Association between sleep duration and metabolic syndrome: a population-based study in China.

INTRODUCTION: The relationship between sleep duration and metabolic syndrome (MetS) remains debatable. In the present study, we analysed the link between total sleep duration (including nighttime sleep and nap duration) and MetS as well as its components among the Chinese population. MATERIAL AND METHODS: This was a cross-sectional study from a prospective population cohort including 8616 participants over 40 years in Guangxi, China, evaluated from April 2011 to January 2012. MetS was diagnosed using modified criteria from the National Cholesterol Education Program's Adult Treatment Panel III. Sleep information was obtained through a standard self-report-based questionnaire. The connection between sleep duration and MetS prevalence as well as its components was evaluated using a logistic regression model. RESULTS: After adjusting for potential confoundings, the longer daily sleep duration (≥ 10 hours) group was observed to have the higher odds of having MetS than the reference group with ≥ 7 and < 8 hours of sleep [odds ratio (OR): 1.25, 95% confidence interval (CI): 1.03-1.52, p = 0.023], as well as the highest odds of having elevated triglycerides (OR: 1.25, 95% CI: 1.03-1.52) and fasting blood glucose (OR: 1.21, 95% CI: 1.01-1.45). Further analysis demonstrated that sleeping > 9 hours per night was correlated to MetS in females (OR: 1.27, 95% CI: 1.02-1.58), while napping ≥ 90 minutes was correlated to MetS (OR: 1.44, 95% CI: 1.11-1.87) in males. CONCLUSION: Both longer nighttime sleep duration and longer naps may be associated with the development of MetS.

Low-frequency whole-body vibration can enhance cartilage degradation with slight changes in subchondral bone in mice with knee osteoarthritis and does not have any morphologic effect on normal joints.

PURPOSES: To evaluate the effects of low frequency whole-body vibration (WBV) on degeneration of articular cartilage and subchondral bone in mice with destabilization of the medial meniscus (DMM)induced osteoarthritis(OA) and mice with normal knee. METHODS: Ten-week-old C57BL/6J male mice received DMM on right knees, while the left knees performed sham operation. There were six groups: DMM, SHAM DMM, DMM+WBV,SHAM DMM+WBV, DMM+ NON-WBV and SHAM DMM+NON-WBV. After four weeks, the knees were harvested from the DMM and SHAM DMM group. The remaining groups were treated with WBV (10 Hz) or NON-WBV. Four weeks later, the knees were harvested. Genes, containing Aggrecan(Acan) and CollagenⅡ(Col2a1), Matrix Metalloproteinases 3 and 13(MMP3,13), TNFα and IL6, were measured and staining was also performed. OA was graded with OARSI scores, and tibial plateaubone volume to tissue volume ratio(BV/TV), bone surface area to bone volume ratio (BS/BV), trabecular number(Tb.N) and trabecular thickness separation(TS) between groups were analyzed. RESULTS: Increased OARSI scores and cartilage degradation were observed after WBV. BV/TV, Tb.N and TS were not significant between the groups. Significant reductions were observed in MMP3, MMP13, Col2a1, Acan, TNFα and IL6 in the DMM+WBV compared to SHAM DMM+WBV group. BV/TV, BS/BV, Tb.N, TS and OARSI scores were not significantly changed in the left knees. IL6 expression in the SHAM DMM+WBV group was significantly increased compared with the SHAM DMM+ NON-WBV group, while Col2a1, Acan and MMP13 expression decreased. CONCLUSION: WBV accelerated cartilage degeneration and caused slight changes in subchondral bone in a DMM-induced OA model. WBV had no morphologic effect on normal joints.

SARS-CoV-2 SUD2 and Nsp5 Conspire to Boost Apoptosis of Respiratory Epithelial Cells via an Augmented Interaction with the G-Quadruplex of BclII.

The molecular mechanisms underlying how SUD2 recruits other proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to exert its G-quadruplex (G4)-dependent pathogenic function is unknown. Herein, Nsp5 was singled out as a binding partner of the SUD2-N+M domains (SUD2core) with high affinity, through the surface located crossing these two domains. Biochemical and fluorescent assays demonstrated that this complex also formed in the nucleus of living host cells. Moreover, the SUD2core-Nsp5 complex displayed significantly enhanced selective binding affinity for the G4 structure in the BclII promoter than did SUD2core alone. This increased stability exhibited by the tertiary complex was rationalized by AlphaFold2 and molecular dynamics analysis. In line with these molecular interactions, downregulation of BclII and subsequent augmented apoptosis of respiratory cells were both observed. These results provide novel information and a new avenue to explore therapeutic strategies targeting SARS-CoV-2. IMPORTANCE SUD2, a unique protein domain closely related to the pathogenesis of SARS-CoV-2, has been reported to bind with the G-quadruplex (G4), a special noncanonical DNA structure endowed with important functions in regulating gene expression. However, the interacting partner of SUD2, among other SARS-CoV-2 Nsps, and the resulting functional consequences remain unknown. Here, a stable complex formed between SUD2 and Nsp5 was fully characterized both in vitro and in host cells. Moreover, this complex had a significantly enhanced binding affinity specifically targeting the Bcl2G4 in the promoter region of the antiapoptotic gene BclII, compared with SUD2 alone. In respiratory epithelial cells, the SUD2-Nsp5 complex promoted BclII-mediated apoptosis in a G4-dependent manner. These results reveal fresh information about matched multicomponent interactions, which can be parlayed to develop new therapeutics for future relevant viral disease.

