Molecular Evolution of Major Epidermal Structure Genes and an Integrative Transcriptome Analysis of Chicken Epidermal Embryogenesis

Αlpha (α) and beta (β) keratins are the major structural proteins found in vertebrate epidermis and the β-keratins are only found in reptiles and birds. With the recent published 48 avian genomes, we searched and studied the molecular evolution of these gene families. We discovered that the expansion and contraction of different α- and β- keratins among the 48 phylogenetically diverse birds supports the importance of their role in the evolution of the feathers and the adaptation of birds to different ecological niches. Using a customized 44K microarray, we also performed transcriptome analysis on different epidermal regions (scutate scale, dorsal feather and wing feather) at important time points (day 8, 17 and 19) during chicken embryonic development. We profiled the differentially expressed α- and β-keratin genes in those comparison groups and demonstrated the important roles of α- and β-keratins in the development of the chicken epidermal appendages. MicroRNAs have been found to widely regulate many biological processes in animals. Here we also utilized the 44K microarray transcriptome data to profile the miRNA expression during chicken embryonic development. With the application of various bioinformatic tools, based on the differentially expressed miRNA genes and mRNAs, we identified highly possible target genes for epidermal development in the chicken, and provided a rational for future miRNA target validation. In previous studies, hundreds of genes (i.e., signaling pathway genes, structural genes, cell adhesion genes, etc.) have been associated with the morphogenesis of chicken epidermal structures as complex, interactive networks. A Weighted Gene Co-expression Network Analysis (WGCNA) using our microarray transcriptome data was performed to construct a co-expression network associated with traits. We identified two modules that were highly correlated with the developmental traits of the chicken scale and feather. The combination of traditional enrichment (KEGG and Gene Ontology) and novel enrichment (MSET and MeSH) analysis further demonstrated the important functional role of epidermal development related genes (EDRGs) and the hub genes to the development of scales and feathers. In the future, the discoveries of trait related modules will contribute to our understanding of the morphogenesis and differentiation of other epidermal appendages

Replacing fossil oil with fresh oil – with what and for what?

Industrial chemicals and materials are currently derived mainly from fossil-based raw materials, which are declining in availability, increasing in price and are a major source of undesirable greenhouse gas emissions. Plant oils have the potential to provide functionally equivalent, renewable and environmentally friendly replacements for these finite fossil-based raw materials, provided that their composition can be matched to end-use requirements, and that they can be produced on sufficient scale to meet current and growing industrial demands. Replacement of 40% of the fossil oil used in the chemical industry with renewable plant oils, whilst ensuring that growing demand for food oils is also met, will require a trebling of global plant oil production from current levels of around 139 MT to over 400 MT annually. Realisation of this potential will rely on application of plant biotechnology to (i) tailor plant oils to have high purity (preferably >90%) of single desirable fatty acids, (ii) introduce unusual fatty acids that have specialty end-use functionalities and (iii) increase plant oil production capacity by increased oil content in current oil crops, and conversion of other high biomass crops into oil accumulating crops. This review outlines recent progress and future challenges in each of these areas

The study of in vitro superfused spiral modiolar artery bioassay on the endothelin-1 antagonistic activity of (+)-myriceric acid a and its novel synthetic tetracyclic terpenoids intermediates

Master of ScienceDepartment of ChemistryDuy H. Hua(+)-myriceric acid A is known as a non-peptide ETA receptor antagonist. It is isolated from the natural plant Myrica cerfera with 0.01% yield which is very low. The total synthesis of (+)-myriceric acid A is being pursued in Hua’s lab. (+)-myriceric acid A specifically blocks the vasoconstriction caused by endothelin-1 (ET-1). Because some derivatives of (+)-myriceric acid A were shown to have ET-1 receptor antagonistic effect, the tetracyclic terpenoid intermediates toward the total synthesis of (+)-myriceric acid A are postulated to have the similar antagonistic activities. The objective of this project is to study the release of vasoconstriction of these synthetic intermediates and compare their antagonistic potency. The ET-1 receptor antagonistic bioactivity of six (+)-myriceric acid A intermediates as well as (+)-myriceric acid A were evaluated by the in vitro spiral modiolar artery (SMA) bioassay. The synthetic intermediates which have not been reported in the literature were previously synthesized in Hua’s laboratory by Dr. Angelo Aguilar and Dr. Aibin Shi. Their synthesis was described in Dr. Aguilar’s PhD thesis. All the antagonistic effect evaluations were based on the SMA’s diameter changes. SMA’s diameter changes were induced by the superfusion of different extracellular solutions. The dose-response curves and straight lines were plotted to compare the antagonistic potency of these compounds. Based on the EC50 value of (+)-myriceric acid A intermediates (0.090 µM ~ 0.582 µM for the curves and 0.095 µM ~ 0.385 µM for the straight lines), all of the compounds have ET-1 receptor antagonistic activity, therefore the synthesis and screening of (+)-myriceric acid A intermediates is probably a promising route to develop new non-peptide ETA receptor antagonists

The delivery of sensitive food bioactive ingredients : Absorption mechanisms, influencing factors, encapsulation techniques and evaluation models

Food-sourced bioactive compounds have drawn much attention due to their health benefits such as anti-oxidant, anti-cancer, anti-diabetes and cardiovascular disease-preventing functions. However, the poor solubility, low stability and limited bioavailability of sensitive bioactive compounds greatly limited their application in food industry. Therefore, numbers of carriers were developed for improving their dispersibility, stability and bioavailability. This review addresses the digestion and absorption mechanisms of bioactive compounds in epithelial cells based on several well-known in vitro and in vivo models. Factors such as environmental stimuli, stomach conditions and mucus barrier influencing the utilization efficacy of the bioactive compounds are discussed. Delivery systems with enhanced utilization efficacy, such as complex coacervates, cross-linked polysaccharides, self-assembled micro−/nano-particles and Pickering emulsions are compared. It is a comprehensive multidisciplinary review which provides useful guidelines for application of bioactive compounds in food industry.</p

