Synthesis and bioactivities evaluation of oleanolic acid oxime ester derivatives as α-glucosidase and α-amylase inhibitors.

Different oleanolic acid (OA) oxime ester derivatives (3a-3t) were designed and synthesised to develop inhibitors against α-glucosidase and α-amylase. All the synthesised OA derivatives were evaluated against α-glucosidase and α-amylase in vitro. Among them, compound 3a showed the highest α-glucosidase inhibition with an IC50 of 0.35 µM, which was ∼1900 times stronger than that of acarbose, meanwhile compound 3f exhibited the highest α-amylase inhibitory with an IC50 of 3.80 µM that was ∼26 times higher than that of acarbose. The inhibition kinetic studies showed that the inhibitory mechanism of compounds 3a and 3f were reversible and mixed types towards α-glucosidase and α-amylase, respectively. Molecular docking studies analysed the interaction between compound and two enzymes, respectively. Furthermore, cytotoxicity evaluation assay demonstrated a high level of safety profile of compounds 3a and 3f against 3T3-L1 and HepG2 cells.HighlightsOleanolic acid oxime ester derivatives (3a-3t) were synthesised and screened against α-glucosidase and α-amylase.Compound 3a showed the highest α-glucosidase inhibitory with IC50 of 0.35 µM.Compound 3f presented the highest α-amylase inhibitory with IC50 of 3.80 µM.Kinetic studies and in silico studies analysed the binding between compounds and α-glucosidase or α-amylase.

TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

Data on isotopic niche differentiation in benthic consumers from shallow-water hydrothermal vents and nearby non-vent rocky reefs in northeastern Taiwan.

This paper presents data on carbon and nitrogen stable isotopes in benthos from shallow-water hydrothermal vents (SV) and nearby non-vent rocky reefs (NV) located in northeastern Taiwan, which is related to the article "Isotopic niche differentiation in benthic consumers from shallow-water hydrothermal vents and nearby non-vent rocky reefs in northeastern Taiwan" [1]. Field sampling work was conducted in July 2009 and July-August 2010 to collect sediment organic matters (SOM), zooplankton, and benthos for carbon and nitrogen stable isotopic analyses. Scuba divers collected macrobenthos, seawater, and surface sediments (0-2 cm). The collection of zooplankton was by a North Pacific standard net and trawled vertically. Testing samples were lyophilized before grounding by a mortar and pestle. For carbon and nitrogen isotope analyses, approximately 1 mg of powder was weighed and encapsulated in a tin capsule. Analyses were performed at the stable isotope laboratory at the University of California at Davis using an Integra Mass Spectrometer elemental analyzer (PDZ Europa, Sandbach, UK). The information is presented as 187 and 53 unprocessed data points from SV and NV, which incorporates δ13C and δ15N values (‰) of sediment, zooplankton, and benthos' tissue samples. Data from SOM provides information about chemosynthetic activity in SV sites. These data can be used to correlate food sources of consumers inhabiting shallow-water hydrothermal vent and rocky reef ecosystems in subtropical regions.

Neurodevelopmental disorder caused by a truncating de novo variant of IRF2BPL.

BACKGROUND: Mutations in the IRF2BPL gene can cause neurodevelopmental disorders. We describe the clinical and genetic characteristics of a Chinese patient with a novel abnormality in this gene, explore the potential pathogenic mechanism and summarize the clinical characteristics of 25 patients with IRF2BPL mutations. METHODS: We identified the gene mutation sites by whole-exome and Sanger sequencing. The protein-protein interaction network of the IRF2BPL gene was constructed using bioinformatic techniques, and its function was enriched. We conducted a functional experiment to explore the potential pathogenicity of the identified IRF2BPL gene mutation. RESULTS: An 8-year-old girl presented with progressive cerebellar ataxia, including involuntary tremor and slurred speech. Electroencephalography and electromyography revealed no abnormalities. Structural cranial MRI was also normal, but genetic analysis identified a truncating de novo variant in IRF2BPL. Bioinformatics predicted that IRF2BPL would be associated with IRF2 and 10 other genes and involved in ubiquitin binding and other pathways. The cellular location of IRF2BPL was altered, and compared to control cells, the level of ubiquitinated proteins was significantly decreased in cells harbouring the mutation. CONCLUSION: In this study, we identified a truncating de novo variant of IRF2BPL as a causative gene in the neurodevelopmental disorder of a Chinese girl. Impairment of the ubiquitin-proteasome pathway caused by this IRF2BPL mutation may play an important role in this neurodevelopmental disorder.

