A comprehensive review on ethnobotanical,phytochemical and pharmacological aspects of the genus Dorema

The genus Dorema (Apiaceae) comprises 12 accepted species, mainly growing in Asia and, particularly, in Iran, where D. ammoniacum and D. aucheri are the most used species in cuisine and folk medicine. The Dorema species are traditionally applied in the treatment of catarrh, asthma, chronic bronchitis, as carminative, mild diuretic and anthelmintic agents. In general, 42 non-volatile secondary metabolites were isolated from the 6 studied species, namely D. aitchisonii, D. ammoniacum, D. aucheri, D. glabrum, D. hyrcanum, and D. kopetdaghense. Among them, phenolic acid, flavonoid, acetophenone, coumarin, and sesquiterpene derivatives were identified as the predominant phytoconstituents. The leaves are characterized by the highest volatile content, and the sesquiterpenes in both hydrocarbon and oxygenated forms were reported as the most abundant compounds. Most of the studied pharmacological activities were assessed in vivo. Nevertheless, in vitro antiradical and antimicrobial potentials were the main investigated activities. Overall, the evaluation of bioactivities confirmed the ethnopharmacological use of the Dorema species, particularly their anti-inflammatory, antibacterial, and hypolipidemic properties. This study comprehensively overviewed, for the first time, the literature relating to the folk medicinal use and to the available phytochemical and pharmacological data. Considering the genus application and the rare clinical trials, the study of the efficacy and safety of the uninvestigated Dorema species might be an interesting and promising approach for further researches.

     

Phenotypic and functional changes of human melanoma xenografts induced by DNA hypomethylation: immunotherapeutic implications

Emerging in vitro evidence points to an immunomodulatory activity of DNA hypomethylating drugs in human malignancies. We investigated the potential of 5-aza-2'-deoxycytidine (5-AZA-CdR) to modulate the expression of cancer testis antigens (CTA) and of HLA class I antigens by melanoma xenografts, and the resulting modifications in immunogenicity of neoplastic cells. Three primary cultures of melanoma cells, selected for immune phenotype and growth rate, were grafted into BALB/c nu/nu mice that were injected intraperitoneally with different dose- and time-schedules of 5-AZA-CdR. Molecular analyses demonstrated a de novo long-lasting expression of the CTA MAGE-1, -2, -3, -4, -10, GAGE 1-6, NY-ESO-1, and the upregulation of MAGE-1, MAGE-3, and NY-ESO-1 levels in melanoma xenografts from 5-AZA-CdR-treated mice. Serological and biochemical analyses identified a de novo expression of NY-ESO-1 protein and a concomitant and persistent upregulation of HLA class I antigens and of HLA-A1 and -A2 alleles. Immunization of BALB/c mice with 5-AZA-CdR-treated melanoma cells generated high titer circulating anti-NY-ESO-1 antibodies. Altogether, the data obtained identify an immunomodulatory activity of 5-AZA-CdR in vivo and strongly suggest for its clinical use to design novel strategies of CTA-based chemo-immunotherapy for melanoma patients.     

Epidemiological survey of Giardia spp. and Blastocystis hominis in an Argentinian rural community

The aim of this study was to relate personal data, socio-cultural and environmental characteristics, and the presence of symptoms/signs with the frequencies of Giardia spp. and Blastocystis hominis among a rural population in Buenos Aires Province, Argentina. Of the surveyed population (350), 3.7% were infected with only Giardia spp. or 22.9% with B. hominis, and 2.3% were infected with both protozoa. The frequency of infection according to sex; 6.1% of males were infected and 1.6% of females by Giardia spp., 26.7% and 19.5% by B. hominis, and 2.4% and 2.2% by both parasites, respectively. Giardia spp. was detected in only three adults (over 14 years), but B. hominis was more frequent in adults than in children. The prevalences of these protozoa in this community are lower than those reported by other Argentinean studies, which is probably associated with the low density of the studied population (5.95 inhab/km2). Statistical analysis revealed that a male sex, flooding of the home, the use of a latrine, and an abdominal pain were correlated with the presence of these parasites, which indicate the importance of these factors in rural communities.     

Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and clinical applications

In the last three decades huge efforts have been made to characterize genetic defects responsible for cancer development and progression, leading to the comprehensive identification of distinct cellular pathways affected by the alteration of specific genes. Despite the undoubtable role of genetic mechanisms in triggering neoplastic cell transformation, epigenetic modifications (i.e., heritable changes of gene expression that do not derive from alterations of the nucleotide sequence of DNA) are rapidly emerging as frequent alterations that often occur in the early phases of tumorigenesis and that play an important role in tumor development and progression. Epigenetic alterations, such as modifications in DNA methylation patterns and post-translational modifications of histone tails, behave extremely different from genetic modifications, being readily revertable by "epigenetic drugs" such as inhibitors of DNA methyl transferases and inhibitors of histone deacetylases. Since epigenetic alterations in cancer cells affect virtually all cellular pathways that have been associated to tumorigenesis, it is not surprising that epigenetic drugs display pleiotropic activities, being able to concomitantly restore the defective expression of genes involved in cell cycle control, apoptosis, cell signaling, tumor cell invasion and metastasis, angiogenesis and immune recognition. Prompted by this emerging clinical relevance of epigenetic drugs, this review will focus on the large amount of available data, deriving both from in vitro experimentations and in vivo pre-clinical and clinical studies, which clearly indicate epigenetic drugs as effective modifiers of cancer phenotype and as positive regulators of tumor cell biology with a relevant therapeutic potential in cancer patients.     

Inter- and intraspecific variation in the germination response to light quality and scarification in grasses growing in two-phase mosaics of the Chihuahuan Desert

BACKGROUND AND AIMS: In many locations, plants are faced with adjacent, contrasting environments, and the between-species differential evolution of life history traits can be interpreted as an evolutionary response to this environmental heterogeneity. However, there has been little research on the intraspecific variability in these attributes as a possible evolutionary response of plants. METHODS: In the two-phase mosaic of the Chihuahuan Desert (adjacent patches with contrasting resource availability), analyses were carried out of the germination response to the scarification and light quality to which grass seeds growing on these patches are exposed (open and closed habitats). KEY RESULTS: Species that grow in open habitats exhibited a higher germination success than those from closed habitats after scarification. At both the inter- and intraspecific level, there were differences in the germination percentage and in the germination speed in response to light quality. Intraspecific variation in the species from the closed habitat (Pleuraphis mutica and Trichloris crinita) and in Chloris virgata (which grows in both habitats) was due to genetic variation (the family factor was significant), but there was no genetic variation in phenotypic plasticity (non-significant interaction between family and light quality). In contrast, for the species that grows only in the open habitat (Dasyochloa pulchella), the family did not have a significant effect, but there was genetic variation in the phenotypic plasticity (significant interaction between family and light quality). CONCLUSIONS: In C. virgata, P. mutica and T. crinita, natural selection could be favouring those genotypes that responded better in each light environment, but it is not possible that the natural selection resulted in different optimal phenotypes in each habitat. On the contrary, in D. pulchella, selection could have reduced the genetic variation, but there is the possibility of the evolution of reaction norms, resulting in the selection of alternative phenotypes for each habitat.     

Associations between arbuscular mycorrhizal fungi and grasses in the successional context of a two-phase mosaic in the Chihuahuan Desert

The hypothesis that plant species are more responsive to mycorrhiza in late than in early successional stages was assessed in grasses from a successional process occurring in two-phase mosaics from the Mexican Chihuahuan Desert. We estimated the density of spores of arbuscular mycorrhizal (AM) fungi and the AM colonization of pioneer and late-successional grasses in the field. In growth chamber experiments, we tested the effect of the native AM fungal community on grasses growing in soils from different successional stages. Spore density was higher in late than in early successional stages. Late-successional species were more responsive to AM (positive AM responsiveness) whereas pioneer species were nondependent on mycorrhiza or if associated to AM fungi, the interaction showed a negative AM responsiveness for the seedling stage. Our findings showed that late successional species fitted the proposed models of mycorrhizal performance, but the two pioneer species differed in their AM condition and responsiveness. This further supports the idea that AM interactions are more complex along the successional processes than the predictions of the more widely cited hypotheses.     

Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells

Medullary thyroid cancer (MTC) is an aggressive malignancy responsible for up to 14% of all thyroid cancer‐related deaths. It is characterized by point mutations in the rearranged during transfection (RET) proto‐oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3‐kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine‐protein kinase B‐Raf (BRAF) inhibitors (RAF265 and SB590885), and a PI3K inhibitor (ZSTK474), on RET‐mediated signalling and proliferation in a MTC cell line (TT cells) harbouring the RETC634W activating mutation. The effects of the inhibitors on VEGFR2, PI3K/Akt and mitogen‐activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF265+ ZSTK474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR2 for RAF265+ ZSTK474 and a signal reduction in activated Akt for ZSTK474. The activated ERK signal also decreased after RAF265 and RAF265+ ZSTK474 treatments. Alone and in combination with ZSTK474, RAF265 induced a sustained increase in necrosis. Only RAF265, alone and combined with ZSTK474, prompted a significant drop in calcitonin production. Combination therapy using RAF265 and ZSTK47 proved effective in MTC, demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC.     

Relationship between spatial strategies and morphological attributes in a Uruguayan grassland: a functional approach

Abstract. In a native grassland in Uruguay subjected to continuous grazing by cattle, four permanent plots of 40 × 40 cm were established. Plots were divided into 16 × 16 cells and the presence of species was recorded seasonally during two years. The spatial dynamic of the dominant species was defined through three parameters: persistence, short-distance spread and long-distance spread. The association between the spatial strategies and certain morphological attributes that were presumed to be important to the spatial behaviour of the species, was examined using Correspondence Analysis. Four types of spatial strategies were observed: (1) persisting over the year in the same cell without showing any type of mobility; (2) continuously growing due to the solid advancing front of ramets, persisting or not persisting (3) in the same cells; and (4) multi-strategy with high persistence and both high short- and long-distance spread. Among the selected attributes, the erect/prostrate habit, the capacity of vegetative propagation by means of bulbs, rhizomes or stolons, the ratio length/width of leaves and the season of active growth were the characteristics most closely associated with the spatial strategies.     

Prevalence of Giardia lamblia, its detection in water and its relationship with environmental factors in Gualeguaychú, Argentina]

The increasing environmental contamination affects the water quality, and is going to raise the waterborne intestinal infections such as giardiosis. This study determined the prevalence of G.lamblia infection in 1201 persons of Gualeguaychú, Argentina. It was observed the relationship between giardiosis and the detection of G.lamblia in the recreational and drinking water and with homes environmental factors. General rate of infection was 19.7%. The group 2-11 years old was the highest (28.0%). No cysts of G.lamblia were found in drinking water, but recreational water was contaminated. Higher rate of infected persons lived in suburban dwellings with dirt floor, latrine, ground-water and close contact with dogs. It is concluded that to drink water is no risk-infection at present, but it will be if this community continues discharging excretsa into the river because this is the source of water for the habitants.     

Methylation-regulated expression of cancer testis antigens in primary effusion lymphoma: immunotherapeutic implications

Primary effusion lymphoma (PEL) is a large B-cell neoplasm with an unfavorable prognosis and limited therapeutic options. In this study, cancer testis antigens (CTA) were investigated as potential immunotherapeutic targets in patients with PEL. Baseline expression of a panel of 11 CTA was highly heterogeneous among five PEL cell lines. In particular, the investigated CTA were not expressed in BC-2 and BC-3 cells, while BC-1, HBL-6, and BCBL-1 cells tested positive for 6, 8, and 9 CTA, respectively. The DNA hypomethylating agent 5-aza-2'-deoxycytdine (5-AZA-CdR) invariably induced or up-regulated the expression of all investigated CTA in all cell lines analyzed. The de novo expression of CTA was still detectable at mRNA and protein level at least 2 months after the end of 5-AZA-CdR treatment. These findings, and the concomitant up-regulation of HLA-class I antigens and ICAM-1 by 5-AZA-CdR, support its clinical use to set-up innovative chemo-immunotherapeutic approaches in PEL.