Larrea divaricata a native Argentine plant with potential activity against SARS-CoV-2? / ¿Larrea divaricata una planta nativa argentina con actividad potencial sobre SARS-CoV-2?

Larrea divaricata Cav. is an autochthonous South American plant popularly used in inflammatory and infectious diseases with reported anti - inflammatory, immunomodulatory, antimicrobial and antioxidant activities. Covid - 19 is an infection ca used by the severe acute respiratory syndrome coronavirus 2 (SARS - CoV - 2). This virus can cause pneumonia and even death in about 5% of the cases. The objective of the article was to demonstrate, through a literature review, that L. divaricata has sufficie nt attributes to be assayed against SARS - CoV - 2. For this, the chemical composition, reported activities and docking studies were taken into account. This review demonstrated that the plant extracts are capable of inhibiting the proliferation of fungi, bact eria and viruses and that they exert anti - inflammatory and immunomodulatory actions in different " in vitro " and " in vivo " models. These results suggest that the plant is a good candidate to be studied for the prevention and/or treatment of SARS - CoV - 2.

Larrea divaricata Cav. es una planta autóctona Sudamericana, utilizada popularmente en enfermedades inflamatorias e infecciosas, con activida d anti - inflamatoria, inmunomoduladora, antimicrobiana y antioxidante reportada. El Covid - 19 es una infección causada por una cepa de coronavirus, SARS - CoV - 2 (coronavirus tipo 2 causante del síndrome respiratorio agudo severo). Este virus puede originar neu monía e incluso la muerte en alrededor del 5% de los casos. Nuestro objetivo fue demostrar, a través de una revisión bibliográfica, que esta planta tiene atributos suficientes para ser ensayada en estudios contra SARS - CoV - 2. Se tuvo en cuenta la composici ón química, los antecedentes científicos y los estudios de acoplamiento molecular. Esta revisión permitió demostrar que extractos de la planta son capaces de inhibir la proliferación de hongos, bacterias y virus y que presentan acción anti - inflamatoria en diferentes modelos " in vitro " e " in vivo ", lo que los hace candidatos a ser estudiados en la prevención y/o tratamiento de la infección contra SARS - CoV - 2.

Vicenin-2 and vitexin participate in the in vitromodulation of the anti-inflammatory and antioxidant activities exerted by two Urtica circularisextracts / Participación de vicenina-2 y vitexina en la modulación de la actividad anti-inflamatoria in vitro y en la actividad antioxidante de dos extractos de Urtica circularis

Urtica circularis is an Argentinean species traditionally used to treat inflammation symptoms and oxidative stress-related diseases. Considering the uses in folk medicine, the purpose of this work was to evaluate and compare the anti-inflammatory and antioxidant activities of two different U. circularisextracts. The contribution of vicenin-2 and vitexin, two compounds identified in the phytochemical analysis, in the biological activity of the extracts was evaluated. The anti-inflammatory activity of the extracts and the isolated compounds was tested on lipopolysaccharide (LPS)-stimulated macrophages, while the antioxidant activity was evaluated through the 2,2 ́ diphenyl-1-picrylhydrazyl (DPPH) radical and 2,2 ́-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt (ABTS) scavenging activities. The popular uses of both extracts were validated, i.e., the use of U. circularis ethanol extract for the treatment of inflammation, and the use of the aqueous extract to treat oxidative stress related-diseases. The differences in the biological activities observed between the extracts are probably due to qualitative and/or quantitative differences in the chemical composition and/or the occurrence of synergism between compounds.

