Nuclear Acly protects the liver from ischemia-reperfusion injury.

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion (IR) injury is the most common complication that occurs in liver surgery and hemorrhagic shock. ATP citrate lyase (Acly) plays a pivotal role in chromatin modification via generating acetyl-CoA for histone acetylation to influence biological processes. We aim to examine the roles of Acly, which is highly expressed in hepatocytes, in liver IR injury. APPROACH AND RESULTS: The functions of Acly in hepatic IR injury were examined in the mouse model with a hepatocyte-specific knockout of Acly . The Acly target genes were analyzed by CUT&RUN assay and RNA sequencing. The relationship between the susceptibility of the steatotic liver to IR and Acly was determined by the gain of function studies in mice. Hepatic deficiency of Acly exacerbated liver IR injury. IR induced Acly nuclear translocation in hepatocytes, which spatially fueled nuclear acetyl-CoA. This alteration was associated with enhanced acetylation of H3K9 and subsequent activation of the Foxa2 signaling pathway. Nuclear localization of Acly enabled Foxa2-mediated protective effects after hypoxia-reperfusion in cultured hepatocytes, while cytosolic Acly demonstrated no effect. The presence of steatosis disrupted Acly nuclear translocation. In the steatotic liver, restoration of Acly nuclear localization through overexpression of Rspondin-1 or Rspondin-3 ameliorated the IR-induced injury. CONCLUSIONS: Our results indicate that Acly regulates histone modification by means of nuclear AcCoA production in hepatic IR. Disruption of Acly nuclear translocation increases the vulnerability of the steatotic liver to IR. Nuclear Acly thus may serve as a potential therapeutic target for future interventions in hepatic IR injury, particularly in the context of steatosis.

Enhancing Iodine Capture of Porous Organic Cages through N-Heteroatom Engineering.

Iodine radioisotopes, produced or released during nuclear-related activities, severely affect human health and the environment. The efficient removal of radioiodine from both aqueous and vapor phases is crucial for the sustainable development of nuclear energy. In this study, we propose an "N-heteroatom engineering" strategy to design three porous organic cages with N-containing functional groups for efficient iodine capture. Among the molecular cages investigated, FT-Cage incorporating tertiary amine groups and RT-Cage with secondary amine groups show higher adsorption capacity and much faster iodine release compared to IT-Cage with imine groups. Detailed investigations demonstrate the superiority of amine groups, along with the influence of crystal structures and porosity, for iodine capture. These findings provide valuable insights for the design of porous organic cages with enhanced capabilities for capturing iodine.

Can depression lead to chronic constipation, or does chronic constipation worsen depression? NHANES 2005-2010 and bidirectional mendelian randomization analyses.

BACKGROUND: Depression and chronic constipation often co-occur, but the reciprocal influence between the two remains unclear. The purpose of this study is to explore the potential association between depression and chronic constipation. METHODS: This study initially utilized data from National Health and Nutrition Examination Survey (NHANES) 2005-2010 to explore the correlation between depression scores and chronic constipation, assessing the non-linear relationship between the two. Subsequently, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal relationship between depression and major depression with chronic constipation. The Inverse Variance Weighting (IVW) method served as the primary reference, supplemented by sensitivity tests. Finally, a reverse MR analysis was performed to assess the presence of any reverse causation. The STROBE-MR checklist for the reporting of MR studies was used in this study. RESULTS: In the NHANES analysis, survey-weighted logistic regression revealed a significantly positive correlation between depression scores and chronic constipation (OR = 1.04, 95% CI = 1.02-1.07, p = 0.002), even after adjusting for the included covariates. The nonlinear analysis using Restricted Cubic Splines (RCS) enhanced the robustness of the association (P-non-liner = 0.01). The MR analysis also confirmed the causal relationship between depression (OR = 11.43, 95% CI = 1.85-70.67, p = 0.008) and major depression (OR = 1.12, 95% CI = 1.03-1.22, p = 0.007) with chronic constipation, passing rigorous sensitivity tests. No evidence of reverse causation was observed in the reverse MR analysis (P > 0.05). CONCLUSIONS: Depression is positively correlated with the risk of chronic constipation. Therefore, enhancing attention to chronic constipation in patients with depression may be effective in clinical practice.

Effect of positive psychological intervention on the treatment and prognosis of patients with acute cerebral infarction.

