Micellar Nanomedicine of Novel Fatty Acid Modified <i>Xenopus</i> Glucagon-like Peptide-1: Improved Physicochemical Characteristics and Therapeutic Utilities for Type 2 Diabetes

To develop novel long-acting antidiabetics with improved therapeutic efficacy, two glucagon-like peptide-1 (GLP-1) analogs were constructed through the hybridization of key sequences of GLP-1, xenGLP-1B, exendin-4, and lixisenatide. Hybrids <b>1</b> and <b>2</b> demonstrated enhanced <i>in vitro</i> and <i>in vivo</i> biological activities and were further site-specifically lipidized at lysine residues to achieve prolonged duration of action and less frequent administration. Compared with their native peptides, compounds <b>3</b>–<b>6</b> showed similar <i>in vitro</i> activities but impaired <i>in vivo</i> acute hypoglycemic potencies due to decreased aqueous solubility and retarded absorption <i>in vivo</i>. To circumvent these issues, compound <b>3</b> (xenoglutide) was selected to be self-associated with sterically stabilized micelles (SSM). The α-helix and solubility of xenoglutide were significantly improved after self-associated with SSM. Notably, the improved physicochemical characteristics of xenoglutide-SSM led to revival of acute hypoglycemic ability without affecting its long-term glucose-lowering activity. Most importantly, preclinical studies demonstrated improved therapeutic effects and safety of xenoglutide-SSM in diabetic <i>db</i>/<i>db</i> mice. Our work suggests the SSM incorporation as an effective approach to improve the pharmacokinetic and biological properties of hydrophobicity peptide drugs. Furthermore, our data clearly indicate xenoglutide-SSM as a novel nanomedicine for the treatment of type 2 diabetics

DataSheet_1_Genes and pathways correlated with heat stress responses and heat tolerance in maize kernels.docx

Global warming leads to frequent extreme weather, especially the extreme heat events, which threating the safety of maize production. Here we selected a pair of maize inbred lines, PF5411-1 and LH150, with significant differences in heat tolerance at kernel development stage. The two maize inbred lines were treated with heat stress at kernel development stage. Compared with the control groups, transcriptomic analysis identified 770 common up- and down-regulated genes between PF5411-1 and LH150 under heat stress conditions, and 41 putative TFs were predicted. Based on the interaction term of the two-factorial design, we also identified 6,744 differentially regulated genes between LH150 and PF5411-1, 111 common up-regulated and 141 common down-regulated genes were overlapped with the differentially regulated genes, respectively. Combined with proteins and metabolites data, several key pathways including seven differentially regulated genes were highly correlated with the heat tolerance of maize kernels. The first is the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway ko04141: protein processing in endoplasmic reticulum, four small heat shock protein (sHSP) genes were enriched in this pathway, participating with the process of ER-associated degradation (ERAD). The second one is the myricetin biosynthesis pathway, a differentially regulated protein, flavonoid 3’,5’-hydroxylase [EC:1.14.14.81], catalyzed the synthesis of myricetin. The third one is the raffinose metabolic pathway, one differentially regulated gene encoded the raffinose synthase controlled the synthesis of raffinose, high level of raffinose enhances the heat tolerance of maize kernels. And the last one is the ethylene signaling pathway. Taken together, our work identifies many genes responded to heat stress in maize kernels, and finds out seven genes and four pathways highly correlated with heat tolerance of maize kernels.</p

Preparation and Pharmaceutical Characterizations of Lipidated Dimeric <i>Xenopus</i> Glucagon-Like Peptide‑1 Conjugates

A pair of glucagon-like peptide-1 (GLP-1) analogs (<b>1</b> and <b>2</b>) were synthesized by hybridizing the key sequences of GLP-1, exendin-4, lixisenatide, and xenGLP-1B (<i>Xenopus</i> GLP-1 analog). To achieve long-acting hypoglycemic effects and to further improve their anti-diabetic potencies, lipidization and dimerization strategies were used to afford two lipidated dimeric conjugates (<b>9</b> and <b>11</b>). Conjugates <b>9</b> and <b>11</b> showed stronger receptor activation potency than GLP-1 and exendin-4 in vitro. Moreover, <b>9</b> and <b>11</b> exhibited superior hypoglycemic and insulinotropic activities to liraglutide in type 2 diabetic C57BL/6J-m^+/+ Lepr^db (db/db) mice. Pharmacokinetic studies revealed that the circulating half-lives (<i>t</i>_1/2) of <b>9</b> and <b>11</b> were 2.3- and 1.7-fold longer than that of liraglutide. The improved pharmacokinetic profiles led to significantly protracted in vivo anti-diabetic effects as confirmed by multiple oral glucose tolerance tests and hypoglycemic duration tests. Most importantly, chronic treatment studies found that once daily administration of <b>9</b> or <b>11</b> in db/db mice achieved more beneficial effects on HbA1c reduction and glucose tolerance normalization than liraglutide. Our research demonstrated lipidization and dimerization as useful tools for the development of novel GLP-1 receptor agonists. The preclinical studies suggested the potential of <b>9</b> and <b>11</b> to be developed as novel anti-diabetic agents