Urtica circularis es una especie argentina utilizada para tratar los síntomas de la inflamación y enfermedades relacionadas con el estrés oxidativo. El objetivo de este trabajo fue evaluar y comparar las actividades anti-inflamatoria y antioxidante de dos extractos teniendo en cuenta su uso popular. Además, se analizó la participación de vicenina-2 y vitexina, compuestos identificados en el análisis fitoquímico, en la actividad de los extractos. La actividad anti-inflamatoria fue evaluada en macrófagos activados con lipopolisacárido (LPS). Se midió su actividad antioxidante con los métodos del 1,1,difenil-2-picril-hidrazilo (DPPH) y del ácido2,2 ́azinobis-3 etilbenzotialzolin-6-sulfónico (ABTS). Los usos populares de ambos extractos fueron validados: el extracto etanólico para la inflamación y el extracto acuoso para el tratamiento de enfermedades relacionadas con el estrés oxidativo. Las diferencias en las actividades biológicas observadas entre los extractos están probablemente relacionadas con diferencias cualitativas y/o cuantitativas en su composición química y/o a la presencia de sinergismo entre compuestos

Anti-hyperglycaemic effect and nutritional properties of an aqueous extract of Larrea divaricata Cav. (jarilla) in streptozotocin-induced diabetes in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Larrea divaricata Cav. (Zygophyllaceae) (jarilla) is a native plant of South America widely distributed across Argentina and used in popular medicine to treat diabetes and hypercholesterolemia by the Diaguita-Calchaquí, Amaichas, and Quilmes indigenous communities and by non-indigenous population (criollos) of Calamuchita, in the province of Córdoba, Argentina. L. divaricata has also proved to have anti-inflammatory properties. However, the antidiabetic effects and the nutritional properties of the aqueous extract (AE) of this plant remain to be scientifically determined. AIM OF THE STUDY: The aim of the present work was to evaluate the capacity of an aqueous extract of L. divaricata (AE) and its main compound nordihydroguaiaretic acid (NDGA) to modulate the glucose, cholesterol, triglycerides and oxidative stress levels in STZ-induced diabetes in mice. The general objective of the present work was to search for extracts that can be used as adjuvant therapy in for diabetes. The suitability of the extract to be used as a dietary supplement was also assessed by determining the proximate amount of fibre, lipids, proteins, and minerals. MATERIALS AND METHODS: Diabetes was induced in mice by administration of streptozotocin (STZ). AE and NDGA were administered by the oral route. The animals' glycaemia was periodically monitored in blood samples obtained from the tail vein. The glucose dehydrogenase method was used. The effect of the AE on cholesterol, triglycerides, oxidative stress, lipid peroxidation and reduced glutathione (GSH) levels were determined in plasma samples by spectrophotometric assays. RESULTS: In STZ-treated mice, AE significantly decreased glucose (33%, ****p < 0.0001) and cholesterol levels (32%, **p < 0.01). AE and NDGA decreased lipid peroxidation (30% and 38%, respectively, ****p < 0.0001), and increased GSH levels (20%, **p < 0.01). The effects of AE on glucose and lipid levels could not be ascribed to NDGA; however, this compound was involved in the extract antioxidant effects. The overall effects of AE were probably related to its antioxidant activity and to the anti-hyperglycaemic effect mainly mediated by flavonoids, fibre (carbohydrates) and mineral elements such as potassium, calcium, magnesium, and zinc. The AE protein content also confers the extract nutritional properties. CONCLUSIONS: These results support the hypothesis that AE could be used as a therapeutic adjuvant or as a nutritional supplement to control glucose levels and lipid metabolism in metabolic syndrome-associated diseases. Moreover, these results scientifically reinforce the popular use of the plant.

Larrea divaricata: anti-inflammatory and antioxidant effects of on macrophages and low density lipoproteins.

BACKGROUND: The oxidized low density lipoprotein (ox-LDL) contributes to inflammation and oxidative stress through the activation of macrophages under hyperglycemia contributing to the development of diabetes mellitus and to atherosclerosis. Plants are a source of effective and innocuous antioxidants. Larrea divaricata Cav. (Zygophyllaceae) is used in Argentina folk medicine for its anti-inflammatory properties. METHODS: The aim of this work was to study the antioxidant and anti-inflammatory effects of the aqueous extract (AE) of L. divaricata on macrophages under glucose stimulation and on human LDL and HDL particles under free radical generators. RESULTS: AE reduced the lipid peroxidation (17%), nitric oxide (NO) (47-50%), tumor necrosis factor-α (TNF-α) (32%) and free radicals (50%) induced by glucose on macrophages. Also prevented HDL nitration (28%), thus preserving its function and structure and inhibited LDL oxidation. The effect on the nitrosative stress was mainly driven by nordihydroguaiaretic acid (NDGA). CONCLUSIONS: These results suggest a potential usefulness of AE as an adjuvant phytotherapy in patients with diabetes mellitus and atherosclerosis.