Objective: To analyze the psychological status of patients with acute cerebral infarction (ACI), and to evaluate the effect of positive psychological intervention on the treatment and prognosis of ACI. Methods: This was retrospective study. Eighty patients with ACI admitted to Institute of Psychology, Chinese Academy of Sciences from January 2021 to September 2022 were included and randomly divided into observation group (n=40) and control group(n=40). Patients in the control group received conventional treatment and routine care, while those in the observation group received positive psychological intervention based on the control group. Adverse psychological scores, treatment and prognosis, and quality of life as well as nursing satisfaction etc. were analyzed and compared between the two groups. Results: Both groups showed a significant decrease in SDS and SAS scores at three months after the intervention compared with the pre-intervention period, with a statistically significant difference(P<0.05). After the intervention, the NIHSS score of both groups decreased, with a statistically significant difference(P<0.05). The FMAS and MBI scores increased in both groups compared with those before the intervention, with a statistically significant difference(P<0.05). The SS-QOL scores of both groups were significantly improved compared with before the intervention, with a statistically significant difference(P<0.05). The hospital satisfaction rate in the observation group was significantly higher than that in the control group, with a statistically significant difference (t=12.325, P=0.000). Conclusion: Positive psychological intervention offers a variety of benefits in the treatment of patients with ACI, such as may alleviate anxiety and depression, reduce neurological deficits, improving quality of life and motor function, and ameliorate the prognosis of patients.

Chiral Molecular Cage with Tunable Stereoinversion Barriers.

The manipulation of chirality in molecular entities that rapidly interconvert between enantiomeric forms is challenging, particularly at the supramolecular level. Advances in controlling such dynamic stereochemical systems offer opportunities to understand chiral symmetry breaking and homochirality. Herein, we report the synthesis of a face-rotating tetrahedron (FRT), an organic molecular cage composed of tridurylborane facial units that undergo stereomutations between enantiomeric trefoil propeller-like conformations. After resolution, we show that the racemization barrier of the enantiopure FRT can be regulated in situ through the reversible binding of fluoride anions onto the tridurylborane moieties. Furthermore, the addition of an enantiopure phenylethanol to the FRT can effectively induce chirality of the molecular cage by preferentially binding to one of its enantiomeric conformers. This study presents a new paradigm for controlling dynamic chirality in supramolecular systems, which may have implications for asymmetric synthesis and dynamic stereochemistry.

Inhibition of AGEs-RAGE-PP2A Axis Alleviates Cognitive Impairment after Chronic Heart Failure.

To investigate the effect of the AGEs-RAGE-PP2A axis on cognitive impairment (CI) after chronic heart failure (CHF). Mice were divided into six groups: Sham, TAC, Sham+RAGE-/-, TAC+RAGE-/-, AG, and FTY720 group. AG mice and FTY720 mice were treated with AGEs inhibitor (aminoguanidine, AG) and PP2A activator (FTY720) respectively after TAC surgery. The cardiac function of AG and TAC+RAGE-/- mice was significantly better than that of TAC mice (P<0.05). However, the heart function of FTY720 mice were just improved a part of that. To behavioral function, the escape latency period of the TAC+RAGE-/-, AG and FTY720 mice were significantly shorter (P<0.05), and the times of platform crossings and residence time of them were significantly improved (P<0.05). HE staining and silver staining show the structure of TAC+RAGE-/-, AG and FTY720 mice were more complete. Also, in these three groups, the expression of Aß and p-tau protein in the brain can be significantly down-regulated (P<0.05) and the PP2A protein expression level was up-regulated (P<0.05). And the expression of hippocampal Bax, Cyt-C, and Caspase-3 of that were all down-regulated (P<0.05), and Bcl-2 was up-regulated (P<0.05). Deficient of AGEs, RAGE and activating PP2A can significantly attenuate the cognitive impairment in CHF mice, and protect the brain structure. This mechanism seems via reducing the expression of Aß, p-tau, and apoptotic protein.

Genome mosaic structure of two novel HIV-1 recombinant forms (CRF01_AE/B) in men who have sex with men in Hebei, China.