Prevalence of dyslipidemia and prediction of 10-year CVD risk among older adults living in southeast coastal regions in China: a cross-sectional study.

Objective: This study aims to analyze the prevalence of dyslipidemia and identify the cardiovascular disease (CVD) risk stratification among older adults living in Quanzhou, China's southeast coastal region, where the ancient Maritime Silk Road starts. Methods: A population-based cross-sectional survey of 2,018 adults was conducted in 60-98-year-old residents in Quanzhou from September 2016 to March 2018 using multistage stratified cluster random sampling. The 10-year CVD risk was also estimated by applying the Chinese model recommended by the Chinese Guidelines for Prevention of Cardiovascular Diseases. Results: The overall prevalence of dyslipidemia among older adults was 56.8%. The prevalence of high total cholesterol (TC), high low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C) and high triglyceride (TG) were 8.4%, 13.9%, 23.1% and 11.4%, respectively. The mean levels of TC, LDL-C, HDL-C and TG were 5.12±1.18, 3.37±0.81, 1.03±0.27 and 1.65±0.76 mmol/L, respectively. Older adults had low risk, moderate risk and high risk for CVD, which were 49.7%, 36.8% and 13.5%, respectively. Age, body mass index and abdominal obesity were significantly associated with the risk of increasing LDL-C levels and were positively correlated to CVD risk. Conclusion: The prevalence of high TC, high LDL-C, low HDL-C and high TG was relatively low among older adults in Quanzhou, but their lipid levels were high. Approximately half of the elderly adults had moderate or high CVD risk. The personalized primary prevention and control of CVD are recommended for elderly people to identify high-risk individuals.

Late-assembly of human ribosomal protein S20 in the cytoplasm is essential for the functioning of the small subunit ribosome.

Using immuno-fluorescent probing and Western blotting analysis, we reveal the exclusive cytoplasm nature of the small subunit ribosomal protein S20. To illustrate the importance of the cellular compartmentation of S20 to the function of small subunit 40S, we created a nuclear resident S20NLS mutant gene and examined polysome profile of cells that had been transfected with the S20NLS gene. As a result, we observed the formation of recombinant 40S carried S20NLS but this recombinant 40S was never found in the polysome, suggesting such a recombinant 40S was translation incompetent. Moreover, by the tactic of the energy depletion and restoration, we were able to restrain the nuclear-resided S20NLS in the cytoplasm. Yet, along a progressive energy restoration, we observed the presence of recombinant 40S subunits carrying the S20NLS in the polysome. This proves that S20 needs to be cytoplasmic in order to make a functional 40S subunit. Furthermore, it also implies that the assembly order of ribosomal protein in eukaryote is orderly regulated.

Mapping the essential structures of human ribosomal protein L7 for nuclear entry, ribosome assembly and function.

Human large subunit protein L7 carries multiple nuclear localization signals (NLS) in its structure: there are three monobasic partite NLSs at the NH2-region of the first 54 amino acid residues and a bipartite in the middle section at position of 156-167. The C-region of the last 50 amino acid residues displays membrane binding nature, and might involve in forming a nuclear microbody for pre-nucleolar ribosome assembly. The middle section covers 144 amino acid residues which are essential for the structure and function of ribosome. This is evident from findings that truncated L7 without the NH2-region or the C-region, or missing both regions, is capable of reaching nucleolus and incorporating in ribosome, however, only ribosomes bearing truncated L7 without the NH2-region is capable of engaging in polysome formation. Combining with the phylogenic findings from homologous sequence alignment, the NH2-region of L7, besides being as a eukaryotic expansion segment, can be excluded from building a functional eukaryotic ribosome.