Clinical trials serve as the fundamental prerequisite for clinical therapy of human disease, which is primarily based on biomedical studies in animal models. Undoubtedly, animal models have made a significant contribution to gaining insight into the developmental and pathophysiological understanding of human diseases. However, none of the existing animal models could efficiently simulate the development of human organs and systems due to a lack of spatial information; the discrepancy in genetic, anatomic, and physiological basis between animals and humans limits detailed investigation. Therefore, the translational efficiency of the research outcomes in clinical applications was significantly weakened, especially for some complex, chronic, and intractable diseases. For example, the clinical trials for human fragile X syndrome (FXS) solely based on animal models have failed such as mGluR5 antagonists. To mimic the development of human organs more faithfully and efficiently translate in vitro biomedical studies to clinical trials, extensive attention to organoids derived from stem cells contributes to a deeper understanding of this research. The organoids are a miniaturized version of an organ generated in vitro, partially recapitulating key features of human organ development. As such, the organoids open a novel avenue for in vitro models of human disease, advantageous over the existing animal models. The invention of organoids has brought an innovative breakthrough in regeneration medicine. The organoid-derived human tissues or organs could potentially function as invaluable platforms for biomedical studies, pathological investigation of human diseases, and drug screening. Importantly, the study of regeneration medicine and the development of therapeutic strategies for human diseases could be conducted in a dish, facilitating in vitro analysis and experimentation. Thus far, the pilot breakthrough has been made in the generation of numerous types of organoids representing different human organs. Most of these human organoids have been employed for in vitro biomedical study and drug screening. However, the efficiency and quality of the organoids in recapitulating the development of human organs have been hindered by engineering and conceptual challenges. The efficiency and quality of the organoids are essential for downstream applications. In this article, we highlight the application in the modeling of human neurodegenerative diseases (NDDs) such as FXS, Alzheimer’s disease (AD), Parkinson’s disease (PD), and autistic spectrum disorders (ASD), and organoid-based drug screening. Additionally, challenges and weaknesses especially for limits of the brain organoid models in modeling late onset NDDs such as AD and PD., and future perspectives regarding human brain organoids are addressed.
Vast emerging evidences are linking the base modifications and gene expression involved in essential metabolic pathways. Among the base modification markers extensively studied, 5-methylcytosine (5mC) and its oxidative derivatives (5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC)) dynamically occur in DNA and RNA and have been acknowledged as the important epigenetic markers involved in regulation of cellular biological processes. The modification of C has been characterized biochemically, molecularly, and phenotypically, including elucidation of its methyltransferase complexes (writer), demethylases (eraser), 10-11 translocation proteins (TETs), and direct interaction proteins (readers). The levels and the landscapes of these epigenetic markers in the epitranscriptomes and epigenomes are precisely and dynamically regulated by the fine-tuned coordination of the writers and erasers in accordance with stages of the growth, development, and reproduction as naturally programmed during the life span. In mammalian genome, the TET family is consisted of three members, including TET1, TET2, and TET3. The link between aberrant modifications and diseases, such as cancers, neurodegenerative disorders, and heart diseases, has been appreciated. This review article will highlight the research advances in the writers and erasers for the modifications of cytosine in genome, as well as the dual function of TET1 in tumorigenesis as a tumor suppressor and a promoter. Additionally, the future research directions are addressed.
4-[((3,4-Dihydroxybenzoyl)oxy)methyl]phenyl β-D-glucopyranoside (DBPG, 1), a polyphenolic glycoside previously isolated from oregano (Origanum vulgare L.) in 0.08 % isolated yield, was synthesized in five chemical steps with 41.4 % overall yield. First, 4-(hydroxymethyl)phenyl -D-glucopyranoside 2,3,4,6-tetraacetate (4) was obtained in 53.2 % yield by selective glycosylation of 4-hydroxybenzyl alcohol (3) with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (2) in a mixture of chlorobenzene and aqueous CsOH using triethylbenzylammonium chloride (TEBAC) as a phase transfer catalyst. Then, this product was esterified with 3,4-diacetoxybenzoyl chloride (7) to generate 4-[((3,4-diacetoxybenzoyl)oxy)methyl]phenyl -D-glucopyranoside 2,3,4,6-tetraacetate (8) in 95 % yield. Finally, selectively global deacetylation of 8 was performed in a mixture of dibutyltin oxide and methanol under reflux to afford 1 in 94.8 % yield.
Highly practical, four-step synthesis of gastrodin was developed using penta-O-acetyl-β-D-glucopyranose and p-cresol as glycosyl donor and glycosyl acceptor, respectively, in 58.1 % overall yield. As the initial step, the penta-O-acetyl-β-D-glucopyranose was treated with p-cresol in the presence of BF 3 ·Et 2 O as catalyst to generate 4-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D--glucopyranoside in 76.3 % yield. Further, this product was subjected to radical bromination with N-bromosuccinimide (NBS) to provide 4-(bromomethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in 91 % yield. Subsequently, reaction of 4-(bromomethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside with a solution of acetone and saturated aqueous sodium bicarbonate led to 4-(hydroxymethyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in 93 % yield. Finally, global deprotection of 4-(hydroxymethyl)phenyl 2,3,4,6-tetra-O--acetyl-β-D-glucopyranoside under Zemplen conditions furnished gastrodin in 90 % yield. Compared to the previously reported methods, this protocol has the advantages of operational simplicity, chromatography-free separation, high overall yield, inexpensive and common reagents as well as less waste pollutants, rendering it an alternative suitable for industrial production.
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