BACKGROUND: Homosexual contact is the main route of human immunodeficiency virus type one (HIV-1) transmission in Cangzhou Prefecture, Hebei, China. Moreover, the number of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) in this key population is ever increasing. METHODS: In this study, we identified two novel URFs (hcz0017 and hcz0045) from two men who have sex with men (MSM) based in Cangzhou Prefecture. Phylogenetic and recombinant breakpoint analyses, based on the near full-length genomes (NFLGs) of the two novel URFs, showed that they originated from a recombination between HIV-1 CRF01_AE and subtype B. RESULTS: HXB2 numbering revealed that the NFLGs of hcz0017 and hcz0045 each contained the following seven subregions: hcz0017: IB (790-1,171 nt), IICRF01_AE (1,172-2,022 nt), IIIB (2,023-4,469 nt), IVCRF01_AE (4,470-5,866 nt), VB (5,867-7,462 nt), VICRF01_AE (7,463-8,379 nt), VIIB (8,380-9,411 nt); hcz0045: ICRF01_AE (790-5,147 nt), IIB (5,148-5,614 nt), IIICRF01_AE (5,615-6,035 nt), IVB (6,036-6,241 nt), VCRF01_AE (6,242-7,325nt), VIB (7,326-8,254 nt), VIICRF01_AE (8,255-9,411 nt). Moreover, the two MSM from whom the novel URFs originated from were diagnosed as recently HIV-1-infected, suggesting that the high prevalence of HIV-1 among MSM was related to high-risk sexual activity such as unprotected anal sex and multiple sexual partners. CONCLUSIONS: Our results highlight the need to continually monitor HIV-1 diversity in Hebei and its neighboring provinces to achieve a more effective control of HIV-1 spread within the MSM community.

The prognostic impact of mild and severe immune-related adverse events in non-small cell lung cancer treated with immune checkpoint inhibitors: a multicenter retrospective study.

Patients treated with immune checkpoint inhibitors (ICIs) often experience unique immune-related adverse events (irAEs), and the previous studies demonstrated an association between irAEs and better outcomes in patients with ICI treatment for advanced non-small cell lung cancer (NSCLC). However, the correlation between the occurrence of mild and severe irAEs and prognosis remains unclear. Additionally, little is known regarding the association between the timing of mild and severe irAEs and clinical outcomes. We retrospectively conducted a multicenter study of advanced NSCLC patients treated with ICI monotherapy. Of the 222 patients, 79 patients (35.6%) experienced at least one irAE, and most were of grade 1 or 2 (mild) (26.6%). The most common irAEs were pneumonitis (n = 21, 9.5%) and skin-related adverse reactions (n = 19, 8.6%). The median progression-free survival of all patients treated with ICIs was 3.2 months. Patients experiencing irAEs had a better prognosis than those without such events (6.5 vs. 2.6 months, p = 0.004), and mild irAEs were associated with the best prognosis. The difference in overall survival between mild and severe irAEs was significant (34.3 vs. 17.3 months, p = 0.021). We further analyzed differences between patients with irAEs occurring at 3 or 6 weeks, and found that the earlier the occurrence of mild irAEs, the better the prognosis; however, the opposite was true for severe irAEs. In summary, patients with early occurring mild irAEs showed better clinical outcomes, whereas those with early severe irAEs tended to show poorer clinical outcomes.

Efficacy and safety of triplet chemotherapy plus anti-EGFR agents in metastatic colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: To date, the optimal treatment for potentially resectable metastatic colorectal cancer (mCRC) patients has yet to be determined. Encouraging results have been reported in studies exploring the efficacy of triplet chemotherapy plus anti-epidermal growth factor receptor (anti-EGFR) target agents. Thus, we conducted a meta-analysis to evaluate the efficacy and safety of triplet chemotherapy plus anti-EGFR target agents. METHODS: We systematically searched the PubMed, Embase, and Web of Science databases from December 2004 to October 2021 for studies examining the efficacy of triplet chemotherapy plus anti-EGFR target agents in mCRC patients. The primary outcomes were the objective response rate (ORR) and R0 resection rate (R0RR), and the secondary outcomes were median progression-free survival (mPFS), median overall survival (mOS), and toxicity. Data were analyzed with R software 4.1.2. RESULTS: Fourteen studies comprising 762 patients with mCRC were included in this meta-analysis. Analysis with a random effects model revealed that after treatment with triplet chemotherapy plus anti-EGFR target agents, the pooled ORR was 82% (95% CI= 76-88%, I2= 76%), and the pooled R0RR of colorectal liver metastasis (CLM) was 59% (95% CI= 49-68%, I2= 60%). The mPFS ranged from 9.5 to 17.8 months, and the mOS ranged from 24.7 to 62.5 months. A total of 648 grade 3 or 4 adverse events were reported; the most commonly reported events were diarrhea (174/648), neutropenia (157/648), and skin toxicity (95/648), which had pooled prevalence rates of 29% (95% CI= 20-39%, I2= 84%), 28% (95% CI= 20-37%, I2= 77%), and 17% (95% CI= 11-24%, I2= 66%), respectively. CONCLUSIONS: Triplet chemotherapy plus anti-EGFR agents therapy seems to be capable of increasing the ORR of mCRC patients and the R0RR of CLM patients. The toxicity of this treatment is manageable. High-quality randomized controlled trial (RCT) studies are required for further validation.

