistic evidence for the widely held belief that cat's claw is an effective anti-inflammatory agent.
Bioassay-guided fractionation of the EtOH extract of the bark of Uncaria guianensis (Aubl.) Gmel (Rubiaceae) using a yeast-based assay for DNA-damaging agents has furnished the two weakly but selectively active indole alkaloids uncarine C (1) and uncarine E (2) as the major bioactive constituents in this assay.
The response of the body to a cancer is not a unique mechanism but has many parallels with inflammation and wound healing. This article reviews the links between cancer and inflammation and discusses the implications of these links for cancer prevention and treatment. We suggest that the inflammatory cells and cytokines found in tumours are more likely to contribute to tumour growth, progression, and immunosuppression than they are to mount an effective host antitumour response. Moreover cancer susceptibility and severity may be associated with functional polymorphisms of inflammatory cytokine genes, and deletion or inhibition of inflammatory cytokines inhibits development of experimental cancer. If genetic damage is the "match that lights the fire" of cancer, some types of inflammation may provide the "fuel that feeds the flames". Over the past ten years information about the cytokine and chemokine network has led to development of a range of cytokine/chemokine antagonists targeted at inflammatory and allergic diseases. The first of these to enter the clinic, tumour necrosis factor antagonists, have shown encouraging efficacy. In this article we have provided a rationale for the use of cytokine and chemokine blockade, and further investigation of non-steroidal anti-inflammatory drugs, in the chemoprevention and treatment of malignant diseases.
A wide array of phenolic substances, particularly those present in edible and medicinal plants, have been reported to possess substantial anticarcinogenic and antimutagenic activities. The majority of naturally occurring phenolics retain antioxidative and anti-inflammatory properties which appear to contribute to their chemopreventive or chemoprotective activity. Cyclooxygenase-2 (COX-2) inducible and nitric oxide synthase (iNOS) are important enzymes that mediate inflammatory processes. Improper up-regulation of COX-2 and/or iNOS has been associated with pathophysiology of certain types of human cancers as well as inflammatory disorders. Since inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activities are anticipated to exert chemopreventive effects on carcinogenesis, particularly in the promotion stage. Examples are curcumin, a yellow pigment of turmeric (Curcuma longa L., Zingiberaceae), the green tea polyphenol epigallocatechin gallate (EGCG), and resveratrol from grapes (Vitis vinifera, Vitaceae) that strongly suppress tumor promotion. Recent studies have demonstrated that eukaryotic transcription factor nuclear factor-kappa B (NF-kappa B) is involved in regulation of COX-2 and iNOS expression. Several chemopreventive phytochemicals have been shown to inhibit COX-2 and iNOS expression by blocking improper NF-kappa B activation. Multiple lines of compelling evidence indicate that extracellular-regulated protein kinase and p38 mitogen-activated protein kinase are key elements of the intracellular signaling cascades responsible for NF-kappa B activation in response to a wide array of external stimuli. Curcumin, EGCG and resveratrol have been shown to suppress activation of NF-kappa B. One of the plausible mechanisms underlying inhibition of NF-kappa B activation by aforementioned phytochemicals involves repression of degradation of the inhibitory unit I kappa B alpha, which hampers subsequent nuclear translocation of the functionally active subunit of NF-kappa B.
Nuclear factor of kappaB (NF-kappaB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-KB in immunity is undisputed, recent evidence indicates that NF-kappaB and the signalling pathways that are involved in its activation are also important for tumour development. NF-kappaB should therefore receive as much attention from cancer researchers as it has already from immunologists.
