Honokiol: A non-adipogenic PPARγ agonist from nature

Background

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators.

Methods

We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists.

Results

The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain.

Conclusion

We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo.

General significance

This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine.     

Histology of “placoderm” dermal skeletons: Implications for the nature of the ancestral gnathostome

The vertebrate dermal skeleton has long been interpreted to have evolved from a primitive condition exemplified by chondrichthyans. However, chondrichthyans and osteichthyans evolved from an ancestral gnathostome stem‐lineage in which the dermal skeleton was more extensively developed. To elucidate the histology and skeletal structure of the gnathostome crown‐ancestor we conducted a histological survey of the diversity of the dermal skeleton among the placoderms, a diverse clade or grade of early jawed vertebrates. The dermal skeleton of all placoderms is composed largely of a cancellar architecture of cellular dermal bone, surmounted by dermal tubercles in the most ancestral clades, including antiarchs. Acanthothoracids retain an ancestral condition for the dermal skeleton, and we record its secondary reduction in antiarchs. We also find that mechanisms for remodeling bone and facilitating different growth rates between adjoining plates are widespread throughout the placoderms. J. Morphol., 2013. © 2013 Wiley Periodicals, Inc.     

Therapeutic angiogenesis for revascularization in peripheral artery disease

Therapeutic angiogenesis for peripheral artery disease (PAD), achieved by gene and cell therapy, has recently raised a great deal of hope for patients who cannot undergo standard revascularizing treatment. Although pre-clinical studies gave very promising data, still clinical trials of gene therapy have not provided satisfactory results. On the other hand, cell therapy approach, despite several limitations, demonstrated more beneficial effects but initial clinical studies must be constantly validated by larger randomized, multi-center, double-blinded, placebo-controlled trials. This review focuses on previous and recent gene and cell therapy studies for limb ischemia, including both experimental and clinical research, and summarizes some important papers published in this field. Moreover, it provides a short comment on combined gene and cell therapy approach on the example of heme oxygenase-1 overexpressing cells with therapeutic properties.     

Non-viral gene therapy for bone tissue engineering

The possibilities of using gene therapy for bone regeneration have been extensively investigated. Improvements in the design of new transfection agents, combining vectors and delivery/release systems to diminish cytotoxicity and increase transfection efficiencies have led to several successful in vitro, ex vivo and in vivo strategies. These include growth factor or short interfering ribonucleic acid (siRNA) delivery, or even enzyme replacement therapies, and have led to increased osteogenic differentiation and bone formation in vivo. These results provide optimism to consider use in humans with some of these gene-delivery strategies in the near future.     

Association of BMPR-1B and GDF9 genes polymorphisms and secondary protein structure changes with reproduction traits in Mehraban ewes

BMPR-1B and GDF9 genes are well known due to their important effects on litter size and mechanisms controlling ovulation rate in sheep. In the present study, polymorphisms of BMPR-1B gene exon 8 and GDF9 gene exon 1 were detected by single strand conformational polymorphism (SSCP) analysis and DNA sequencing methods in 100 Mehraban ewes. The PCR reaction forced to amplify 140 and 380-bp fragments of BMPR-1B and GDF9 genes, respectively. Two single nucleotide polymorphisms (SNP_S) were identified in two different SSCP patterns of BMPR-1B gene (CC and CA genotypes) that deduced one amino acid exchange. Also, two SNP_S were identified in three different SSCP patterns of GDF9 gene (AA, AG and GG genotypes) that deduced one amino acid exchanges. Two different secondary structures of protein were predicted for BMPR-1B exon 8, but the secondary protein structures predicted for GDF9 exon 1 were similar together. The evaluation of the associations between the SSCP patterns and the protein structure changes with reproduction traits showed that BMPR-1B exon 8 genotypes have significant effects on some of reproduction traits but the GDF9 genotypes did not have any significant effect. The CA genotype of BMPR-1B exon 8 had a significant positive effect on reproduction performance and could be considered as an important and new mutation, affecting the ewes reproduction performance. Marker assisted selection using BMPR-IB gene could be noticed to improve the reproduction traits in Mehraban sheep.     

Delivery and processing of exogenous double-stranded DNA in mouse CD34 + hematopoietic progenitor cells and their cell cycle changes upon combined treatment with cyclophosphamide and double-stranded DNA

We previously reported that fragments of exogenous double-stranded DNA can be internalized by mouse bone marrow cells without any transfection. Our present analysis shows that only 2% of bone marrow cells take up the fragments of extracellular exogenous DNA. Of these, ~ 45% of the cells correspond to CD34 + hematopoietic stem cells. Taking into account that CD34 + stem cells constituted 2.5% of the total cell population in the bone marrow samples analyzed, these data indicate that as much as 40% of CD34 + cells readily internalize fragments of extracellular exogenous DNA. This suggests that internalization of fragmented dsDNA is a general feature of poorly differentiated cells, in particular CD34 + bone marrow cells.     