Anti-inflammatory Polyketides from the Marine-Derived Fungus Eutypella scoparia.

Three new polyketides, eutyketides A and B (1 and 2) and cytosporin X (3), along with four known compounds (4-7), were obtained from the marine-derived fungus Eutypella scoparia. The planar structures of 1 and 2 were elucidated by extensive HRMS and 1D and 2D NMR analyses. Their relative configurations of C-13 and C-14 were determined with chemical conversions by introducing an acetonylidene group. The absolute configurations of 1-3 were determined by comparing their experimental electronic circular dichroism (ECD) data with their computed ECD results. All of the isolated compounds were tested for their anti-inflammatory activities on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages. Compounds 5 and 6 showed stronger anti-inflammatory activities than the other compounds, with the inhibition of 49.0% and 54.9% at a concentration of 50.0 µg/mL, respectively.

Effect of self-control on health promotion behavior in patients with coronary heart disease: mediating effect of ego-depletion.

The present study used a cross-sectional survey design to explore the role of ego-depletion in the relationship between self-control and health-promoting behaviors in patients with coronary heart disease (CHD). This study recruited 277 patients with CHD to measure the levels of ego-depletion, self-control and health-promotion (HP) behavior using Self-Regulatory Fatigue Scale (SRF-s), Dual-Mode of Self-Control Scale (DMSD-s) and Health Promotion Lifestyle Profile-II (HPLP-II) to examine the relationship between the three. Study found that self-control improved the patients' HP behaviors to some extent. Self-control in patients with CHD uses ego-depletion as the mediating variable to indirectly and positively predict the level of HP behavior, and the mediating effects account for 47.76% (impulsive system) and 15.6% (control system) of the total effects, respectively.

Structure Revision and Protein Tyrosine Phosphatase Inhibitory Activity of Drazepinone.

From the marine-derived fungus Penicillium sumatrense (Trichocomaceae), a pair of enantiomers [(+)-1 and (-)-1] were isolated with identical 1D NMR data to drazepinone, which was originally reported to have a trisubstituted naphthofuroazepinone skeleton. In this study, we confirmed the structures of the two enantiomers as drazepinone and revised their structures by detailed analysis of extensive 2D NMR data and a comparison of the calculated 13C chemical shifts, ECD, VCD, and ORD spectra with those of the experiment ones. (+)-1 and (-)-1 were evaluated for their PTP inhibitory activity in vitro. (-)-1 showed selective PTP inhibitory activity against PTP1B and TCPTP with IC50 values of 1.56 and 12.5 µg/mL, respectively.

Chemical suppression of specific C-C chemokine signaling pathways enhances cardiac reprogramming.

Reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a potentially promising strategy for regenerating a damaged heart. However, low fibroblast-cardiomyocyte conversion rates remain a major challenge in this reprogramming. To this end, here we conducted a chemical screen and identified four agents, insulin-like growth factor-1, Mll1 inhibitor MM589, transforming growth factor-ß inhibitor A83-01, and Bmi1 inhibitor PTC-209, termed IMAP, which coordinately enhanced reprogramming efficiency. Using α-muscle heavy chain-GFP-tagged mouse embryo fibroblasts as a starting cell type, we observed that the IMAP treatment increases iCM formation 6-fold. IMAP stimulated higher cardiac troponin T and α-actinin expression and increased sarcomere formation, coinciding with up-regulated expression of many cardiac genes and down-regulated fibroblast gene expression. Furthermore, IMAP promoted higher spontaneous beating and calcium transient activities of iCMs derived from neonatal cardiac fibroblasts. Intriguingly, we also observed that the IMAP treatment repressed many genes involved in immune responses, particularly those in specific C-C chemokine signaling pathways. We therefore investigated the roles of C-C motif chemokine ligand 3 (CCL3), CCL6, and CCL17 in cardiac reprogramming and observed that they inhibited iCM formation, whereas inhibitors of C-C motif chemokine receptor 1 (CCR1), CCR4, and CCR5 had the opposite effect. These results indicated that the IMAP treatment directly suppresses specific C-C chemokine signaling pathways and thereby enhances cardiac reprogramming. In conclusion, a combination of four chemicals, named here IMAP, suppresses specific C-C chemokine signaling pathways and facilitates Mef2c/Gata4/Tbx5 (MGT)-induced cardiac reprogramming, providing a potential means for iCM formation in clinical applications.