Antiproliferative activity of aqueous and polyphenol-rich extracts of Larrea divaricata Cav. on a melanoma cell line.

Most of the deaths from skin cancer are caused by melanoma, a malignancy in which STAT3 plays a crucial role. The inhibition of STAT3 is considered a potential target to induce cell death, tumor regression and metastasis inhibition. The objective of this work was to evaluate the activity of the aqueous extract of Larrea divaricata (Aq), a fraction rich in polyphenols (EA),and the isolated compound quercetin-3-methyl ether (Q3ME) on B16F10 melanoma cells. The effects of Aq, EA and Q3ME were assessed on B16F10 cells by determining the proliferation, viability, apoptosis induction and the expression and phosphorylation of STAT3. The phytochemical composition of the extracts was determined by High Performance Liquid Chromatography. Aq, EA and Q3ME presented antiproliferative activity on B6F10 cells through p-STAT3 inhibition and early and late apoptosis induction (EC50 EA= ≤0.1 µg/ml; Aq= 316 ± 30 µg/ml; Q3ME= <0.1 µg/ml). L. divaricata could be considered for the development of adjuvant phytotherapies in melanoma treatment.

Apigenin-7-Glucuronide from Urera aurantiaca Inhibits Tumor Necrosis Factor Alpha and Total Nitrite Release in Lipopolysaccharide-Activated Macrophages.

Urera aurantiaca is an Argentinean medicinal and edible species traditionally used to treat symptoms of inflammation. The aim of this study was to evaluate the anti-inflammatory activity of a methanol extract and its major compound. U. aurantiaca aerial parts were extracted with methanol by maceration. A phytochemical analysis was performed, and the extract's major component, apigenin-7-glucuronide (A7G), was identified by spectroscopic and HPLC methods. The analysis of the inflammatory mediators nitric oxide (NO) and tumor necrosis factor alpha (TNF-α) in lipopolysaccharide- (LPS-) stimulated macrophages were used in the evaluation of the extract and the major compound anti-inflammatory effects. The extract reduced LPS-augmented NO release from 100 µg/mL (27%), reaching the highest inhibition at 1000 µg/mL (96.3%), while A7G reduced it 30.7% at 1 µg/mL, and its maximum effect was 97.1% at 10 µg/mL. In the TNF-α model, the extract at 500 and 1000 µg/mL reduced LPS-augmented TNF-α by 13.5% and 93.9%, respectively; meanwhile, A7G reduced it by 26.2% and 83.8% at 5 and 10 µg/mL, respectively. U. aurantiaca popular use was validated. In the present study, for the first time, A7G was isolated from U. aurantiaca; furthermore, A7G showed anti-inflammatory effect in the macrophage cell line RAW264.7 (ATCC) and seems to be responsible for the extract anti-inflammatory effect.

Larrea divaricata Cav. aqueous extract and nordihydroguariaretic acid modulate oxidative stress in submandibular glands of diabetic rats: a buccal protective in diabetes.