Tuning the Se Content in Cu₂ZnSn(S, Se)₄ Absorber to Achieve 9.7% Solar Cell Efficiency from a Thiol/Amine-Based Solution Process

The Se content in a Cu₂ZnSn­(S, Se)₄ absorber layer has a significant impact on the electronic properties, but it is rather challenging to control the Se/(S + Se) ratio due to a complicated selenization process. Here, a low-toxicity thiol/amine-based solution process was developed to tune the Se content in a Cu₂ZnSn­(S, Se)₄ absorber layer to an optimal value by ingeniously controlling the SeO₂ in the precursor solution. We demonstrated that the crystal growth and the band gap of Cu₂ZnSn­(S, Se)₄ thin films are affected by the Se/(S + Se) ratio. By this approach, the open-circuit voltage deficit (<i>V</i>_oc,def) of the device was effectively decreased, and the short-circuit density (<i>J</i>_sc) and fill factor (FF) were remarkably improved; thus, the power conversion efficiency of the Cu₂ZnSn­(S, Se)₄ solar cells was successfully increased from 5.6% to 9.7% for the optimal band gap (<i>E</i>_g = 1.13 eV)

Glioma and microenvironment dual targeted nanocarrier for improved antiglioblastoma efficacy

<p>Drug delivery systems based on nanoparticles (nano-DDS) have aroused attentions for the treatment of glioblastoma (GBM), the most malignant brain cancer with a dismal prognosis. However, there are still numerous unmet challenges for traditional nano-DDS, such as the poor nanoparticle penetration, short retention in the GBM parenchyma and low glioma targeting ability. Herein, we used Pep-1 and CREKA peptides to construct a novel multifunctional GBM targeting nano-DDS (PC-NP). Pep-1 was used to overcome the blood–brain tumor barrier (BBTB) and home to glioma cells via interleukin-13 receptor-α2-mediated endocytosis, and CREKA was used to bind to fibrin–fibronectin complexes abundantly expressed in tumor microenvironment for enhanced retention in the GBM. Biological studies showed that the cellular uptake of PC-NP by U87MG cells was significantly enhanced compared with the non-targeting NP. Furthermore, CREKA modification increased the binding capacity of PC-NP to fibrin–fibronectin complexes as confirmed by the competition experiment. In accordance with the increased cellular uptake, PC-NP remarkably increased the cytotoxicity of its payload paclitaxel (PTX) against U87MG cells with an IC₅₀ of 0.176 μg/mL. <i>In vivo</i> fluorescence imaging and antiglioma efficacy evaluation further confirmed that PC-NP accumulated effectively and penetrated deeply into GBM tissue. PC-NP-PTX exhibited a median survival time as long as 61 days in intracranial GBM-bearing mice. In conclusion, our findings indicated PC-NP as a promising nano-DDS for GBM targeting delivery of anticancer drugs.</p

Antigenicity evaluation of synthetic α-(1,3)-linked D, D-heptoglycan of <i>Helicobacter pylori</i> serotype O6 lipopolysaccharide

Helicobacter pylori, a gram‐negative bacterium, is known to be associated with various gastric pathologies including chronic gastritis, peptic ulcers and gastric carcinoma. Despite the emerging issue of bacterial resistance to antibiotic-based combination therapy, there is currently no vaccine available for H. pylori infection in the market. Here, we report the synthesis of α-(1,3)-D,D-heptoglycan with different chain length from the lipopolysaccharide of H. pylori serogroup O6. The [n + 1] iterative glycosylation strategy was used for heptoglycan chain elongation. The trifluoroacetimidate heptoside donor exhibited much higher efficiency than thioglycoside donor during glycosylation. An antigenicity evaluation using glycan microarrays indicated that α-(1,3)-D,D-hepto-disaccharide, pentasaccharide and hexasaccharide showed stronger binding affinity to IgG antibodies of H. pylori O6 LPS immunized rabbit serum or serum of H. pylori infected patients. These findings provide significant structure − activity relationship information for developing carbohydrate-based vaccines against H. pylori containing α-(1,3)-D,D-heptoglycan.</p

The role of potassium transporters in programmed cell death of yeasts

The role of potassium transporters in programmed cell death of yeasts Abstract The programmed cell death was originally connected only to ontogenesis of metazoan. It was later shown that it plays an important role in physiological processes too. An insufficiency or an increased rate of the programmed cell death lead to many pathologies. The term apoptosis was taken as synonym for the term programmed cell death but it designates one of its types. Other types of the programmed cell death are not explored so far as apoptosis. The original classification was based on morphological features, however, there is an approach to distinguish them based on biochemical features. The programmed cell death was found in plants too, where its roles are similar to roles in metazoan and, surprisingly, it occurs in unicellular organisms. The prokaryotic mechanism is different but many common features with metazoan apoptosis exist in unicellular eukaryotes. Nevertheless, certain differences led to use of the term "apoptosis-like programmed cell death". One of the most studied unicellular eukaryotes is a yeast species Saccharomyces cerevisiae. There was found a range of metazoan homologues proteins and thus it can be used as a model organism to deepen our knowledge on metazoan apoptosis and to understand the occurrence of such a..

