{\pi}-{\pi} Interaction-facilitated formation of interwoven trimeric cage-catenanes with topological chirality

Catenanes as interlocked molecules with a nonplanar graph have gained increasing attention for their unique features such as topological chirality. To date, the majority of research in this field has been focusing on catenanes comprising monocyclic rings. Due to the lack of rational synthetic strategy, catenanes of cage-like monomers are hardly accessible. Here we report on the construction of an interwoven trimeric catenane that is composed of achiral organic cages, which exhibits topological chirality. Our rational design begins with a pure mathematical analysis, revealing that the formation probability of the interwoven trimeric catenane surpasses that of its chain-like analogue by 20%; while driven by efficient template effect provided by strong {\pi}-{\pi} stacking of aromatic panels, the interwoven structure emerges as the dominant species, almost ruling out the formation of the chain-like isomer. Its topological chirality is unambiguously unravelled by chiral-HPLC, CD spectroscopy and X-ray diffraction. Our probability analysis-aided rational design strategy would pave a new venue for the efficient synthesis of topologically sophisticated structures in one pot

Calreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a chronic intestinal inflammatory condition initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Calreticulin (CRT), a calcium-binding chaperone, is known as a partner in the activation of integrin α subunits (ITGAs). The relationship between their interaction and the pathogenesis of IBD is largely unknown. Here we show that a small molecule, orally active ER-464195-01, inhibits the CRT binding to ITGAs, which suppresses the adhesiveness of both T cells and neutrophils. Transcriptome analysis on colon samples from dextran sodium sulfate-induced colitis mice reveals that the increased expression of pro-inflammatory genes is downregulated by ER-464195-01. Its prophylactic and therapeutic administration to IBD mouse models ameliorates the severity of their diseases. We propose that leukocytes infiltration via the binding of CRT to ITGAs is necessary for the onset and development of the colitis and the inhibition of this interaction may be a novel therapeutic strategy for the treatment of IBD

Chronic obstructive pulmonary disease severity in middle-aged and older men with osteoporosis associates with decreased bone formation

Objectives: Chronic obstructive pulmonary disease (COPD) is a risk factor for osteoporosis. Nevertheless, much remains unclear regarding the bone metabolism dynamics associated with COPD. The present study focuses on the associations between the COPD severity and serum bone metabolism biomarkers. Methods: We enrolled 40 patients who visited the orthopedics departments at our institutions and underwent dual-energy X-ray absorptiometry between September 2015 and December 2017. Only male osteoporosis patients over 45 years of age were included, and 5 patients were excluded due to disease or use of internal medicines affecting bone metabolism. All subjects underwent lung function testing, spine radiography, and blood tests. We measured percent forced expiratory volume in 1 second (%FEV1), which reflects COPD severity, and we examined the relationships between %FEV1 and serum levels of bone metabolism biomarkers. Results: All subjects were diagnosed with osteoporosis based on T-scores. %FEV1 correlated with body weight, body mass index (BMI), and Z-score/T-scores. %FEV1 moderately correlated with serum levels of alkaline phosphatase (ALP), procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase 5b in the partial correlation analysis adjusted for BMI or T-score in the lumbar vertebrae. We performed a hierarchical multiple regression analysis to identify that serum ALP and P1NP were the independent explanatory variables to %FEV1 independent of other factors. Conclusions: The data suggest that the COPD severity in middle-aged and older men with osteoporosis associates with decreased bone formation. COPD patients may exhibit bone metabolism dynamics characterized by low bone turnover with osteogenesis dysfunction as COPD becomes severe

A Donor–Acceptor Cage for Thermally Activated Delayed Fluorescence: toward a New Kind of TADF Exciplex Emitters

We present the rational design of an organic cage combining an electron-donating (D) triazatruxene and electron-accepting (A) triphenyl triazine connected by three electronically inert pillars. This controlled architecture leads to a precise spatial separation and cofacial alignment of the D and A motifs. Such an architecture induces an efficient intramolecular through-space charge transfer (TSCT), providing a small singlet–triplet energy difference (ΔEST) of 0.049 eV, and thus gives rise to a thermally activated delayed fluorescence (TADF) macrocyclic exciplex emitter