BACKGROUND: Oxidative stress is an imbalance between the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS) and endogenous antioxidants. The aetiology and pathogenesis of several oral diseases are attributed to this process. The antioxidant enzymes secreted in the saliva by submandibular glands maintain oral health through the scavenging of ROS. The objective of this work was to study the capacity of an aqueous extract of L. divaricata (AE), and its majority compound, nordihydroguariaretic acid (NDGA), to modulate the pro-oxidant/antioxidant status in submandibular glands in a model of oxidative stress induced by streptozotocin (STZ) in rats. METHODS: To induce oxidative stress with STZ, a group of animals was treated i.p. with 1 X PBS (control group) and other group was injected i.p. once with STZ (60 mg/kg). Ten days after the treatment, blood samples were taken from the tail vain to determine the glucose levels. Animals with glucose values ≥300 mg/ml were selected. The submandibular glands of control and STZ treated animals were incubated with either the AE (500 µg/ml) or with NDGA (1.5 µg/ml), and the content of malondialdehyde (MDA), protein carbonyl groups, ROS and RNS, and the activity and expression of peroxidase (Px), superoxide dismutase (SOD) and inducible nitric oxide synthase (iNOS) were assayed. RESULTS: AE decreased the levels of MDA (##P < 0.01) and protein carbonyl groups (#P < 0.05), and modulated the levels of ROS such as hydrogen peroxide (H2O2)(##P < 0.01), superoxide anion (O2.-) (#P < 0.05) and nitric oxide (NO) (#P < 0.05) in relation to the modulation of Px and iNOS expression. NDGA was found to be involved in these effects. CONCLUSIONS: The antioxidant activity of the AE in the submandibular glands would allow the maintenance of the antioxidant pool to prevent oral oxidative diseases.

Jarilla-Coffea extract: a natural cosmetic product that improves eyelash and eyebrow growth in women.

PURPOSE: A combination of extracts, from two plant species, ie, Coffea arabica and Larrea divaricata (Jarilla) (ECOHAIR®), is being successfully used in Argentina as a cosmetic for hair recovery in androgenic and areata alopecia, and for eyelash and eyebrow growth. The objectives of this prospective study were to evaluate the capacity of Jarilla-Coffea extract gel of improving hair growth in relation to thickness, appearance of new hair, and hair length in comparison with a placebo in premenopausal and postmenopausal volunteers and to identify possible signs of ocular adverse local reactions related to the application of the gel. VOLUNTEERS AND METHODS: An open-label, placebo-controlled, prospective study was performed in healthy premenopausal and postmenopausal women during a daily administration period of 2 months (eyebrow growth) and 3 months (eyelash growth). The thickness of hair was determined using a video microscope MedicalScope®. The appearance of new hairs and total area with hair in eyebrow and eyelash length were quantified using a photographic record with Fotofinder® (Germany). The number of volunteers presenting variation in growth of new hair and length were also recorded. RESULTS: The product significantly increased the thickness of eyebrows (20% in 80% women) and eyelashes (19.44% in 100% of women). The gel also increased the appearance of new hairs, total area with hair, and length but there was no statistical difference between treatment and placebo. CONCLUSION: The gel was capable of improving growth of eyelashes and eyebrows by inducing principally hair thickening without causing local adverse effects in a high percentage of volunteers.

Development of pH-responsive biopolymer-silica composites loaded with Larrea divaricata Cav. extract with antioxidant activity.

A detailed study of biomaterials is mandatory to comprehend their feasible biomedical applications in terms of drug delivery and tissue regeneration. Particularly, mucoadhesive biopolymers such as chitosan (chi) and carboxymethylcellulose (CMC) have become interesting biomaterials regards to their biocompatibility and non-toxicity for oral mucosal drug delivery. In this work, pH-responsive biopolymer-silica composites (Chi-SiO2, Chi-CMC-SiO2) were developed. These two types of composites presented a different swelling behavior due to the environmental pH. Moreover, the nanocomposites were loaded with aqueous Larrea divaricata Cav. extract (Ld), a South American plant which presents antioxidant properties suitable for the treatment of gingivoperiodontal diseases. Chi-CMC-SiO2 composites showed the highest incorporation and reached the 100% of extract release in almost 4 days while they preserved their antioxidant properties. In this study, thermal and swelling behavior were pointed out to show the distinct water-composite interaction and therefore to evaluate their mucoadhesivity. Furthermore, a cytotoxicity test with 3T3 fibroblasts was assessed, showing that in both composites the addition of Larrea divaricata Cav. extract increased fibroblast proliferation. Lastly, preliminary in vitro studies were performed with simulated body fluids. Indeed, SEM-EDS analysis indicated that only chi-SiO2 composite may provide an environment for possible biomineralization while the addition of CMC to the composites discouraged calcium accumulation. In conclusion, the development of bioactive composites could promote the regeneration of periodontal tissue damaged throughout periodontal disease and the presence of silica nanoparticles could provide an environment for biomineralization.