Different coexpressions of arthritis-relevant genes between different body organs and different brain regions in the normal mouse population

Structural changes in different parts of the brain in rheumatoid arthritis (RA) patients have been reported. RA is not regarded as a brain disease. Body organs such as spleen and lung produce RA-relevant genes. We hypothesized that the structural changes in the brain are caused by changes of gene expression in body organs. Changes in different parts of the brain may be affected by altered gene expressions in different body organs. This study explored whether an association between gene expressions of an organ or a body part varies in different brain structures. By examining the association of the 10 most altered genes from a mouse model of spontaneous arthritis in a normal mouse population, we found two groups of gene expression patterns between five brain structures and spleen. The correlation patterns between the prefrontal cortex, nucleus accumbens, and spleen were similar, while the associations between the other three parts of the brain and spleen showed a different pattern. Among overall patterns of the associations between body organs and brain structures, spleen and lung had a similar pattern, and patterns for kidney and liver were similar. Analysis of the five additional known arthritis-relevant genes produced similar results. Analysis of 10 nonrelevant-arthritis genes did not result in a strong association of gene expression or clearly segregated patterns. Our data suggest that abnormal gene expressions in different diseased body organs may influence structural changes in different brain parts.     

Remodelling of skeletal tissues bone and structural specialisations in an elasmosaurid (Sauropterygia: Plesiosauroidea) from the Upper Cretaceous of Patagonia,Argentina

Elasmosauridae were cosmopolitan Late Cretaceous plesiosaurs with conspicuous morphological diversity. Within this group, vertebral morphology is a criterion for estimating relative age in plesiosaur. On the other hand, the microstructure of plesiosaur bone is considered as indicative of ontogenetic stage. However, knowledge about ontogenetic tissue transformation in different elements of the skeleton is poorly known. Resorption and remodelling of skeletal tissues are required for development and growth, mechanical adaptation, repair and mineral homeostasis of the vertebrate skeleton. This contribution analyses different postcranial elements of a Late Cretaceous elasmosaurid from Patagonia. Characterisation of bone microstructure indicates the presence of compact bone inner organisation in an adult derived plesiosaur from the Cretaceous and that the distribution of bone specialisations depicts conspicuous variations within a single skeleton depending on the skeletal element considered. Bone compactness or degree of remodelling in elasmosaurids is not necessarily correlated with the ontogenetic age of the animal or to costal versus pelagic lifestyles. The available data are still scarce, but we propose a topic of discussion: perhaps the degree of remodelling and compactness also may be related to the activity level and increased mechanical load in different skeletal elements.     

Stable and radiogenic isotope analyses on shark teeth from the Early to the Middle Permian (Sakmarian–Roadian) of the southwestern USA

δ¹⁸O_P values and ⁸⁷Sr/⁸⁶Sr ratios were determined on disarticulated xenacanthiform, hybodontid and ctenacanthid shark tooth material from several Early Permian (Sakmarian–Kungurian) continental bone beds of northern Texas and southern Oklahoma as well as from the marine Middle Permian (Roadian) of northern Arizona. The δ¹⁸O_P values derived from the teeth of bone beds are in the range of 17.6–23.5‰ VSMOW, and are mostly depleted in ¹⁸O by 0.5–5‰ relative to proposed coeval marine δ¹⁸O_P values. This indicates an adaptation to freshwater habitats on the Early Permian coastal plain by several sharks. Distinctly higher δ¹⁸O_P values from two bone beds are attributed to significant evaporative enrichment in ¹⁸O in flood plain ponds. ⁸⁷Sr/⁸⁶Sr ratios of around 0.71077 are notably more radiogenic than ⁸⁷Sr/⁸⁶Sr of contemporaneous seawater. In contrast, the isotopic composition of teeth from the marine Kaibab Formation is characterised by low δ¹⁸O_P values in the range of 13.4–15.6‰ VSMOW while ⁸⁷Sr/⁸⁶Sr ratios of around 0.70821 are closer to the Roadian seawater value. The distinctly depleted δ¹⁸O_P values cannot be readily explained by fluvially affected freshening in a nearshore marine environment, so a diagenetic alteration of the Kaibab material seems to be more likely, excluding it from further interpretation.