Cat's claw is an herbal medicine from the Amazon that is used widely to treat inflammatory disorders. The purpose of this study was to characterize the antioxidative and antiinflammatory properties of cat's claw, Uncaria tomentosa (UT) and Uncaria guianensis (UG). Alkaloids and flavanols were determined using reversed-phase HPLC; scavenging of 1,1-diphenyl-2-picrilhydrazyl (DPPH), hydroxyl radicals, and lipid peroxidation by spectrophotometry; and TNFalpha production by ELISA. Anti-inflammatory activity was assessed in vitro by inhibition of TNFalpha and nitrite production from RAW 264.7 cells exposed to LPS (50 ng/ml) and in vivo using the indomethacin-induced gastritis model. Apoptosis was assessed using the TUNEL technique and TNFalpha mRNA by in situ RT-PCR. In each of the antioxidant assays tested, UG was more potent than UT (P < 0.01). The total oxindole and pentacyclic alkaloid content of UT was 35-fold > UG. The IC50 value for inhibition of TNFalpha production was significantly (P < 0.01) higher for UT (14.1 ng/ml) vs UG (9.5 ng/ml), yet at concentrations that were considerable lower than that required for antioxidant activity. Non-alkaloid HPLC fractions from UT decreased LPS-induced TNFalpha and nitrite production in RAW 264.7 cells (P < 0.01) at a concentration range comparable to the parent botanical. Oral pretreatment for 3 d with UT protected against indomethacin-induced gastritis, and prevented TNFalpha mRNA expression and apoptosis. These results indicate that while both species of cat's claw provide effective antioxidant and anti-inflammatory activities, U. guianensis is more potent. In conclusion, the presence of oxindole or pentacyclic alkaloids did not influence the antioxidant and anti-inflammatory properties of cat's claw.
Water extracts of the bark of Uncaria tomentosa, a vine indigenous to South America, has been used for generations as an "immuno modulator". To understand the basis of this immuno modulatory effect we fed mice in their drinking water with C-Med 100, which is a commercially available water extract from Uncaria tomentosa. We found a dose-dependent increase in spleen cell numbers in the supplemented mice, but the proportions of B cells, T cells, NK cells, granulocytes, and memory lymphocytes were normal. However, there were no detectable changes of the lymphoid architecture of the spleen even after long-term treatment. Further, when C-Med 100 treatment was interrupted the cellularity returned to normal level within four weeks. The increased number of lymphocytes was most likely not due to increased production because C-Med 100 did not have any significant effect on precursor cells nor on the accumulation of recent thymic emigrants in the spleen. We conclude that accumulation is most likely due to prolonged cell survival, because adoptive transfer experiments demonstrated that C-Med 100 treatment significantly prolonged lymphocyte survival in peripheral lymphoid organs, without increasing their proliferation rate. Since the accumulation was reversible and without detectable pathological effects, these results suggest the use of C-Med 100 as a potential agent for clinically accelerating the recovery of patients from leukopenia.
The alkaloids of the pantropical genus Uncaria (Rubiaceae) were reviewed extensively by Phillipson et al. in (1978) Since then a host of papers with new results has been published. The compounds discovered are from three major groups: (1) alkaloids; (2) terpenoids; and (3) flavonoids. Some highly unusual structures have been reported. Although there are at least 35 species of Uncaria known, recent research focussed on a relatively small number of species. During recent years bioactivity of extracts and pure compounds isolated from Uncaria species have been increasingly investigated. These include anticonvulsive, antiinflammatory, antimutagenic, antioxidant, cytoprotective, hypotensive, and immunoregulatory effects. The literature since 1978 is reviewed and 133 references are given.
Opposing effects of inflammation on cancer have been described. Acute inflammation usually counteracts cancer development, while chronic inflammation promotes cancer development. Just as inactivation of the p53 pathway may be universal in the neoplasia, the activation of the NFkappaB pathway may, conversely, be frequent in carcinogenesis, and a requirement for inflammation and promotion. TNF, a key pro-inflammatory cytokine when binding to TNF receptor 1 (TNFR1), may cause survival or apoptosis, dependent on biochemical modifications that determine the type of complex formed; one complex causes NFkappaB activation and gives a cell survival signal (pro-oncogenic), while the other (modified) complex recruits caspases and causes apoptosis (anti-oncogenic). Fas-ligand (FasL)-Fas interaction can also result in opposing effects on carcinogenesis due to similar mechanisms. While IL-6 counteracts apoptosis and can promote cancer development, interferons can increase DNA repair and stabilize p53, thereby be anti-oncogenic.
