The first cyclomegastigmane rhododendroside A from Rhododendron brachycarpum alleviates HMGB1-induced sepsis

Background

Endangered plant species are a vital resource for exploring novel drug prototypes. A Korean endangered plant Rhododendron brachycarpum G. Don is a broad-leaved shrub native to northern Korea and central Japan. The high mobility group box 1 protein (HMGB1) could be a specific target for the discovery of novel antiseptic agents.

Methods

Gauge-invariant atomic orbital (GIAO) NMR chemical shift calculations were applied for investigation of stereochemical details with accuracy improved by application of DP4 analysis. In vitro antiseptic mechanisms were investigated utilizing immunofluorescence staining, ELISA and cell–cell adhesion assay. Cecal ligation and puncture (CLP) operation was employed to evaluate in vivo potential alleviating severe sepsis and septic shock.

Results

The first bicyclic megastigmane glucoside rhododendroside A (1) along with known megastigmane glucosides (2–5) were isolated from the leaves of R. brachycarpum. The structure of 1 was established by NMR analysis as well as comparison of the experimental chemical shifts with those of computed values employing DP4 application. In the CLP operation model that simulates severe sepsis, rhododendroside A (1) improved the survival rate up to 60%.

Conclusions

Our results exhibit that R. brachycarpum may produce a unique scaffold that is developed into a drug lead mitigating HMGB1-induced vascular pro-inflammatory stimuli and thus alleviating severe sepsis and related manifestations.

General significance

Discovery of new drug leads would warrant conservation efforts of endangered species.     

Cyclic dipeptides from lactic acid bacteria inhibit the proliferation of pathogenic fungi

Lactobacillus plantarum LBP-K10 was identified to be the most potent antifungal strain from Korean traditional fermented vegetables. The culture filtrate of this strain showed remarkable antifungal activity against Ganoderma boninense. Five fractions from the culture filtrate were observed to have an inhibitory effect against G. boninense. Also, the electron ionization and chemical ionization indicated that these compounds might be cyclic dipeptides. Of the five active fractions, two fractions showed the most significant anti-Ganoderma activity, and one of these fractions inhibited the growth of Candida albicans. These compounds were identified to be cis-cyclo(l-Val-l-Pro) and cis-cyclo(l-Phe-l-Pro), as confirmed by X-ray crystallography.     

Nitrogen transformation rates are affected by cover soil type but not coarse woody debris application in reclaimed oil sands soils

Forest floor mineral soil mix (FMM) and peat mineral soil mix (PMM) are cover soils commonly used for reclamation of open‐pit oil sands mining disturbed land in northern Alberta, Canada; coarse woody debris (CWD) is another source of organic matter for land reclamation. We investigated net nitrogen (N) transformation rates in FMM and PMM cover soils near and away from CWD 4–6 years after oil sands reclamation. Monthly net nitrification and N mineralization rates varied over time; however, mean rates across the incubation periods and microbial biomass were greater (p < 0.05) in FMM than in PMM. Net N mineralization rates were positively related to soil temperature (p < 0.001) and microbial biomass carbon (p = 0.045). Net N transformation rates and inorganic N concentrations were not affected by CWD; however, the greater ¹⁵N isotope ratio of ammonium near CWD than away from CWD indicates that CWD application increased both gross N mineralization/nitrification (causing N isotope fractionation) and gross N immobilization (no isotopic fractionation). Microbial biomass was greater near CWD than away from CWD, indicating the greater potential for N immobilization near CWD. We conclude that (1) CWD application affected soil microbial properties and would create spatial variability and diverse microsites and (2) cover soil type and CWD application had differential effects on net N transformation rates. Applying FMM with CWD for oil sands reclamation is recommended to increase N availability and microsites.     

Ixodid Tick Infestation in Cattle and Wild Animals in Maswa and Iringa,Tanzania

Ticks and tick-borne diseases are important in human and livestock health worldwide. In November 2012, ixodid ticks were collected and identified morphologically from cattle and wild animals in the Maswa district and Iringa urban, Tanzania. Amblyomma gemma, A. lepidum, and A. variegatum were identified from Maswa cattle, and A. variegatum was the predominant species. A. marmoreum, Hyalomma impeltatum, and Rhipicephalus pulchellus were identified from Iringa cattle in addition to the above 3 Amblyomma species, and A. gemma was the most abundant species. Total 4 Amblyomma and 6 Rhipicephalus species were identified from wild animals of the 2 areas. A. lepidum was predominant in Maswa buffaloes, whereas A. gemma was predominant in Iringa buffaloes. Overall, A. variegatum in cattle was predominant in the Maswa district and A. gemma was predominant in Iringa, Tanzania.     

