Direct Synthesis of α- and ß-2'-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation.

2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.

Synthesis and Structural Revision of a Natural Tetrasaccharide from Starfish Asterias rollestoni Bell.

Starfish provide important saponins with diverse bioactivities as the secondary metabolites, among which 2-O-glycosylated glycosides are commonly found. Preparation of those 1,2-trans 2-O-glycosylated glycosides usually relies on 2-O-acyl participation requiring the selective installation and cleavage of 2-O-acyl groups. A convergent synthesis using 2-O-glycosylated oligosaccharide donors would be more straightforward but also pose greater challenges. Herein, we report a convergent synthesis of a distinctive tetrasaccharide isolated from starfish Asterias rollestoni Bell. Dual 2-(diphenylphosphinoyl)acetyl (DPPA) groups at O3 and O4 on galactose moiety led to high ß-selectivities (ß/α=12/1 or ß only) in the challenging [2+2] glycosylation, giving the desired tetrasaccharides in >90 % yields from the 2-O-glycosylated disaccharide donors. These synthetic studies have also unambiguously revised the structure of these natural tetrasaccharides. This work would facilitate further studies on new inhibitors of α-glucosidase as hypoglycemic drugs.

A scoping review on the methodological and reporting quality of scoping reviews in China.

BACKGROUND: Scoping reviews have emerged as a valuable method for synthesizing emerging evidence, providing a comprehensive contextual overview, and influencing policy and practice developments. The objective of this study is to provide an overview of scoping reviews conducted in Chinese academic institutions over the last decades. METHOD: We conducted a comprehensive search of nine databases and six grey literature databases for scoping reviews conducted in Chinese academic institutions. The reporting quality of the included reviews was assessed using the Preferred Reporting Items for PRISMA-ScR checklist. We performed both quantitative and qualitative analyses, examining the conduct of the scoping reviews and exploring the breadth of research topics covered. We used Chi-squared and Wilcoxon rank-sum tests to compare methodological issues and reporting quality in English and Chinese-language reviews. RESULTS: A total of 392 reviews published between 2013 and 2022 were included, 238 English-reported reviews and 154 Chinese-reported reviews, respectively. The primary purposes of these reviews were to map and summarize the evidence, with a particular focus on health and nursing topics. 98.7% of reviews explicitly used the term "scoping review", and the Arksey and O'Malley framework was the most frequently cited framework. Thirty-five English-reported scoping reviews provided a protocol for scoping review. PubMed was the most common source in English-reported reviews and CNKI in Chinese-reported reviews. Reviews published in English were more likely to search the grey literature (P = 0.005), consult information specialists (P < 0.001) and conduct an updated search (P = 0.012) than those in Chinese. Reviews published in English had a significantly high score compared to those published in Chinese (16 vs. 14; P < 0.001). The reporting rates in English-reported reviews were higher than those in Chinese reviews for seven items, but lower for structured summary (P < 0.001), eligibility criteria (P < 0.001), data charting process (P = 0.009) and data items (P = 0.015). CONCLUSION: There has been a significant increase in the number of scoping reviews conducted in Chinese academic institutions each year since 2020. While the research topics covered are diverse, the overall reporting quality of these reviews is need to be improved. And there is a need for greater standardization in the conduct of scoping reviews in Chinese academic institutions.

LncRNA NKILA relieves astrocyte inflammation and neuronal oxidative stress after cerebral ischemia/reperfusion by inhibiting the NF-κB pathway.

BACKGROUND: Ischemic stroke is one of the major diseases of the cerebral vasculature. Currently, Ischemic stroke is the leading cause of neurological disability worldwide and has a high morbidity and mortality rate. The NF-κB interacting lncRNA (NKILA), the recently identified, is a key booster of NF-κB pathway. Accumulating studies have shown that NKILA plays a cancer suppressor in a variety of malignancies by regulating the NF-κB pathway. Nevertheless, the role of NKILA in ischemic stroke remains to be elucidated. METHODS: We constructed a mouse model of middle cerebral artery occlusion-reperfusion (MCAO/R). TTC staining and dry and wet weight method were used to evaluate infarction and water content of brain tissue. RT-qPCR was performed to detect NKILA expression in cerebral infarction tissues. After labeling astrocytes and neurons with GFAP and NeuN, respectively, EDU and TUNEL staining were performed. Inflammatory factor levels were detected by ELISA. Commercial kits were used to detect the levels of oxidative stress-related factors. In in vitro, the HT22/U251 cell co-culture model was used for oxygen-glucose deprivation and re-introduction (OGD/R) to verify the effect of NKILA on neuronal cell inflammation and oxidative stress through astrocytes. RESULTS: In in vivo experiments, NKILA significantly reduced cerebral infarction volume, brain water content and neurological score caused by MCAO/R. Moreover, NKILA blocked the activation of the NF-κB pathway, and inhibited astrocyte proliferation and neuron apoptosis as well as inflammation and oxidative stress. In in vitro experiments, NKILA significantly inhibited NF-κB pathway in HT22 cells. In addition, NKILA alleviated the inflammatory response and oxidative stress of U251 cells mediated by HT22 cells after OGD/R, and promoted U251 cell proliferation and inhibit their apoptosis. CONCLUSIONS: In summary, we found for the first time that NKILA alleviates inflammatory response and oxidative stress after cerebral ischemia/reperfusion by blocking the activation of NF-κB pathway.