A Gene-Oriented Haplotype Comparison Reveals Recently Selected Genomic Regions in Temperate and Tropical Maize Germplasm

<div><p>The extensive genetic variation present in maize (<i>Zea mays</i>) germplasm makes it possible to detect signatures of positive artificial selection that occurred during temperate and tropical maize improvement. Here we report an analysis of 532,815 polymorphisms from a maize association panel consisting of 368 diverse temperate and tropical inbred lines. We developed a gene-oriented approach adapting exonic polymorphisms to identify recently selected alleles by comparing haplotypes across the maize genome. This analysis revealed evidence of selection for more than 1100 genomic regions during recent improvement, and included regulatory genes and key genes with visible mutant phenotypes. We find that selected candidate target genes in temperate maize are enriched in biosynthetic processes, and further examination of these candidates highlights two cases, sucrose flux and oil storage, in which multiple genes in a common pathway can be cooperatively selected. Finally, based on available parallel gene expression data, we hypothesize that some genes were selected for regulatory variations, resulting in altered gene expression.</p></div

Hybrid Molecule from <i>O</i>²‑(2,4-Dinitrophenyl)diazeniumdiolate and Oleanolic Acid: A Glutathione <i>S</i>‑Transferase π‑Activated Nitric Oxide Prodrug with Selective Anti-Human Hepatocellular Carcinoma Activity and Improved Stability

A series of hybrids from <i>O</i>²-(2,4-dinitrophenyl)­diazeniumdiolate and oleanolic acid (OA) were designed, synthesized, and biologically evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione <i>S</i>-transferase π (GSTπ) overexpressed in a number of cancer cells. It was discovered that the most active compound, <b>21</b>, released high levels of NO selectively in HCC cells but not in the normal cells and exhibited potent antiproliferative activity in vitro as well as remarkable tumor-retarding effects in vivo. Compared with the reported GSTπ-activated prodrugs JS-K and PABA/NO, <b>21</b> exhibited remarkably improved stability in the absence of GSTπ. Importantly, the decomposition of <b>21</b> occurred in the presence of GSTπ and was much more effective than in glutathione <i>S</i>-transferase α. Additionally, <b>21</b> induced apoptosis in HepG2 cells by arresting the cell cycle at the G2/M phase, activating both the mitochondrion-mediated pathway and the MAPK pathway and enhancing the intracellular production of ROS

Lithocholic Acid-Based Peptide Delivery System for an Enhanced Pharmacological and Pharmacokinetic Profile of <i>Xenopus</i> GLP‑1 Analogs

GLP-1 analogs suffer from the main disadvantage of a short in vivo half-life. Lithocholic acid (LCA), one of the four main bile acids in the human body, possesses a high albumin binding rate. We therefore envisioned that a LCA-based peptide delivery system could extend the half-life of GLP-1 analogs by facilitating the noncovalent binding of peptides to human serum albumin. On the basis of our previously identified <i>Xenopus</i> GLP-1 analogs (<b>1</b>–<b>3</b>), a series of LCA-modified <i>Xenopus</i> GLP-1 conjugates were designed (<b>4a</b>–<b>4r</b>), and the bioactivity studies of these conjugates were performed to identify compounds with balanced in vitro receptor activation potency and plasma stability. <b>4c</b>, <b>4i</b>, and <b>4r</b> were selected, and their LCA side chains were optimized to further increase their stability, affording <b>5a</b>–<b>5c</b>. Compound <b>5b</b> showed a more increased albumin affinity and prolonged in vitro stability than that of <b>4i</b> and liraglutide. In <i>db</i>/<i>db</i> mice, <b>5b</b> exhibited comparable hypoglycemic and insulinotropic activity to liraglutide and semaglutide. Importantly, the enhanced albumin affinity of <b>5b</b> resulted in a prolonged in vivo antidiabetic duration. Finally, chronic treatment investigations of <b>5b</b> demonstrated the therapeutic effects of <b>5b</b> on HbA1c, body weight, blood glucose, and pancreatic endocrine deficiencies on <i>db</i>/<i>db</i> mice. Our studies revealed <b>5b</b> as a promising antidiabetic candidate. Furthermore, our study suggests the derivatization of <i>Xenopus</i> GLP-1 analogs with LCA represents an effective strategy to develop potent long-acting GLP-1 receptor agonists for the treatment of type 2 diabetes