Phosphorylation of the Arabidopsis AtrbohF NADPH oxidase by OST1 protein kinase

The plant hormone abscisic acid (ABA) triggers production of reactive oxygen species (ROS) in guard cells via the AtrbohD and AtrbohF NADPH oxidases, leading to stomatal closure. The ABA-activated SnRK2 protein kinase open stomata 1 (OST1) (SRK2E/SnRK2.6) acts upstream of ROS in guard cell ABA signaling. Here, we report that OST1 phosphorylates Ser13 and Ser174 on AtrbohF. In addition, substitution of Ser174 to Ala results in a ∼40% reduction in the phosphorylation of AtrbohF by OST1. We also show that OST1 physically interacts with AtrbohF. These results provide biochemical evidence suggesting that OST1 regulates AtrbohF activity.

Structured summary

MINT-7260179, MINT-7260147, MINT-7260165: OST1 (uniprotkb:Q940H6) phosphorylates (MI:0217) ATRBOHF (uniprotkb:O48538) by protein kinase assay (MI:0424)MINT-7260208: OST1 (uniprotkb:Q940H6) and ATRBOHF (uniprotkb:O48538) physically interact (MI:0915) by bimolecular fluorescence complementation (MI:0809)     

Calcium-permeable AMPA channels in neurodegenerative disease and ischemia

Compelling evidence supports contributions of glutamate receptor overactivation ('excitotoxicity') to neurodegeneration in both acute conditions, such as stroke, and chronic neurodegenerative conditions, such as amyotrophic lateral sclerosis. However, anti-excitotoxic therapeutic trials, which have generally targeted highly Ca2+ permeable NMDA-type glutamate channels, have to date failed to demonstrate impressive efficacy. Whereas most AMPA type glutamate channels are Ca2+ impermeable, an evolving body of evidence supports the contention that relatively unusual Ca2+ permeable AMPA channels might be crucial contributors to injury in these conditions. These channels are preferentially expressed in discrete neuronal subpopulations, and their numbers appear to be upregulated in amyotrophic lateral sclerosis and stroke. In addition, unlike NMDA channels, Ca2+ permeable AMPA channels are not blocked by Mg2+, but are highly permeable to another potentially harmful endogenous cation, Zn2+. The targeting of these channels might provide efficacious new avenues in the therapy of certain neurological diseases.     

The genomic analysis of the impact of steroid receptor coactivators ablation on hepatic metabolism

Members of the steroid receptor coactivator (SRC) family, which include SRC-1 (NcoA-1/p160), SRC-2(TIF2/GRIP1/NcoA-2) and SRC-3(pCIP/RAC3/ACTR/pCIP/ AIB1/TRAM1), are critical mediators of steroid receptor action. Gene ablation studies previously identified SRC-1 and SRC-2 as being involved in the control of energy homeostasis. A more precise identification of the molecular pathways regulated by these coactivators is crucial for understanding the role of steroid receptor coactivators in the control of energy homeostasis and obesity. A genomic approach using microarray analysis was employed to identify the subsets of genes that are altered in the livers of SRC-1-/-, SRC-2-/-, and SRC-3-/- mice. Microarray analysis demonstrates that gene expression changes are specific and nonoverlapping for each SRC member in the liver. The overall pattern of altered gene expressions in the SRC-1-/- mice was up-regulation, whereas SRC-2-/- mice showed an overall down-regulation. Several key regulatory enzymes of energy metabolism were significantly altered in the liver of SRC-2-/- mice, which are consistent with the prior observation that SRC-2-/- mice have increased energy expenditure. This study demonstrates that the molecular targets of SRC-2 regulation in the murine liver stimulate fatty acid degradation and glycolytic pathway, whereas fatty acid, cholesterol, and steroid biosynthetic pathways are down-regulated.