Stability of an Aqueous Extract of Larrea divaricata Cav. during a Simulated Digestion Process.

Larrea divaricata Cav. (Zygophyllaceae) is a South American plant widely distributed in Argentina that is used in folk medicine to treat inflammatory diseases. The aqueous extract is known to have well-documented biological activities such as antitumour, immunomodulatory, antimicrobial, antiinflammatory and antioxidant. However, its stability in gastrointestinal fluids is unknown. The latter is an important factor to assure the bioavailability of plant extracts intended to be administered via the oral route. The aim of this work was to study the stability of a lyophilized aqueous extract of L. divaricata compressed as a pill. To this end, the main polyphenol compound found in the extract, that is, the nordihydroguaiaretic acid, the total polyphenols and flavonoids content and the antioxidant activity such as diphenylpicrylhydrazyl scavenger activity and reducing power were assayed after subjecting the extract to different incubation times in simulated digestive fluids. The HPLC and spectroscopic methods were employed. Although the levels of polyphenols and flavonoids decreased upon incubation in gastric and intestinal fluids, the extract maintained its antioxidant activity related to the presence of nordihydroguaiaretic acid. These results are promising and encourage the potential use of the extract by the oral route as a supplement or phytomedicine with antioxidant activity. Copyright © 2017 John Wiley & Sons, Ltd.

Clinical Evidence of Increase in Hair Growth and Decrease in Hair Loss without Adverse Reactions Promoted by the Commercial Lotion ECOHAIR®.

BACKGROUND/AIMS: Hair exerts protection, sensory functions, thermoregulation, and sexual attractiveness. Hair loss (alopecia) is caused by several diseases, drug intake, hormone imbalance, stress, and infections (Malassesia furfur). Drugs usually used in alopecia produce irreversible systemic and local side effects. An association of extracts of Coffea arabica and Larrea divaricata (ECOHAIR®) is successfully being commercialized in Argentina for hair growth. The aim of this study was to provide scientific support for the efficacy and innocuousness of ECOHAIR® in patients with noncicatricial alopecia during a 3-month treatment. METHODS: The efficacy was determined through the assessment of an increase in hair volume, improvement in hair looks, growth of new hair, and a decrease in hair loss by the test of hair count and hair traction. The capacity to decrease the amount of dandruff was also evaluated as well as the adverse local effects caused by the treatment. RESULTS: ECOHAIR® spray improved the overall hair volume and appearance; it increased its thickness, induced hair growth, and decreased hair loss. Besides, no adverse local reactions were observed upon treatment with the product. CONCLUSION: This study provides scientific support for the clinical use of ECOHAIR® as a treatment to be used in noncicatricial alopecia.

Modulatory Effect of an Urera Aurantiaca Extract on Immune and Tumoral Cells During Inflammation.

There is a well known link between inflammation and cancer during initiation, propagation and metastasis. Urera aurantiaca (UA) Wedd. (Urticaceae) is a medicinal plant used in traditional medicine to treat inflammatory processes with proven in vivo antiinflammatory and antinociceptive effects. The effects of a methanolic extract (UA) and a purified fraction (PF) on the proliferation of normal and tumoral lymphocytes under the effect of prostaglandin E2 (PGE2 ) and on nitric oxide production by lipopolysaccharide-stimulated macrophages was evaluated. Both UA and PF stimulated normal lymphocytes but, in presence of PGE2, a modulatory effect was observed. The normal lymphocyte proliferation induced by PGE2 was driven by pathways involving both PKC and H2 O2 . In macrophages, UA and PF did not modify cell viability and abrogated the synthesis of nitric oxide induced by lipopolysaccharide. In tumoral lymphocytes, the UA exerted a biphasic effect: at low concentrations it increased cell proliferation, while at high concentrations, it displayed an antiproliferative effect. UA and PF were capable of reverting the proliferative action of PGE2 . The tumoral cell proliferation induced by PGE2 is related to PKC, ERK 1/2 and MAP Kinase P38 pathways. The observed effects could be attributed to polyphenols, flavonoids and tannins. This work demonstrates the modulatory effects of the UA on different cell types during inflammatory conditions, which reinforces its antiinflammatory action. Copyright © 2016 John Wiley & Sons, Ltd.