Structural insight into SSE15206 in complex with tubulin provides a rational design for pyrazolinethioamides as tubulin polymerization inhibitors.

Background: Tubulin protein is a promising target for antitumor drugs. Some tubulin inhibitors targeting the colchicine binding site are not substrates of the multidrug-resistance efflux pump, which can overcome the mechanism of drug resistance mediated by P-glycoprotein. Methodology/results: SSE15206 is a colchicine binding site inhibitor with antiproliferative activity against different drug-resistant cell lines. Unfortunately, the lack of detailed interaction information about SSE15206 in complex with tubulin impeded the development of potent drugs that possess similar scaffolds. Herein, the authors report the crystal structure of the tubulin-SSE15206 complex at a resolution of 2.8 Å. Conclusion: The complex structure reveals the intermolecular interactions between SSE15206 and tubulin, providing a rationale for the development of pyrazolinethioamides as tubulin polymerization inhibitors and to overcome multidrug resistance.

The synthesis and bioactivity of pyrrolo[2,3-d]pyrimidine derivatives as tyrosine kinase inhibitors for NSCLC cells with EGFR mutations.

EGFR mutations are an ongoing challenge in the treatment of NSCLC, and demand continuous updating of EGFR TKI drug candidates. Pyrrolopyrimidines are one group of versatile scaffolds suitable for tailored drug development. However not many precedents of this type of pharmacophore have been investigated in the realm of third generation of covalent EGFR-TKIs. Herein, a series of pyrrolo[2,3-d]pyrimidine derivatives able to block mutant EGFR activity in a covalent manner were synthesized, through optimized Buchwald-Hartwig C-N cross coupling reactions. Their preliminary bioactivity and corresponding inhibitory mechanistic pathways were investigated at molecular and cellular levels. Several compounds exhibited increased biological activity and enhanced selectivity compared to the control compound. Notably, compound 12i selectively inhibits HCC827 cells harboring the EGFR activating mutation with up to 493-fold increased efficacy compared to in normal HBE cells. Augmented selectivity was also confirmed by kinase enzymatic assay, with the test compound selectively inhibiting the T790 M activating mutant EGFRs (IC50 values of 0.21 nM) with up to 104-fold potency compared to the wild-type EGFR (IC50 values of 22 nM). Theoretical simulations provide structural evidence of selective kinase inhibitory activity. Thus, this series of pyrrolo[2,3-d]pyrimidine derivatives could serve as a starting point for the development of new EGFR-TKIs.

Guanosine and uridine alleviate airway inflammation via inhibition of the MAPK and NF-κB signals in OVA-induced asthmatic mice.

Asthma is one of the most common respiratory diseases. Lack of response or poor adherence to corticosteroids demands the development of new drug candidates for asthma. Endogenous nucleosides could be potential options since uridine has been reported to have an anti-inflammatory effect in asthma model. However, its molecular pathways and whether other nucleosides have similar therapeutic effects remain untouched. Thus, we herein report our investigation into the anti-inflammatory effects of guanosine and uridine, and the related inner signaling pathways in asthma model. Present study shows that administration of guanosine or uridine can reduce lung inflammation in OVA-challenged mice. Total cell counts in BALF, cytokines such as IL-4, IL-6, IL-13, OVA-specific IgE and mRNA level of Cxcl1, Cxlc3, IL-17 and Muc5ac were decreased in asthmatic mice after treatment. Besides, the production of IL-6 in LPS/IFN-γ induced THP-1 cells was also decreased by both nucleosides. In vivo and in vitro expressions of key molecules in the MAPK and NF-κB pathways were reduced after the treatment of both compounds. These findings suggest that guanosine has a similar potential therapeutic value in asthma as uridine and they exert anti-inflammatory effects through suppression of the MAPK and NF-κB pathways.

Low-Frequency Vibration Promotes Tumor Necrosis Factor-α Production to Increase Cartilage Degeneration in Knee Osteoarthritis.

