Killing cancer with platycodin D through multiple mechanisms

Cancer is a multi‐faceted disease comprised of a combination of genetic, epigenetic, metabolic and signalling aberrations which severely disrupt the normal homoeostasis of cell growth and death. Rational developments of highly selective drugs which specifically block only one of the signalling pathways have been associated with limited therapeutic success. Multi‐targeted prevention of cancer has emerged as a new paradigm for effective anti‐cancer treatment. Platycodin D, a triterpenoid saponin, is one the major active components of the roots of Platycodon grandiflorum and possesses multiple biological and pharmacological properties including, anti‐nociceptive, anti‐atherosclerosis, antiviral, anti‐inflammatory, anti‐obesity, immunoregulatory, hepatoprotective and anti‐tumour activities. Recently, the anti‐cancer activity of platycodin D has been extensively studied. The purpose of this review was to give our perspectives on the current status of platycodin D and discuss its anti‐cancer activity and molecular mechanisms which may help the further design and conduct of pre‐clinical and clinical trials to develop it successfully into a potential lead drug for oncological therapy. Platycodin D has been shown to fight cancer by inducing apoptosis, cell cycle arrest, and autophagy and inhibiting angiogenesis, invasion and metastasis by targeting multiple signalling pathways which are frequently deregulated in cancers suggesting that this multi‐target activity rather than a single effect may play an important role in developing platycodin D into potential anti‐cancer drug.     

Rosin Surfactant QRMAE Can Be Utilized as an Amorphous Aggregate Inducer: A Case Study of Mammalian Serum Albumin

Quaternary amine of diethylaminoethyl rosin ester (QRMAE), chemically synthesized biocompatible rosin based cationic surfactant, has various biological applications including its use as a food product additive. In this study, we examined the amorphous aggregation behavior of mammalian serum albumins at pH 7.5, i.e., two units above their isoelectric points (pI ~5.5), and the roles played by positive charge and hydrophobicity of exogenously added rosin surfactant QRMAE. The study was carried out on five mammalian serum albumins, using various spectroscopic methods, dye binding assay, circular dichroism and electron microscopy. The thermodynamics of the binding of mammalian serum albumins to cationic rosin modified surfactant were established using isothermal titration calorimetry (ITC). It was observed that a suitable molar ratio of protein to QRMAE surfactant enthusiastically induces amorphous aggregate formation at a pH above two units of pI. Rosin surfactant QRMAE-albumins interactions revealed a unique interplay between the initial electrostatic and the subsequent hydrophobic interactions that play an important role towards the formation of hydrophobic interactions-driven amorphous aggregate. Amorphous aggregation of proteins is associated with varying diseases, from the formation of protein wine haze to the expansion of the eye lenses in cataract, during the expression and purification of recombinant proteins. This study can be used for the design of novel biomolecules or drugs with the ability to neutralize factor(s) responsible for the aggregate formation, in addition to various other industrial applications.     

A Two-Level Computation Model Based on Deep Learning Algorithm for Identification of piRNA and Their Functions via Chou’s 5-Steps Rule

International Journal of Peptide Research and Therapeutics - Piwi interacting RNA (piRNA) molecules belong to a largest class of small non coding RNA molecules which are originally discovered in...     

Characterization and pharmacological properties of in vitro propagated clones of <Emphasis Type="Italic">Echinacea tennesseensis</Emphasis> (Beadle) Small

Tissue culture techniques have been used to establish and maintain a repository of medicinal Echinacea. In vitro clones obtained from hypocotyls of germinated seeds, varied macroscopically, microscopically and exhibited variation in immune enhancing activity. Two in vitro produced clones of Echinacea tennesseensis (Beadle) Small (ETN 03 and ETN 11) were identified as high and low activity based on the activation of human monocytes. Phenotypic analyses of ETN 03 and ETN 11 clones were done using AFLP (Amplified Fragment Length Polymorphism) assay. Results of the AFLP assay revealed that no mutation has occurred during in vitro multiplication, storage, and acclimatization into soil. Plants of ETN 03, ETN 11 clones were cultivated for two growing seasons. Extracts of their dry leaves and roots exhibited immune enhancing activity; however, the variation in activity noticed between clones during micropropagation diminished and was no longer statistically relevant.     