Polyphenol-Rich Fraction from Larrea divaricata and its Main Flavonoid Quercetin-3-Methyl Ether Induce Apoptosis in Lymphoma Cells Through Nitrosative Stress.

Larrea divaricata is a plant with antiproliferative principles. We have previously identified the flavonoid quercetin-3-methyl ether (Q-3-ME) in an ethyl acetate fraction (EA). Both the extract and Q-3-ME were found to be effective against the EL-4 T lymphoma cell line. However, the mechanism underlying the inhibition of tumor cell proliferation remains to be elucidated. In this work, we analyzed the role of nitric oxide (NO) in the induction of apoptosis mediated by Q-3-ME and EA. Both treatments were able to induce apoptosis in a concentration-dependent and time-dependent manner. The western blot analysis revealed a sequential activation of caspases-9 and 3, followed by poly-(ADP-ribose)-polymerase cleavage. EA and Q-3-ME lowered the mitochondrial membrane potential, showing the activation of the intrinsic pathway of apoptosis. Q-3-ME and EA increased NO production and inducible NO synthase expression in tumor cells. The involvement of NO in cell death was confirmed by the nitric oxide synthases inhibitor L-NAME. In addition, EA and Q-3-ME induced a cell cycle arrest in G0/G1 phase. These drugs did not affect normal cell viability. This data suggested that EA and Q-3-ME induce an increase in NO production that would lead to the cell cycle arrest and the activation of the intrinsic pathway of apoptosis. Copyright © 2016 John Wiley & Sons, Ltd.

A fraction containing kaempferol-3,4'-dimethylether from Larrea divaricata Cav. induces macrophage activation on mice infected with Candida albicans.

Larrea divaricata Cav. is a plant growing in South America. Both the infusion and a derived fraction (F1) of L. divaricata have proved to have immunomodulatory properties. Moreover, F1 can activate macrophages obtained from mice infected with Candida albicans. In this work, F1 was administrated to infected animals, and the state and type of activation of resident macrophages were studied. Results showed that F1 was able to activate macrophages obtained from infected mice by both classical and alternative pathways, probably by inducing a translocation of nuclear factor kappa-B. F1 increases not only the lysosomal activity of macrophages but also the production of phagosomal superoxide anion as a consequence of the activation of the Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) complex. F1 induced an increase in the macrophage capacity to kill the fungus, which was reflected in a decrease in the levels of colonization of organs. A main flavonoid, kaempferol-3,4'-dimethylether, was identified in F1 by HPLC. This compound increased in vitro production of nitric oxide in heat-killed C. albicans-stimulated macrophages. The flavonoid could thus be considered one of the responsible molecules mediating the overall effects of F1 on the immune system in infected animals.

A fraction rich in phenyl propanoids from L. divaricata aqueous extract is capable of inducing apoptosis, in relation to H2O2 modulation, on a murine lymphoma cell line.

Leukemia and lymphoma are a group of heterogeneous neoplastic disorder of white blood cells characterized by the uncontrolled proliferation and block in differentiation of hematopoietic cells. Nowadays, there is an interest in therapy with drugs of plant origin because conventional medicine can be inefficient or also results in side effects. Larrea divaricata Cav., is a plant widely distributed in Argentina that possess antiproliferative and antioxidant activities reported. Nordihydroguaiaretic acid (NDGA) was previously found in the plant and related to both antiproliferative and pro-proliferative actions on a lymphoma cell line. In order to demonstrate whether the presence of NDGA may be beneficial or not in the antiproliferative action of the aqueous extract, the extract of L. divaricata was submitted to a fractionation and fractions with and without NDGA were studied in a murine lymphocitic leukemia cell line (EL-4) proliferation. The effect of the most active fraction was studied in relation to H2O2 modulation and the synergistic action between compounds, found in fractions, was analyzed. The presence of NDGA was not a detonator for pro-proliferative action and its presence could be beneficial in low concentrations allowing a synergist antiproliferative action with other compounds.

