Efficacy and safety of an antiviral Iota-Carrageenan nasal spray: a randomized, double-blind, placebo-controlled exploratory study in volunteers with early symptoms of the common cold

Background: The common cold, the most prevalent contagious viral disease in humans still lacks a safe and effective antiviral treatment. Iota-Carrageenan is broadly active against respiratory viruses in-vitro and has an excellent safety profile. This study investigated the efficacy and safety of an Iota-Carrageenan nasal spray in patients with common cold symptoms. Methods: In a randomized, double-blind, placebo-controlled exploratory trial, 35 human subjects suffering from early symptoms of common cold received Iota-Carrageenan (0.12%) in a saline solution three times daily for 4 days, compared to placebo. Results: Administration of Iota-Carrageenan nasal spray reduced the symptoms of common cold (p = 0.046) and the viral load in nasal lavages (p = 0.009) in patients with early symptoms of common cold. Pro-inflammatory mediators FGF-2, Fractalkine, GRO, G-CSF, IL-8, IL-1α, IP-10, IL-10, and IFN-α2 were reduced in the Iota-Carrageenan group. Conclusions: Iota-Carrageenan nasal spray appears to be a promising treatment for safe and effective treatment of early symptoms of common cold. Larger trials are indicated to confirm the results

Management Impacts on Forest Floor and Soil Organic Carbon in Northern Temperate Forests of the US

<p>Abstract</p> <p>Background</p> <p>The role of forests in the global carbon cycle has been the subject of a great deal of research recently, but the impact of management practices on forest soil dynamics at the stand level has received less attention. This study used six forest management experimental sites in five northern states of the US to investigate the effects of silvicultural treatments (light thinning, heavy thinning, and clearcutting) on forest floor and soil carbon pools.</p> <p>Results</p> <p>No overall trend was found between forest floor carbon stocks in stands subjected to partial or complete harvest treatments. A few sites had larger stocks in control plots, although estimates were often highly variable. Forest floor carbon pools did show a trend of increasing values from southern to northern sites. Surface soil (0-5 cm) organic carbon content and concentration were similar between treated and untreated plots. Overall soil carbon (0-20 cm) pool size was not significantly different from control values in sites treated with partial or complete harvests. No geographic trends were evident for any of the soil properties examined.</p> <p>Conclusions</p> <p>Results indicate that it is unlikely that mineral soil carbon stocks are adversely affected by typical management practices as applied in northern hardwood forests in the US; however, the findings suggest that the forest floor carbon pool may be susceptible to loss.</p

Identification of Human IKK-2 Inhibitors of Natural Origin (Part I): Modeling of the IKK-2 Kinase Domain, Virtual Screening and Activity Assays

BACKGROUND: Their large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design and development. Consequently, there has been great interest in determining whether such molecules show biological activity toward protein targets of pharmacological relevance. One target of particular interest is hIKK-2, a serine-threonine protein kinase belonging to the IKK complex that is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Indeed, this has led to the development of synthetic ATP-competitive inhibitors for hIKK-2. Therefore, the main goals of this study were (a) to use virtual screening to identify potential hIKK-2 inhibitors of natural origin that compete with ATP and (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits. METHODOLOGY/PRINCIPAL FINDINGS: We thus predicted that 1,061 out of the 89,425 natural products present in the studied database would inhibit hIKK-2 with good ADMET properties. Notably, when these 1,061 molecules were merged with the 98 synthetic hIKK-2 inhibitors used in this study and the resulting set was classified into ten clusters according to chemical similarity, there were three clusters that contained only natural products. Five molecules from these three clusters (for which no anti-inflammatory activity has been previously described) were then selected for in vitro activity testing, in which three out of the five molecules were shown to inhibit hIKK-2. CONCLUSIONS/SIGNIFICANCE: We demonstrated that our virtual-screening protocol was successful in identifying lead compounds for developing new inhibitors for hIKK-2, a target of great interest in medicinal chemistry. Additionally, all the tools developed during the current study (i.e., the homology model for the hIKK-2 kinase domain and the pharmacophore) will be made available to interested readers upon request

Natural products in drug discovery: advances and opportunities

Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities

Anti-cancer drug development: Computational strategies to identify and target proteins involved in cancer metabolism

Cancer remains a fundamental burden to public health despite substantial efforts aimed at developing effective chemotherapeutics and significant advances in chemotherapeutic regimens. The major challenge in anti-cancer drug design is to selectively target cancer cells with high specificity. Research into treating malignancies by targeting altered metabolism in cancer cells is supported by computational approaches, which can take a leading role in identifying candidate targets for anti-cancer therapy as well as assist in the discovery and optimisation of anti-cancer agents. Natural products appear to have privileged structures for anti-cancer drug development and the bulk of this particularly valuable chemical space still remains to be explored. In this review we aim to provide a comprehensive overview of current strategies for computer-guided anti-cancer drug development. We start with a discussion of state-of-the art bioinformatics methods applied to the identification of novel anti-cancer targets, including machine learning techniques, the Connectivity Map and biological network analysis. This is followed by an extensive survey of molecular modelling and cheminformatics techniques employed to develop agents targeting proteins involved in the glycolytic, lipid, NAD+, mitochondrial (TCA cycle), amino acid and nucleic acid metabolism of cancer cells. A dedicated section highlights the most promising strategies to develop anti-cancer therapeutics from natural products and the role of metabolism and some of the many targets which are under investigation are reviewed. Recent success stories are reported for all the areas covered in this review. We conclude with a brief summary of the most interesting strategies identified and with an outlook on future directions in anti-cancer drug development

Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans

Neurodegenerative disorders (ND) like Alzheimer's (AD), Parkinson's (PD), Huntington's or Prion diseases share similar pathological features. They are all age dependent and are often associated with disruptions in analogous metabolic processes such as protein aggregation and oxidative stress, both of which involve metal ions like copper, manganese and iron. Bush and Tanzi proposed 2008 in the 'metal hypothesis of Alzheimer's disease' that a breakdown in metal homeostasis is the main cause of NDs, and drugs restoring metal homeostasis are promising novel therapeutic strategies. We report here that metallothionein (MT), an endogenous metal detoxifying protein, is increased in young amyloid &#xDF; (A&#xDF;) expressing Caenorhabditis elegans, whereas it is not in wild type strains. Further MT induction collapsed in 8&#xA0;days old transgenic worms, indicating the age dependency of disease outbreak, and sharing intriguing parallels to diminished MT levels in human brains of AD. A medium throughput screening assay method was established to search for compounds increasing the MT level. Compounds known to induce MT release like progesterone, ZnSO4, quercetin, dexamethasone and apomorphine were active in models of AD and PD. Thioflavin T, clioquinol and emodin are promising leads in AD and PD research, whose mode of action has not been fully established yet. In this study, we could show that the reduction of A&#xDF; and &#x3B1;-synuclein toxicity in transgenic C. elegans models correlated with the prolongation of MT induction time and that knockdown of MT with RNA interference resulted in a loss of bioactivity