Truncated Face-Rotating Polyhedra Constructed from Pentagonal Pentaphenylpyrrole through Graph Theory.

Discovering novel families of molecular polyhedra through graph theory has attracted increasing interest. Nevertheless, the design principles of molecular polyhedra based on graph theory remain elusive, especially for those containing five-node units. Herein, we construct a series of chiral truncated face-rotating polyhedra (T-FRP) from pentagonal pentaphenylpyrrole (PPP) derivatives and chiral diamines. Graph theory is used to elucidate the geometry of these novel T-FRP, which represent a new family of molecular polyhedra. The phenyl flipping of PPP faces in these T-FRP is significantly restricted, thus making T-FRP chiral and strongly emissive in solution. In addition, T-FRP also generate circularly polarized luminescence. This study provides new insights into the rational design of novel molecular polyhedra through graph theory.

Nano magnetic liposomes-encapsulated parthenolide and glucose oxidase for ultra-efficient synergistic antitumor therapy.

Multifunctional nanoplatforms yield extremely high synergistic therapeutic effects on the basis of low biological toxicity. Based on the unique tumor microenvironment (TME), a liposomes (Lips)-based multifunctional antitumor drug delivery system known as GOD-PTL-Lips@MNPs was synthesized for chemotherapy, chemodynamic therapy (CDT), starvation therapy, and magnetic targeting synergistic therapy. Evidence has suggested that parthenolide (PTL) can induce apoptosis and consume excessive glutathione (GSH), thereby increasing the efficacy of chemodynamic therapy. On the other hand, glucose oxidase (GOD) can consume intratumoral glucose, lower pH and increase the level of H2O2 in the tumor tissue. Integrated Fe3O4 magnetic nanoparticles (MNPs) containing Fe2+ and Fe3+ effectively catalyzes H2O2 to a highly toxic hydroxyl radical (•OH) and provide magnetic targeting. During the course of in vitro and in vivo experiments, GOD-PTL-Lips@MNPs demonstrated remarkable synergistic antitumor efficacy. In particular, in mice receiving a 14 day treatment of GOD-PTL-Lips@MNPs, tumor growth was significantly inhibited, as compared with the control group. Moreover, toxicology study and histological examination demonstrated low biotoxicity of this novel therapeutic approach. In summary, our data suggests great antitumor potential for GOD-PTL-Lips@MNPs which could provide an alternative means of further improving the efficacy of anticancer therapies.

Surfactin and fengycin B extracted from Bacillus pumilus W-7 provide protection against potato late blight via distinct and synergistic mechanisms.

Potato late blight caused by Phytophthora infestans is one of the most serious plant diseases worldwide. Cyclic lipopeptides (CLPs) extracted from Bacillus strains exhibit a promising effect in the biocontrol of a variety of phytopathogens. However, the specific inhibitory effects and underlying mechanisms of CLPs against P. infestans are poorly understood. In this study, we showed that Bacillus pumilus W-7 can inhibit the growth of P. infestans mycelium. Two metabolites from W-7, surfactin and fengycin B, were identified using MS/MS. Fengycin B inhibited mycelium growth by inducing mycelium deformations, oxidative damage, and mitochondrial dysfunction. Surfactin induced potato plant defense responses by increasing the expression of the biocontrol genes (pod, pal, and cat) and their enzyme activities (POD, PAL, and CAT). Also, surfactin and fengycin B could exhibit a synergistic inhibitory effect on P. infestans. Taken together, our findings indicate that B. pumilus W-7 and its CLPs are potential environmentally friendly and effective biocontrol agents for the preservation of potato crops. KEY POINTS: • Lipopeptides of surfactin and fengycin B are extracted from Bacillus pumilus W-7. • Fengycin B inhibits Phytophthora infestans mycelium growth in a direct manner. • Surfactin induces potato plant defense responses to control late blight.

Absolute Configurations and Chitinase Inhibitions of Quinazoline-Containing Diketopiperazines from the Marine-Derived Fungus Penicillium polonicum.