Antiadipogenic effect of carnosic acid, a natural compound present in Rosmarinus officinalis, is exerted through the C/EBPs and PPARγ pathways at the onset of the differentiation program.

BACKGROUND: Obesity is a serious health problem all over the world, and inhibition of adipogenesis constitutes one of the therapeutic strategies for its treatment. Carnosic acid (CA), the main bioactive compound of Rosmarinus officinalis extract, inhibits 3T3-L1 preadipocytes differentiation. However, very little is known about the molecular mechanism responsible for its antiadipogenic effect. METHODS: We evaluated the effect of CA on the differentiation of 3T3-L1 preadipocytes analyzing the process of mitotic clonal expansion, the level of adipogenic markers, and the subcellular distribution of C/EBPß. RESULTS: CA treatment only during the first day of 3T3-L1 differentiation process was enough to inhibit adipogenesis. This inhibition was accompanied by a blockade of mitotic clonal expansion. CA did not interfere with C/EBPß and C/EBPδ mRNA levels but blocked PPARγ, and FABP4 expression. C/EBPß has different forms known as LIP and LAP. CA induced an increase in the level of LIP within 24h of differentiation, leading to an increment in LIP/LAP ratio. Importantly, overexpression of LAP restored the capacity of 3T3-L1 preadipocytes to differentiate in the presence of CA. Finally, CA promoted subnuclear de-localization of C/EBPß. CONCLUSIONS: CA exerts its anti-adipogenic effect in a multifactorial manner by interfering mitotic clonal expansion, altering the ratio of the different C/EBPß forms, inducing the loss of C/EBPß proper subnuclear distribution, and blocking the expression of C/EBPα and PPARγ. GENERAL SIGNIFICANCE: Understanding the molecular mechanism by which CA blocks adipogenesis is relevant because CA could be new a food additive beneficial for the prevention and/or treatment of obesity.

Prevention of hydrogen peroxide-induced red blood cells lysis by Ilex paraguariensis aqueous extract: participation of phenolic and xanthine compounds.

The fresh leaves and stems of Ilex paraguariensis (Aquifoliaceae) are employed to prepare the commercial product used in North-eastern Argentina, Southern Brazil and Eastern Paraguay named yerba maté. The presence of polyphenols and xanthines, which present antioxidant activity, has been described in I. paraguariensis. In living organism, reactive oxygen species can cause tissue damage affecting erythrocyte membranes leading to hemolysis. The aim of this work was to evaluate the protective effect of an aqueous extract of I. paraguariensis (green leaves) on the hemolysis of red blood cells induced by hydrogen peroxide and to correlate this activity with the enzymatic activity related to hydrogen peroxide metabolism. The antioxidant activity of chlorogenic acid and caffeine was also analysed to evaluate their contribution to the activity of the crude extract. The extract as well as the isolated compounds protected red blood cells from hemolysis. This effect was related to a catalase-like activity. This study could contribute to the knowledge of the antioxidant activity of I. paraguariensis in view of the great quantities of yerba maté consumed by the population.

Macrophages activation by a purified fraction, free of nordihydroguaiaretic acid (NDGA), from Larrea divaricata Cav. as a potential novel therapy against Candida albicans.

Larrea divaricata Cav. (jarilla) is a plant with well-documented applications in Argentinean folk medicine. In order to determine if the treatment with a purified fraction named F1 was capable to maintain a state of priming of macrophages after 15 days of mice infection with Candida albicans. Infected and uninfected mice were used. The effect of F1 on: cytosolic protein levels, apoptosis, phagocytosis, reactive oxygen species production, nitric oxide (NO), cell activity, lysosomal activity and the tissue fungal burden were studied. The results showed that F1 increased macrophages yeast phagocytosis and reactive oxygen species and NO production. All these effects were related to a decrease of cell activity and possible apoptosis. In conclusion, it was observed that F1 could induce a state of long-term activation of macrophages, since we observed increased activity of macrophages 15 days after infection, and it could be related to the elimination of C. albicans. These data may suggest that F1 fraction could be useful against disseminated candidiasis in patients and further studies on this field are desirable.

