From transforming growth factor-β signaling to androgen action: Identification of Smad3 as an androgen receptor coregulator in prostate cancer cells

Although transforming growth factor-β (TGF-β) has been identified to mainly inhibit cell growth, the correlation of elevated TGF-β with increasing serum prostate-specific antigen (PSA) levels in metastatic stages of prostate cancer has also been well documented. The molecular mechanism for these two contrasting effects of TGF-β, however, remains unclear. Here we report that Smad3, a downstream mediator of the TGF-β signaling pathway, functions as a coregulator to enhance androgen receptor (AR)-mediated transactivation. Compared with the wild-type AR, Smad3 acts as a strong coregulator in the presence of 1 nM 5α-dihydrotestosterone, 10 nM 17β-estradiol, or 1 μM hydroxyflutamide for the LNCaP mutant AR (mtAR T877A), found in many prostate tumor patients. We further showed that endogenous PSA expression in LNCaP cells can be induced by 5α-dihydrotestosterone, and the addition of the Smad3 further induces PSA expression. Together, our findings establish Smad3 as an important coregulator for the androgen-signaling pathway and provide a possible explanation for the positive role of TGF-β in androgen-promoted prostate cancer growth.

Speciation through homoploid hybridization between allotetraploids in peonies (Paeonia)

Phylogenies of Adh1 and Adh2 genes suggest that a widespread Mediterranean peony, Paeonia officinalis, is a homoploid hybrid species between two allotetraploid species, Paeonia peregrina and a member of the Paeonia arietina species group. Three phylogenetically distinct types of Adh sequences have been identified from both accessions of P. officinalis, of which two types are most closely related to the two homoeologous Adh loci of the P. arietina group and the remaining type came from one of the two Adh homoeologs of P. peregrina. The other Adh homoeolog of P. peregrina was apparently lost from the hybrid genome, possibly through backcrossing with the P. arietina group. This is a documentation of homoploid hybrid speciation between allotetraploid species in nature. This study suggests that hybrid speciation between allotetraploids can occur without an intermediate stage of genome diploidization or a further doubling of genome size.

Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor

Whereas several apoptosis-related proteins have been linked to the antiapoptotic effects of Akt serine–threonine kinase, the search continues to explain the Akt signaling role in promoting cell survival via antiapoptotic effects. Here, we demonstrate that Akt phosphorylates the androgen receptor (AR) at Ser-210 and Ser-790. A mutation at AR Ser-210 results in the reversal of Akt-mediated suppression of AR transactivation. Activation of the phosphatidylinositol-3-OH kinase/Akt pathway results in the suppression of AR target genes, such as p21, and the decrease of androgen/AR-mediated apoptosis, which may involve the inhibition of interaction between AR and AR coregulators. Together, these findings provide a molecular basis for cross-talk between two signaling pathways at the level of Akt and AR–AR coregulators that may help us to better understand the roles of Akt in the androgen/AR-mediated apoptosis.

Expression of β-Amylase from Alfalfa Taproots1

Alfalfa (Medicago sativa L.) roots contain large quantities of β-amylase, but little is known about its role in vivo. We studied this by isolating a β-amylase cDNA and by examining signals that affect its expression. The β-amylase cDNA encoded a 55.95-kD polypeptide with a deduced amino acid sequence showing high similarity to other plant β-amylases. Starch concentrations, β-amylase activities, and β-amylase mRNA levels were measured in roots of alfalfa after defoliation, in suspension-cultured cells incubated in sucrose-rich or -deprived media, and in roots of cold-acclimated germ plasms. Starch levels, β-amylase activities, and β-amylase transcripts were reduced significantly in roots of defoliated plants and in sucrose-deprived cell cultures. β-Amylase transcript was high in roots of intact plants but could not be detected 2 to 8 d after defoliation. β-Amylase transcript levels increased in roots between September and October and then declined 10-fold in November and December after shoots were killed by frost. Alfalfa roots contain greater β-amylase transcript levels compared with roots of sweetclover (Melilotus officinalis L.), red clover (Trifolium pratense L.), and birdsfoot trefoil (Lotus corniculatus L.). Southern analysis indicated that β-amylase is present as a multigene family in alfalfa. Our results show no clear association between β-amylase activity or transcript abundance and starch hydrolysis in alfalfa roots. The great abundance of β-amylase and its unexpected patterns of gene expression and protein accumulation support our current belief that this protein serves a storage function in roots of this perennial species.

Improved antitumor activity of a recombinant anti-Lewis(y) immunotoxin not requiring proteolytic activation.

B1(dsFv)-PE33 is a recombinant immunotoxin composed of a mutant form of Pseudomonas exotoxin (PE) that does not need proteolytic activation and a disulfide-stabilized Fv fragment of the anti-Lewis(y) monoclonal antibody B1, which recognizes a carbohydrate epitope on human carcinoma cells. In this molecule, amino acids 1-279 of PE are deleted and domain Ib (amino acids 365-394) is replaced by the heavy chain variable region (VH) domain of monoclonal antibody B1. The light chain (VL) domain is connected to the VH domain by a disulfide bond. This recombinant toxin, termed B1(dsFv)-PE33, does not require proteolytic activation and it is smaller than other immunotoxins directed at Lewis(y), all of which require proteolytic activation. Furthermore, it is more cytotoxic to antigen-positive cell lines. B1(dsFv)-PE38 has the highest antitumor activity of anti-Lewis(y) immunotoxins previously constructed. B1(dsFv)-PE33 caused complete regression of tumors when given at 12 micrograms/kg (200 pmol/kg) every other day for three doses, whereas B1(dsFv)-PE38 did not cause regressions at 13 micrograms/kg (200 pmol/kg). By bypassing the need for proteolytic activation and decreasing molecular size we have enlarged the therapeutic window for the treatment of human cancers growing in mice, so that complete remissions are observed at 2.5% of the LD50.

