Month: April 2022

Water-soluble and amphiphilic phospholipid
copolymers having 2-methacryloyloxyethyl
phosphorylcholine units for the solubilization of
bioactive compounds

We summarize the development and evaluation of new type of phospholipid polymers as a solubilizer for poorly water-soluble compounds. That is, a water-soluble and amphiphilic poly(2-methacryloyloxyethyl phosphorylcholine-random-n-butyl methacrylate) contains 30 mol% hydrophilic 2-methacryloyloxyethyl phosphorylcholine units and its weight-averaged molecular weight is around 5.0 × 104 .When the polymer is dissolved in an aqueous medium, a large portion of hydrophobic n-butyl methacrylate units assemble, forming polymer aggregates. To avoid severe biological reactions caused by conventional solubilizers, the phospholipid polymer can be applied for the solubilization of poorly water-soluble bioactive compounds. The polarity inside these polymer aggregate is the same as that of ethanol and n-butanol. Therefore, bioactive compounds, whose solubility is poor in water but good in these alcohols, can be entrapped in the polymer aggregate. The phospholipid polymer can penetrate the cell membrane by molecular diffusion, carrying inside the cell the bioactive compound, without exhibiting significant cytotoxicity. Several animal experiments have revealed that the pharmacological performance of various bioactive compound/phospholipid polymer complexes is excellent. Furthermore,functionalization of the polymer aggregate with biomolecules, such as antibodies and oligonucleotides, can be done, leading to selective capturing of the target molecules. These examples clearly indicate that water-soluble and amphiphilic phospholipid polymer is a candidate for preparing safer formulations and more effective pharmaceutical treatment with several bioactive compounds.

Poly(MPC-random-BMA) (PMB) is a typical water-soluble and amphiphilic MPC copolymer, whose weight-averaged molecular weight (Mw) is less than 5.0 × 104, and which is composed of 30 mol% MPC units in the polymer. The fact that 30 mol% MPC units in the polymer is enough to result in high water solubility of the relatively low Mw PMB,which contains hydrophobic BMA units, is a remarkable property of the MPC unit, since other hydrophilic methacrylate units, including carboxylate, sulfonate, and trimethylammonium groups, cannot provide enough solubility in water when the resulting polymers contain 70 mol% BMA units.

PMB is one of the candidate solubilizers for poorly water-soluble bioactive compounds administered orally or through the bloodstream. Water-soluble PMB of two different MWs is commercially available worldwide as PUREBRIGHT® from NOF Co. Ltd,Tokyo, Japan, as a solubilizing test kit for bioactive compounds. Moreover, many animal studies have revealed that PMB has a good potential to be used as a new solubilizer. We hope that the application of water-soluble and amphiphilic PMB will realize safer and more effective pharmaceutical treatment in the future. (Journal of Biomaterials Science, Polymer Edition, DOI: 10.1080/09205063.2017.1377023)

A Review of Nervonic Acid Production in Plants: Prospects for the Genetic Engineering of High Nervonic Acid Cultivars Plants

Nervonic acid (NA) is a very-long-chain monounsaturated fatty acid that plays crucial roles in brain development and has attracted widespread research interest. The markets encouraged the development of a refined, NA-enriched plant oil as feedstocks for the needed further studies of NA biological functions to the end commercial application. Plant seed oils offer a renewable and environmentally friendly source of NA, but their industrial production is presently hindered by various factors. This review focuses on the NA biosynthesis and assembly, NA resources from plants, and the genetic engineering of NA biosynthesis in oil crops, discusses the factors that affect NA production in genetically engineered oil crops, and provides prospects for the application of NA and prospective trends in the engineering of NA. This review emphasizes the progress made toward various NA-related topics and explores the limitations and trends, thereby providing integrated and comprehensive insight into the nature of NA production mechanisms during genetic engineering. Furthermore, this report supports further work involving the manipulation of NA production through transgenic technologies and molecular breeding for the enhancement of crop nutritional quality or creation of plant biochemical factories to produce NA for use in nutraceutical, pharmaceutical, and chemical industries.

Nervonic acid (NA; 24:1 Δ15, 24:1 ω-9; cis-tetracos-15-enoic acid) is a very-long-chain monounsaturated fatty acid (VLCMFA, 22–26 carbons) (Merrill et al., 1997; Figure 1) that was first isolated in shark brain and molecular structure was determined more than 100 years ago; it is also known as shark oil acid or selacholeic Acid (Tsujimoto and Kimura, 1926). It was found that the shark brain could repair itself in a short time after being severely damaged, suggesting the exceptional effect of NA in promoting the repair and regeneration of nerve fibers in damaged brain tissues (Sinclair and Crawford, 1972). NA combines with sphingosines via amide bonds to form nervonyl sphingolipids, which are chiefly found in nervous and brain tissues, comprising the white matter and myelin sheath of nerve fibers (Poulos, 1995; Merrill et al., 1997; Martínez and Mougan, 1998). NA plays a vital role in developing and maintaining the brain and biosynthesizing and improving nerve cells. NA is a natural component of maternal milk and can promote infant growth by assisting nervous system development (Farquharson et al., 1996; Ntoumani et al., 2013; Yu et al., 2019). Decreased NA levels are closely associated with a high risk of developing psychotic disorders in individuals (Coupland and Raoul, 2001; Amminger et al., 2012; Vozella et al., 2017), and supplementation with NA is an established effective treatment for symptoms of several neurological diseases, such as demyelinating disorders (Sargent et al., 1994; Vozella et al., 2017; Lewkowicz et al., 2019). NA can also function as a non-competitive inhibitor of human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) in a dose-dependent manner (Kasai et al., 2002). Increasing dietary NA improves energy metabolism in mice and may be an effective strategy for the treatment of obesity and obesity-related complications (Keppley et al., 2020). (Front. Plant Sci., 05 March 2021)

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

Ganglioside GM1 (GM1) has been reported to functionally recover degenerated nervous system in vitro and in vivo, but the possibility to translate GM1′s potential in clinical settings is counteracted by its low ability to overcome the blood–brain barrier (BBB) due to its amphiphilic nature. Interestingly, the soluble and hydrophilic GM1-oligosaccharide (OligoGM1) is able to punctually replace GM1 neurotrophic functions alone, both in vitro and in vivo. In order to take advantage of OligoGM1 properties, which overcome GM1′s pharmacological limitations, here we characterize the OligoGM1 brain transport by using a human in vitro BBB model. OligoGM1 showed a 20-fold higher crossing rate than GM1 and time–concentration-dependent transport. Additionally, OligoGM1 crossed the barrier at 4 °C and in inverse transport experiments, allowing consideration of the passive paracellular route. This was confirmed by the exclusion of a direct interaction with the active ATP-binding cassette (ABC) transporters using the “pump out” system. Finally, after barrier crossing, OligoGM1 remained intact and able to induce Neuro2a cell neuritogenesis by activating the TrkA pathway. Importantly, these in vitro data demonstrated that OligoGM1, lacking the hydrophobic ceramide, can advantageously cross the BBB in comparison with GM1, while maintaining its neuroproperties. This study has improved the knowledge about OligoGM1′s pharmacological potential, offering a tangible therapeutic strategy. (Int J Mol Sci. 2020 Apr; 21(8): 2858.)

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