Pharmacovigilance: Effects of herbal components on human drugs interactions involving Cytochrome P450

Cytochrome P450 (CYP P450) enzymes are a superfamily of mono-oxygenases that are found in all kingdoms of life. The CYP P450 enzymes constitute a large superfamily of haem-thiolate proteins involved in the metabolism of a wide variety of both exogenous and endogenous compounds. The CYP activities have been shown to be involved in numerous interactions especially between drugs and herbal constituents. The majority of serious cases of drug interactions are as a result of the interference of the metabolic clearance of one drug by yet another co-administered drug, food or natural product. Gaining mechanistic knowledge towards such interactions has been accepted as an approach to avoid adverse reactions. The inductions and inhibition of CYP enzymes by natural products in the presence of a prescribed drug has led to adverse effects. Herbal medicines such as St. John's wort (Hypericum perforatum), garlic (Allium sativa), piperine (from Piper sp.), ginseng (Ginseng sp.), gingko (Gingko biloba), soya beans (Glycine max), alfalfa (Medicago sativa) and grape fruit juice show clinical interactions when co-administered with medicines. This review documents the involvement of CYP enzymes in the metabolism of known available drugs and herbal products. We also document the interactions between herbal constituents &#38; CYP enzymes showing potential drug-herb interactions. Data on CYP450 enzymes in activation (i.e. induction or inhibition) with natural constituents is also reviewed.     

Novel effect of plant lectins on the inhibition of Streptococcus mutans biofilm formation on saliva-coated surface

Aims:  Dental caries is caused by the disturbance in oral homeostasis, marked by a notable increase in the population of Streptococcus mutans . Lectins are a group of plant proteins that are capable of recognizing the glycoconjugates present on the bacterial surface. The aim of this study was to evaluate the effect of seven plant lectins on the growth and initial adhesion of S. mutans .
Methods and Results:  Lectins of different carbohydrate specificities were isolated from plant sources by conventional methods of protein purification. The effect on growth of S. mutans was evaluated following CLSI guidelines. None of the lectins used in this study inhibited the bacterial growth and multiplication. The adherence and biofilm formation of bacteria to saliva-coated polystyrene plates was tested in the presence of plant lectins. All the plant lectins tested, inhibited both the adherence and biofilm in a concentration dependent manner. Confocal microscopy and scanning electron microscopy were employed to assess the biofilm formation in the presence of plant lectin (glucose/mannose-specific) at sub-minimal inhibitory concentrations. These evaluations revealed that lectins inhibited the clumping and attachment of S. mutans .
Conclusions:  Lectins tested here inhibited initial biofilm formation by S. mutans. Glucose/Mannose-specific lectin altered the adhesion arrangement of the bacteria on the saliva-coated surfaces.
Significance and Impact of the Study:  The plant lectins used in this study may offer a novel strategy to reduce development of dental caries by inhibiting the initial adhesion and subsequent biofilm formation of S. mutans.     

An insecticidal GroEL protein with chitin binding activity from Xenorhabdus nematophila