We have previously reported that the C-Med 100 extract of the plant Uncaria tomentosa induces prolonged lymphocyte half life and hence increased spleen cell number in mice receiving the extract in their drinking water. Further, the extract induces cell proliferation arrest and inhibits activation of the transcriptional regulator nuclear factor kappaB (NF-kappaB) in vitro. We now report that mice exposed to quinic acid (QA), a component of this extract, had significantly increased number of spleen cells, thus recapitulating the in vivo biological effect of C-Med 100 exposure. Commercially supplied QA (H(+) form) did not, however, inhibit cell proliferation in vitro, while the ammonia-treated QA (QAA) was a potent inhibitor. Both QA and QAA inhibited NF-kappaB activity in exposed cells at similar concentrations. Thus, our present data identify QA as a candidate component for both in vivo and in vitro biological effects of the C-Med 100 extract.
Decoctions prepared from the bark of Uncaria tomentosa (cat's claw) are widely used in the traditional Peruvian medicine for the treatment of several diseases, in particular as a potent anti-inflammatory agent. Therefore, the main purpose of this study was to determine if the well-known anti-inflammatory activity of cat's claw decoction was related with its reactivity with the oxidant species generated in the inflammatory process and to establish a relationship between such antioxidant ability and its phenolic composition. We observed that the decoction prepared according to the traditional Peruvian medicine presented a potent radical scavenger activity, as suggested by its high capacity to reduce the free radical diphenylpicrylhydrazyl, and by its reaction with superoxide anion, peroxyl and hydroxyl radicals as well as with the oxidant species, hydrogen peroxide and hypochlorous acid. It also protected membrane lipids against peroxidation induced by the iron/ascorbate system, as evaluated by the formation of thiobarbituric acid-reactive substances (TBARs). The decoction phenolic profile was established by chromatographic analysis (HPLC/DAD and TLC) revealing essentially the presence of proanthocyanidins (oligomeric procyanidins) and phenolic acids, mainly caffeic acid. Thus, our results provide evidence for an antioxidant mechanism underlying the anti-inflammatory activity of cat's claw and support some of the biological effects of proanthocyanidins, more exactly its antioxidant and radical scavenging activities.
The Uncaria genus is an important source of medicinal natural products, particularly alkaloids and triterpenes. The collected information is an attempt to cover the more recent developments in the ethnobotany, pharmacology and phytochemistry of this genus. During the past 20 years, alkaloids, terpenes, quinovic acid glycosides, flavonoids and coumarins have been isolated from Uncaria. Fifty-three novel structures are reported in this review. The species in which the largest number of compounds has been identified is the Peruvian Uncaria tomentosa or 'cat's claw.' Pharmacological studies are described according to cytotoxicity, anti-inflammatory, antiviral, immunostimulation, antioxidant, CNS-related response, vascular, hypotensive, mutagenicity and antibacterial properties. The potential for development of leads from Uncaria continues to grow, particularly in the area of immunomodulatory, anti-inflammatory and vascular-related conditions. The information summarized here is intended to serve as a reference tool to practitioners in the fields of ethnopharmacology and natural products chemistry.
It has long been suspected that NF-kappaB signaling has a pivotal role in chronic inflammation-associated malignancies, although genetic evidence for this hypothesis has been lacking. However, recent papers have lent credence to this concept and show that NF-kappaB activation in pre-malignant cells contributes to cell survival and metastatic potential. Furthermore, NF-kappaB activation in tumor-associated leukocytes, especially macrophages, contributes towards tumorigenesis by upregulating tumor-promoting proinflammatory proteins. This emphasizes the importance of NF-kappaB inhibitors as immunotherapeutic agents for chronic inflammation and suggests that these reagents might prevent, or at least inhibit, chronic inflammation-associated tumorigenesis.
There has been much effort recently to probe the long-recognized relationship between the pathological processes of infection, inflammation and cancer. For example, epidemiological studies have shown that approximately 15% of human deaths from cancer are associated with chronic viral or bacterial infections. This Review focuses on the molecular mechanisms that connect infection, inflammation and cancer, and it puts forward the hypothesis that activation of nuclear factor-kappaB (NF-kappaB) by the classical, IKK-beta (inhibitor-of-NF-kappaB kinase-beta)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.