Larrea divaricata Cav: scientific evidence showing its beneficial effects and its wide potential application / Larrea divaricata Cav: evidencia específica mostrando sus efectos beneficiosos y su amplia aplicación potencial

Larrea divaricata Cav. (jarilla) (Zygophyllaceae) is used in Argentinean folk medicine. It contains nordihydroguaiaretic acid (NDGA), a lignan with nefrotoxic and hepatotoxic effects. The presence of NDGA converts controversial the use of L. divaricata. The amount of NDGA is higher in alcoholic extracts than in aqueous extracts (AE). The last 20 years had a great advance on the use of AE to treat different conditions in a safe manner. In this review, we present the scientific results tending to confirm the potential beneficial effects of the AE on human health. The anti-proliferative effects of AE of L. divaricata have been assayed on a tumor lymphoid line (BW 5147) and the pathways involved in such effects were described. The anti-microbial activity was determined by tests for bacteria and fungus. The anti-inflammatory activity was assayed by using carrageen and TPA induced-inflammation tests. The Immunomodulatory effects were investigated ¯in vivo and ¯in vitro on mice. Sub-fractions of aqueous extracts were obtained and analyzed. The immunogenicity of proteins from crude AE was characterized and antioxidant and nutritional activity were studied. The effect of an AE on hair loss was assayed. In summary, AE from L. divaricata has pharmacological activities including anti-microbial, anti-inflammatory, anti-cancer effects.

Larrea divaricata Cav. (Jarilla) (Zygophyllaceae) es utilizada en medicina popular Argentina. Contiene ácido nordihidroguaiarético (NDGA), un lignano con efectos nefrotóxicos y hepatotóxicos. La presencia de NDGA hace controvertido el uso de L. divaricata. La cantidad de NDGA es mayor en extractos alcohólicos que en extractos acuosos (EA). Los últimos 20 años han tenido un gran avance en el uso de EA para el tratamiento de diferentes condiciones en forma segura. En esta revisión se presentan resultados científicos que confirman los efectos potencialmente beneficiosos de los EA sobre la salud humana. Los efectos anti-proliferativos se han ensayado en una línea de tumor linfoide, así como los mecanismos involucrados. La actividad anti-microbiana se determinó usando pruebas para bacterias y hongos. La actividad anti-inflamatoria fue evaluada mediante el uso de inflamación inducida por carragenina y TPA. Los efectos inmunomoduladores fueron investigados "in vivo" e "in vitro" en ratones. Sub-fracciones de los EA fueron obtenidos y analizados. La inmunogenicidad de las proteínas del EA crudo se caracterizaron y se estudiaron las actividades antioxidantes nutricionales. Además, se ensayó el efecto del EA en la caída del cabello. En resumen, los EA de L. divaricata presentan actividades farmacológicas como por ejemplo, anti-microbiana, anti-inflamatoria y efectos anti-cancerígenos.

In vivo immunomodulatory effect of Tilia x viridis extracts on normal lymphocyte proliferation: a direct and an indirect action.

The flowers of Tilia species have been used in Europe for many years to treat colds, bronchitis, fever, inflammations and influenza. It is well known that lymphocytes play a role in acquired immunity related to pathogens and tumor cells attachment. The aim of this study was to determine the effect of an aqueous (AE) and a dichloromethane extract (DM) from Tilia x viridis which is widely used and distributed in Argentina, on normal murine lymphocyte proliferation after being administered to mice. Both extracts presented a stimulatory effect on normal murine lymphocyte proliferation. The effect exerted by DM was principally related to macrophage activation, meanwhile AE exerted an important direct effect on lymphocytes related to the rutin presence. The stimulating effect, exerted on normal lymphocytes was due to a protective effect of apoptosis and also to cell IL2 production.