Xenorhabdus nematophila secretes insecticidal proteins to kill its larval prey. We have isolated an approximately 58-kDa GroEL homolog, secreted in the culture medium through outer membrane vesicles. The protein was orally insecticidal to the major crop pest Helicoverpa armigera with an LC50 of approximately 3.6 microg/g diet. For optimal insecticidal activity all three domains of the protein, apical, intermediate, and equatorial, were necessary. The apical domain alone was able to bind to the larval gut membranes and manifest low level insecticidal activity. At equimolar concentrations, the apical domain contained approximately one-third and the apical-intermediate domain approximately one-half bioactivity of that of the full-length protein. Interaction of the protein with the larval gut membrane was specifically inhibited by N-acetylglucosamine and chito-oligosaccharides. Treatment of the larval gut membranes with chitinase abolished protein binding. Based on the three-dimensional structural model, mutational analysis demonstrated that surface-exposed residues Thr-347 and Ser-356 in the apical domain were crucial for both binding to the gut epithelium and insecticidal activity. Double mutant T347A,S356A was 80% less toxic (p < 0.001) than the wild type protein. The GroEL homolog showed alpha-chitin binding activity with Kd approximately 0.64 microm and Bmax approximately 4.68 micromol/g chitin. The variation in chitin binding activity of the mutant proteins was in good agreement with membrane binding characteristics and insecticidal activity. The less toxic double mutant XnGroEL showed an approximately 8-fold increase of Kd in chitin binding assay. Our results demonstrate that X. nematophila secretes an insecticidal GroEL protein with chitin binding activity.     

Drought Effects in Climate Change Manipulation Experiments: Quantifying the Influence of Ambient Weather Conditions and Rain-out Shelter Artifacts

Extreme drought events challenge ecosystem functioning. Ecological response to drought is studied worldwide in a growing number of field experiments by rain-out shelters. Yet, few meta-analyses face severe challenges in the comparability of studies. This is partly because build-up of drought stress in rain-out shelters is modified by ambient weather conditions. Rain-out shelters can further create confounding effects (radiation, temperature), which may influence plant responses. Yet, a quantification of ecophysiological effects within rain-out shelters under opposing ambient weather conditions and of microclimatological artifacts is missing. Here, we examined phytometers—standardized potted individuals of Plantago lanceolata—under rain-out shelter, rain-out shelter artifact control, and ambient control during opposing outside microclimatological conditions. Furthermore, we tested for artifacts of rain-out shelters on plant responses in a long-term semi-natural grassland experiment. Phytometer plants below the rain-out shelters showed lower stomatal conductance, maximum quantum efficiency, and leaf water potential during warm ambient conditions with high evaporative demand than during cold conditions with low evaporative demand. Plant performance was highly correlated with ambient temperature and vapor pressure deficit (VPD). Rain-out shelter artifacts on plant responses were nonsignificant. Rain-out shelters remain a viable tool for studying ecosystem responses to drought. However, drought manipulations using rain-out shelters are strongly modified by ambient weather conditions. Attributing the results from rain-out shelter studies to drought effects and comparability among studies and study years therefore requires the quantification of the realized drought stress, for example, by relating ecosystem responses to measured microclimatological parameters such as air temperature and VPD.     

Sympatric snow leopards and Tibetan wolves: coexistence of large carnivores with human-driven potential competition

The snow leopard Panthera uncia coexists with the wolf Canis lupus throughout most of its distribution range. We analysed the food habits of snow leopards and wolves in their sympatric range in the Karakoram mountains of Pakistan. A total of 131 genotyped scats (N?=?74, snow leopard; N?=?57, Tibetan wolf) were collected during the cold periods (i.e. winter and spring) of 2011 and 2012 in the Hushey valley. Large mammals, i.e. livestock and ibex, accounted for 84.8 and 83.1% of the diet (relative frequency) of the snow leopard and the wolf, respectively. Domestic prey was the staple of the diet of both snow leopards (66.6%) and wolves (75.1%). Ibex Capra ibex, the only wild ungulate in our study area, contributed 18.2 and 16.9% of relative frequencies in the diets of the snow leopard and the wolf, respectively. In winter, the snow leopard heavily relied on domestic sheep (43.3%) for food, whereas the wolf preyed mainly on domestic goats (43.4%). Differently from other study areas, both snow leopards and wolves showed no apparent prey preference (Jacobs index: snow leopard min. ??0.098, max. 0.102; Tibetan wolf min. ??0.120, max. 0.03). In human depauperate areas, with livestock and only a few wild prey, should competitive interactions arise, two main scenarios could be expected, with either predator as a winner. In both cases, the best solution could primarily impinge on habitat restoration, so that a balance could be found between these predators, who have already coexisted for thousands of years.