The antioxidant properties of aqueous and ethanolic extracts of the Uncaria tomentosa bark were evaluated. The analysis included trolox equivalent antioxidant capacity (TEAC), peroxyl radical-trapping capacity (PRTC), superoxide radical scavenging activity (SOD) and quantitation of total tannins (TT) and total phenolic compounds (TPC). The obtained results indicate high antioxidant capacity of the studied materials in comparison to the other extracts of fruits, vegetables, cereals and medicinal plants. Higher antioxidant activity and total phenolic compounds of the alcoholic preparations -- TEAC=0.57 mmol of Trolox/g, PRTC=0.52 mmol of Trolox/g and SOD=0.39 U/mg than of the aqueous preparation -- TEAC=0.34 mmol of Trolox/g, PRTC=0.19 mmol of Trolox/g and SOD=0.10 U/mg were observed. These results might suggest higher medical suitability of alcoholic extracts. However, the highly elevated level of tannins in alcoholic extracts may cause undesirable gastric effects.
Macrophages within the tumor microenvironment facilitate angiogenesis and extracellular-matrix breakdown and remodeling and promote tumor cell motility. Recent studies reveal that direct communication between macrophages and tumor cells leads to invasion and egress of tumor cells into the blood vessels (intravasation). Thus, macrophages are at the center of the invasion microenvironment and are an important drug target for cancer therapy.
Investigations on the anti-inflammatory and anti-allergic activities of the leaves of Uncaria guianensis (Aublet) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis
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- C Penido
- A C Siani
- L M M Valente
- M G M O Henriques
- J Condeelis
- J W Pollard
Carvalho, M.V., Penido, C., Siani, A.C., Valente, L.M.M., Henriques, M.G.M.O., 2006. Investigations on the anti-inflammatory and anti-allergic activities of the leaves of Uncaria guianensis (Aublet) J. F. Gmelin. Inflammopharmacology 14, 48. Condeelis, J., Pollard, J.W., 2006. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266.
Uncaria tomentosa exerts extensive anti-neoplastic effects against the Walker-256 tumour by modulating oxidative stress and not by alkaloid activity Evaluation of flavonoids from Bauhinia megalandra leaves as inhibitors of glucose-6-phosphatase system
- A A Dreifuss
- A L Pereira
- I A Fabossi
- Reis Lívero
- F A Stolf
- A M Souza
- C E A De Oliveira Gomes
- L Constantin
- R P Furman
- A E F Strapasson
Dreifuss, A.A., Bastos-Pereira, A.L., Fabossi, I.A., dos Reis Lívero, F.A., Stolf, A.M., de Souza, C.E.A., de Oliveira Gomes, L., Constantin, R.P., Furman, A.E.F., Strapasson, R.L.B., 2013. Uncaria tomentosa exerts extensive anti-neoplastic effects against the Walker-256 tumour by modulating oxidative stress and not by alkaloid activity. PLOS ONE 8, e54618. Estrada, O., Hasegawa, M., Gonzalez-Mujíca, F., Motta, N., Perdomo, E., Solorzano, A., Méndez, J., Méndez, B., Zea, E.G., 2005. Evaluation of flavonoids from Bauhinia megalandra leaves as inhibitors of glucose-6-phosphatase system. Phytother. Res. 19, 859–863.
Inflammation as a tumour promoter in cancer induction
- M Philip
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Philip, M., Rowley, D.A., Schreiber, H., 2004. Inflammation as a tumour promoter in
cancer induction. Semin. Cancer Biol. 14, 433-439.
- A A Dreifuss
- A L Bastos-Pereira
- I A Fabossi
- F A Dos Reis Lívero
- A M Stolf
- C E A De Souza
- L De Oliveira Gomes
- R P Constantin
- A E F Furman
- R L B Strapasson
Dreifuss, A.A., Bastos-Pereira, A.L., Fabossi, I.A., dos Reis Lívero, F.A., Stolf, A.M.,
de Souza, C.E.A., de Oliveira Gomes, L., Constantin, R.P., Furman, A.E.F.,
Strapasson, R.L.B., 2013. Uncaria tomentosa exerts extensive anti-neoplastic
effects against the Walker-256 tumour by modulating oxidative stress and not
by alkaloid activity. PLOS ONE 8, e54618.
Inflammation and cancer: back to Virchow?
- Balkwill
NF-KB in cancer: from innocent bystander to major culprit
- Karin
Inflammation as a tumour promoter in cancer induction
- Philip