Isomeric Effect of Nano-Inhibitors on Aß40 Fibrillation at The Nano-Bio Interface.

Chemical and physical properties of nanobio interface substantially affect the conformational transitions of adjacent biomolecules. Previous studies have reported the chiral effect and charge effect of nanobio interface on the misfolding, aggregation, and fibrillation of amyloid protein. However, the isomeric effect of nanobio interface on protein/peptides amyloidosis is still unclear. Here, three isomeric nanobio interfaces were designed and fabricated based on the same sized gold nanoclusters (AuNCs) modified with 4-mercaptobenzoic acid (p-MBA), 3-mercaptobenzoic acid (m-MBA), and 2-mercaptobenzoic acid (o-MBA). Then three isomeric AuNCs were employed as models to explore the isomeric effect on the misfolding, aggregation, and fibrillation of Aß40 at nanobio interfaces. Site-specific replacement experiments on the basis of theoretical analysis revealed the possible mechanism of Aß40 interacting with isomeric ligands of AuNCs at the nanobio interfaces. The distance and orientation of -COOH group from the surface of AuNCs can affect the electrostatic interaction between isomeric ligands and the positively charged residues (R5, K16, and K28) of Aß40, which may affect the inhibition efficiency of isomeric AuNCs on protein amyloidosis. Actually, the amyloid fibrillation kinetics results together with atomic force microscope (AFM) images, dynamic light scattering (DLS) results and circular dichroism (CD) spectra indeed proved that all the three isomeric AuNCs could inhibit the misfolding, aggregation and fibrillation of Aß40 in a dose-dependent manner, and the inhibition efficiency was definitely different from each other. The inhibition efficiency of o-MBA-AuNCs was higher than that of m-MBA-AuNCs and p-MBA-AuNCs at the same dosage. These results provide an insight for isomeric effect at nanobio interfaces, and open an avenue for structure-based nanodrug design target Alzheimer's disease (AD) and even other protein conformational diseases.

Charge effects at nano-bio interfaces: a model of charged gold nanoclusters on amylin fibrillation.

The misfolding and abnormal amyloid fibrillation of proteins/peptides are associated with more than 20 human diseases. Although dozens of nanoparticles have been investigated for the inhibition effect on the misfolding and fibrillation of pathogenesis-related proteins/peptides, there are few reports on charge effects of nano inhibitors on amyloid fibrillation. Herein, same-sized gold nanoclusters modified with 2-aminoethanethiol hydrochloride (CSH-AuNCs, positively charged in pH 7.4) or 3-mercaptopropionic acid (MPA-AuNCs, negatively charged in pH 7.4) were synthesized and adopted as models to explore the charge effect of nano inhibitors on amylin fibrillation at the nano-bio interface. ThT fluorescence kinetics analysis, AFM images and circular dichroism (CD) spectra showed that electropositive CSH-AuNCs inhibited the misfolding and fibrillation of amylin in a dosage-dependent manner, but electronegative MPA-AuNCs accelerated the misfolding and fibrillation of amylin in a dosage-dependent manner. Moreover, the theoretical and experimental results revealed the interaction mechanism between amylin and ligands of AuNCs at the nano-bio interfaces. Electropositive CSH-AuNCs could be bound to the main nucleating region of amylin via hydrogen bonding and endowed the nanocomplex with more positive net charges (amylin monomer with a positive +26.23 ± 0.80 mV zeta potential), which would inhibit the misfolding and aggregation of amylin via electrostatic repulsion and steric hindrance. In contrast, electronegative MPA-AuNCs could absorb electropositive amylin via strong electrostatic attractions, which accelerated the fibrillation process of amylin via enhancing local concentrations. Moreover, cell experiments showed that both the charged AuNCs had good biocompatibility and electronegetive MPA-AuNCs showed a better protective effect in the amylin-induced cell model than electropositive CSH-AuNCs. These results provide an insight into structure-based nanodrug design for protein conformational diseases.

Cichoric acid from witloof inhibit misfolding aggregation and fibrillation of hIAPP.

The misfolding, aggregation and fibrillation of human islet amyloid polypeptide (hIAPP) has been acknowledged as a hallmark event in type-II diabetes. Hence, inhibiting the misfolding, aggregation and fibrillation of hIAPP have been accepted as a vital factor to treat the disease. Here cichoric acid was extracted from witloof to explore its inhibition effects on misfolding, aggregation and fibrillation of hIAPP. Thioflavin-T (ThT) fluorescence assay, dynamic light scattering (DLS) and atomic force microscopy (AFM) images showed that cichoric acid inhibited the aggregation and fibrillation of hIAPP in a dosage-dependent manner. Circular dichroism (CD) spectra showed that cichoric acid inhibited the misfolding of hIAPP from unfolded to ß-sheet. Molecular docking and further experiments revealed interactions between hIAPP and cichoric acid. Cichoric acid could bind to K1 and R11 of hIAPP via electrostatic interaction. In addition, cichoric acid could form π-π stacking with hIAPP residues F15 and F23. These interactions inhibited the misfolding, aggregation and fibrillation of hIAPP. These results, together with cichoric acid's good cytocompatibility and significant protective effects in hIAPP lesioned cell models, not only showed that cichoric acid could be used to fight against amyloidosis, but also brought a new perspective for Chinese herbal medicine as natural compound's medical potential.