Traditional knowledge of medicinal plants in the Serra de Mariola Natural Park, South-eastern Spain

The present study aims to inventory and analyse the ethnobotanical knowledge about medicinal plants in the Serra de Mariola Natural Park. In respect to traditional uses, 93 species reported by local informants were therapeutic, 27 food, 4 natural dyes and 13 handcrafts. We developed a methodology that allowed the location of individuals or vegetation communities with a specific popular use. We prepared a geographic information system (GIS) that included gender, family, scientific nomenclature and common names in Spanish and Catalan for each species. We also made a classification of 39 medicinal uses from ATC (Anatomical, Therapeutic, Chemical classification system). Labiatae (n=19), Compositae (n=9) and Leguminosae (n=6) were the families most represented among the plants used to different purposes in humans. Species with the most elevated cultural importance index (CI) values were Thymus vulgaris (CI=1.431), Rosmarinus officinalis (CI=1.415), Eryngium campestre (CI=1.325), Verbascum sinuatum (CI=1.106) and Sideritis angustifolia (CI=1.041). Thus, the collected plants with more therapeutic uses were: Lippia triphylla (12), Thymus vulgaris and Allium roseum (9) and Erygium campestre (8). The most repeated ATC uses were: G04 (urological use), D03 (treatment of wounds and ulcers) and R02 (throat diseases). These results were in a geographic map where each point represented an individual of any species. A database was created with the corresponding therapeutic uses. This application is useful for the identification of individuals and the selection of species for specific medicinal properties. In the end, knowledge of these useful plants may be interesting to revive the local economy and in some cases promote their cultivation.

Medicinal plants - prophylactic and therapeutic options for gastrointestinal and respiratory diseases in calves and piglets? A systematic review.

BACKGROUND Gastrointestinal and respiratory diseases in calves and piglets lead to significant economic losses in livestock husbandry. A high morbidity has been reported for diarrhea (calves ≤ 35 %; piglets ≤ 50 %) and for respiratory diseases (calves ≤ 80 %; piglets ≤ 40 %). Despite a highly diverse etiology and pathophysiology of these diseases, treatment with antimicrobials is often the first-line therapy. Multi-antimicrobial resistance in pathogens results in international accordance to strengthen the research in novel treatment options. Medicinal plants bear a potential as alternative or additional treatment. Based on the versatile effects of their plant specific multi-component-compositions, medicinal plants can potentially act as 'multi-target drugs'. Regarding the plurality of medicinal plants, the aim of this systematic review was to identify potential medicinal plant species for prevention and treatment of gastrointestinal and respiratory diseases and for modulation of the immune system and inflammation in calves and piglets. RESULTS Based on nine initial sources including standard textbooks and European ethnoveterinary studies, a total of 223 medicinal plant species related to the treatment of gastrointestinal and respiratory diseases was identified. A defined search strategy was established using the PRISMA statement to evaluate 30 medicinal plant species starting from 20'000 peer-reviewed articles published in the last 20 years (1994-2014). This strategy led to 418 references (257 in vitro, 84 in vivo and 77 clinical trials, thereof 48 clinical trials in veterinary medicine) to evaluate effects of medicinal plants and their efficacy in detail. The findings indicate that the most promising candidates for gastrointestinal diseases are Allium sativum L., Mentha x piperita L. and Salvia officinalis L.; for diseases of the respiratory tract Echinacea purpurea (L.) MOENCH, Thymus vulgaris L. and Althea officinalis L. were found most promising, and Echinacea purpurea (L.) MOENCH, Camellia sinensis (L.) KUNTZE, Glycyrrhiza glabra L. and Origanum vulgare L. were identified as best candidates for modulation of the immune system and inflammation. CONCLUSIONS Several medicinal plants bear a potential for novel treatment strategies for young livestock. There is a need for further research focused on gastrointestinal and respiratory diseases in calves and piglets, and the findings of this review provide a basis on plant selection for future studies.

Pollen profile from sediment core KB1, Holzminden, Northern Germany

The Nachtigall clay pit near Holzminden, northern Germany, is located in a subrosional basin filled with 43 m of interglacial, interstadial and stadial deposits adjacent to the Weser River. The succession separates the Older Middle Terrace from the Younger Middle Terrace of the Weser River. Nachtigall core KB1 (1998) mainly contains silt and clay with intercalated peat layers. The layers of fen peat and intercalated humic silt are between 36 and 22.5 m depth. According to palynological studies, the peat layers and some humic silts were deposited during interglacial and interstadial periods marked by forest vegetation, termed Nachtigall 1 and Nachtigall 2. They are subdivided by a stadial, termed Albaxen. The peat of Nachtigall 1 is interrupted twice by silt and clay strata (Allochthonous Unit I, II) which are reworked sediments of older glacial periods, possibly of late Elsterian or early Holsteinian age. The palynological sequences of Nachtigall and Göttingen/Ottostrasse show the same pattern. Moreover, the contemporaneous pollen profiles of Nachtigall and Göttingen/Ottostrasse can be compared with the Velay pollen sequence (France). The Nachtigall core section 36-26.02 m corresponds to Bouchet 2 - Bonnefond - Bouchet 3 in Velay. The profiles of Velay and Nachtigall are independently correlated to the MIS-timescale and correspond to MIS 7c, 7b, and 7a. TIMS 230Th/U-dating shows ages ranging from 227 + 9/-8 to 201 + 15/-13 ka, which are in good agreement with the inferred MIS 7 age.