OBJECTIVE: Low-frequency vibration accelerates cartilage degeneration in knee osteoarthritis (KOA) rat model. In this article, we investigated whether whole-body vibration (WBV) increases cartilage degeneration by regulating tumor necrosis factor-α (TNF-α) in KOA. DESIGN: Proteomics analysis was used to filter candidate protein from synovial fluid (SF) in KOA people after WBV. Enzyme-linked immunosorbent assay (ELISA) was used to estimate changes in TNF-α levels in SF. The C57 mice and TNF-α knock-out mice were sacrificed for the KOA model and WBV intervention. The cartilage was tested by ELISA, histology, terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL), immunohistochemistry, and reverse transcriptase polymerase chain reaction. Luciferase activity test in vitro study was conducted to confirm the relationship between TNF-α and the candidate protein. RESULTS: Differentially expressed proteins were enriched in the glycolytic process, glucose catabolic, and regulation of interleukin-8 (IL-8) secretion processes. Phosphoglycerate kinase, triosephosphate isomerase 1, T cell immunoglobulin- and mucin-domain-containing molecules 2, fumarylacetoacetate hydrolase (FAH), and TNF were the hub node. TNF-α expression increased in SF after WBV (P < 0.05). The cartilage was more degenerated in the TNF-α-/- mice group compared to controls. A significant change was observed in collagen II and FAH (P < 0.05). TNF-α expression improved in C57 mice (P < 0.05). Apoptosis of chondrocytes was inhibited in TNF-α-/- mice by the TUNEL test. Luciferase activity significantly increased in TNF-α + FAH-Luc cells (P < 0.05). CONCLUSION: A novel mechanism underlying WBV-triggered cartilage degeneration was found in KOA that demonstrated the critical regulatory function of TNF-α and FAH during WBV.

Acyclic Janus-AT Nucleoside Host Channels Precisely Lock Water into Single-File Wires with Local Rotational Flexibility.

Confining polar water molecules to particular geometries demands sophisticated intermolecular interactions, and not many small synthetic molecules have accomplished such a task. Herein, regioisomeric acyclic Janus-AT nucleosides (1 and 2), with a self-complementary fused genetic alphabet and conformationally flexible side chains, have been selectively synthesized. 1 and 2 adopt disparate base-pair motifs from the π-π stacked hydrophobic base moieties and distinct hydrogen bond (HB) interconnections from the hydrophilic sugar residues, which in turn lead to divergent, intricate intermolecular interaction networks with different capacities to confine water molecules. Under the precise control of the host framework of the N8 -regioisomer, separate ordered single-file water wires can be locked through special three-HB clamps into unique inter- and intra-wire geometrical alignments. Localized dynamic synchronized rotations within the fixed framework coordinated by both the host hydroxy groups and guest water molecules were observed in a temperature-induced reversible single-crystal-to-single-crystal transition (SCSCT).

Supermacrocyclic Assemblies by Hydrogen-Bond Codes of C7-Phenol Pyrazolo and Pyrrolo Derivatives of Adenine.

Hydrogen bond (HB) mediated base pair motifs are versatile scaffolds of diverse supramolecular constructs. Here, we report that two new four- and six-membered supermacrocyclic assemblies with intriguing geometries could self-assemble from two new adenine derivatives, APN (1) and APC (2). The conversion of a conventional HB acceptor, N8 of 1, to a non-conventional HB donor, C8-H of 2, had a pronounced impact on the overall intricate HB network and self-assembly patterns, epitomizing the subtleties in design and exploitation of such base-pair motifs as promising tectons for building supramolecular architectures.

[Cloning and sequence analysis of the DHBV genome of the brown ducks in Guilin region and establishment of the quantitative method for detecting DHBV].

Brown ducks carrying DHBV were widely used as hepatitis B animal model in the research of the activity and toxicity of anti-HBV dugs. Studies showed that the ratio of DHBV carriers in the brown ducks in Guilin region was relatively high. Nevertheless, the characters of the DHBV genome of Guilin brown duck remain unknown. Here we report the cloning of the genome of Guilin brown duck DHBV and the sequence analysis of the genome. The full length of the DHBV genome of Guilin brown duck was 3 027bp. Analysis using ORF finder found that there was an ORF for an unknown peptide other than S-ORF, PORF and C-ORF in the genome of the DHBV. Vector NTI 8. 0 analysis revealed that the unknown peptide contained a motif which binded to HLA * 0201. Aligning with the DHBV sequences from different countries and regions indicated that there were no obvious differences of regional distribution among the sequences. A fluorescence quantitative PCR for detecting DHBV was establishment based on the recombinant plasmid pGEM-DHBV-S constructed. This study laid the groundwork for using Guilin brown duck as a hepatitis B animal model.