Bioinspired peptosomes with programmed stimuli-responses for sequential drug release and high-performance anticancer therapy

Combination therapy with enhanced therapeutic and antimetastatic efficacy has become promising for cancer treatment. There is an urgent need to design a co-delivery system to sequentially release the drug pair at desired locations that can increase the intra-tumoral drug concentration and reduce the side effects. Inspired by virus architecture and function, herein, we developed a peptosome (PS)-based codelivery system, PePm/PS/Curcumin (Cur), for the sequential release of the therapeutic peptide Pe and chemodrug Cur. PS was formed by the self-assembly of amphiphilic a-lactalbumin peptides obtained from enzymatic partial hydrolysis. Then, PS was self-cross-linked with disulfide bonds utilizing their endogenous thiol groups. The system is responsive to multiple tumor microenvironments and releases the drugs at specific tumor locations. First, after PS accumulation in tumor tissue via the EPR effect, the linkage peptide Pm in PS can be cleaved by matrix metalloproteinases (MMP) enzymatic hydrolysis. Pe can stay on the cell surface and antagonize the ErbB-2 receptor expression on the tumor cells. Moreover, the positively charged nature of remaining Mal-PS/Cur facilitates tumor cell internalization and induces a subsequent proton-sponge effect for lysosomal escape. Finally, Cur is released in the cytoplasm via a reduction-induced PS disassembly due to the high level of intracellular GSH. Both the in vitro and in vivo results exhibited an enhanced antitumor and antimetastatic efficacy of this system.</p

Cell Membrane Camouflaged Hydrophobic Drug Nanoflake Sandwiched with Photosensitizer for Orchestration of Chemo-Photothermal Combination Therapy

Many candidate anticancer drugs have suffered from their intrinsic hydrophobicity, which poses several obstacles for clinical application. To overcome this challenge and further improve the performance, herein a nanocrystal-based biomimetic formulation with a sandwich structure is developed. As the core, flake shaped nanocrystals (NCs) with high loading of the hydrophobic drug hydroxycamptothecin (HCPT) are synthesized via a mild nanoprecipitation process by exploring the template effect of serum albumin. Meanwhile, the camouflaged cancer cell membrane (CM) composed of plentiful membrane proteins endows the NCs with homotypic targeting capacity at tumor sites. In addition, the photosensitizer indocyanine green sandwiched between NCs and CM not only converts near infrared light to heat for photothermal treatment but also improves the dissolution of HCPT NCs for chemotherapy. These features corporately achieve the orchestration of chemo-photothermal combination therapy and completely inhibit tumor growth with few adverse effects, showing promise as a new modality for the utilization of hydrophobic drugs to treat cancer

Near-infrared light-triggered platelet arsenal for combined photothermal-immunotherapy against cancer

To address long-standing issues with tumor penetration and targeting among cancer therapeutics, we developed an anticancer platelet-based biomimetic formulation (N+R@PLTs), integrating photothermal nanoparticles (N) and immunostimulator (R) into platelets (PLTs). Exploiting the aggregative properties of platelets and high photothermal capacity, N+R@PLTs functioned as an arsenal by targeting defective tumor vascular endothelial cells, accumulating in a positive feedback aggregation cascade at sites of acute vascular damage induced by N-generated local hyperthermia, and subsequently secreting nanosized proplatelets (nPLTs) to transport active components to deep tumor tissue. The immunostimulator augmented the immunogenicity of antigens released from ablated tumors, inducing a stronger immunological response to attack residual, metastatic, and recurrent tumors. Following activation by low-power near-infrared light irradiation, the photothermal and immunological components synergistically provide exceptionally high therapeutic efficacy across nine murine models that mimicked a range of clinical requirements, and, most notably, a sophisticated model based on humanized mouse and patient-derived tumor xenograft

Harnessing Phosphato-Platinum Bonding Induced Supramolecular Assembly for Systemic Cisplatin Delivery

To improve the therapeutic index of cisplatin (CDDP), we present here a new paradigm of drug-induced self-assembly by harnessing phosphato-platinum cornplexation. Specifically, we show that a phosphato-platinum cross-linked micelle (PpY/Pt) can be generated by using a block copolymer methoxy-poly(ethylene glycol)block-poly(L-phosphotyrosine) (mPEG-b-PpY). Coating of PpY/Pt with aR9-iRGD peptide by simple mixing affords a targeting micelle with near neutral-charged surface (iPpY/Pt). The micelles feature in well-controlled sizes below 50 nm and high, stability under physiological conditions, and can withstand various environmental stresses. Importantly, the micelles demonstrate on-demand drug release profiles in response to pathological cues such as high ATP concentration and acidic pH. In vitro, the micelles are efficiently internalized and almost equally potent compared to CDDP. Moreover, iPpY/Pt induce greater cytotoxicity than PpY/Pt in a 3D tumor spheroid model likely due to its deeper tumor penetration. In vivo, the micelles exhibit prolonged circulation half-lives, enhanced tumor accumulation, excellent tumor growth inhibition in a xenograft HeLa model and an orthotropic mammary 4T1 model, and improved safety profiles evidenced by the reduced nephrotoxicity. Together) this work demonstrates for the first time that phosphato-platinurn complexation can be exploited for effective delivery of CDDP, and suggests a paradigm shift of constructing nanosystems for other anticancer metallodrugs.</p