Three new quinazoline-containing diketopiperazines, polonimides A-C (1-3), along with four analogues (4-7), were obtained from the marine-derived fungus Penicillium polonicum. Among them, 2 and 4, 3 and 5 were epimers, respectively, resulting the difficulty in the determination of their configurations. The configurations of 1-3 were determined by 1D nuclear overhauser effect (NOE), Marfey and electron circular dichroism (ECD) methods. Nuclear magnetic resonance (NMR) calculation with the combination of DP4plus probability method was used to distinguish the absolute configurations of C-3 in 3 and 5. All of 1-7 were tested for their chitinase inhibitory activity against OfHex1 and OfChi-h and cytotoxicity against A549, HGC-27 and UMUC-3 cell lines. Compounds 1-7 exhibited weak activity towards OfHex1 and strong activity towards OfChi-h at a concentration of 10.0 µM, with the inhibition rates of 0.7%-10.3% and 79.1%-95.4%, respectively. Interestingly, 1-7 showed low cytotoxicity against A549, HGC-27 and UMUC-3 cell lines, suggesting that good prospect of this cluster of metabolites for drug discovery.

Selective Loading of Atomic Platinum on a RuCeOx Support Enables Stable Hydrogen Evolution at High Current Densities.

High-performance electrocatalysts for the hydrogen evolution reaction (HER) have an important role to play in the development of renewable energy. Platinum remains the most efficient known HER electrocatalyst. Therefore, it is necessary to find ways to maximize Pt utilization in actual practical applications. Herein we demonstrate a facile strategy for synthesizing RuCeOx -supported, selectively loaded, atomic Pt (0.49 wt. %) (denoted Pt/RuCeOx -PA) by photoactivation at ambient temperature and pressure. Through the photoelectron transfer at the Mott-Schottky heterojunction in RuCeOx , Pt atoms became embedded into the RuO2 lattice. The resulting selectively loaded Pt-O-Ru moieties in Pt/RuCeOx -PA give a stronger hydrogen spillover effect than Pt complexes randomly loaded by either chemical activation or thermal activation. As a result, Pt/RuCeOx -PA shows superior HER performance to the materials prepared by random loading and is even better than a commercial Pt/C catalyst with much higher Pt loading (20 wt. %) at high current densities (from 50-600 mA cm-2 ).

Promoting therapeutic angiogenesis of focal cerebral ischemia using thrombospondin-4 (TSP4) gene-modified bone marrow stromal cells (BMSCs) in a rat model.

BACKGROUND: A stroke caused by angiostenosis always has a poor prognosis. Bone marrow stromal cells (BMSC) are widely applied in vascular regeneration. Recently, thrombospondin-4 (TSP4) was reported to promote the regeneration of blood vessels and enhance the function of endothelial cells in angiogenesis. In this work, we observed the therapeutic effect of TSP4-overexpressing BMSCs on angiogenesis post-stroke. METHODS: We subcloned the tsp4 gene into a lentivirus expression vector system and harvested the tsp4 lentivirus using 293FT cells. Primary BMSCs were then successfully infected by the tsp4 virus, and overexpression of GFP-fused TSP4 was confirmed by both western blot and immunofluorescence. In vitro, TSP4-overexpressing BMSCs and wild-type BMSCs were co-cultured with human umbilical vein endothelial cells (HUVECs). The expression level of TSP4, vascular endothelial growth factor (VEGF) and transforming growth factor-ß (TGF-ß) in the supernatant were detected by enzyme-linked immunosorbent assay (ELISA). Wound healing, tube formation and an arterial ring test were performed to estimate the ability of TSP4-overexpressing BMSCs to promote the angiogenesis of endothelial cells. Using a rat permanent middle cerebral artery occlusion (MCAO) model, the effect of TSP4-overexpressing BMSCs on the regeneration of blood vessels was systematically tested by the neurological function score, immunohistochemistry and immunofluorescence staining assays. RESULTS: Our results demonstrated that TSP4-overexpressing BMSCs largely increased the expression of VEGF, angiopoietin-1 (Ang-1), matrix metalloprotein 9 (MMP9), matrix metalloprotein 2 (MMP2) and p-Cdc42/Rac1 in endothelial cells. TSP4-BMSC treatment notably up-regulated the TGF-ß/Smad2/3 signalling pathway in HUVECs. In vivo, the TSP4-BMSC infusion improved the neurological function score of MCAO rats and expanded the expression of the von Willebrand factor (vWF), Ang-1, MMP2 and MMP9 proteins in cerebral ischemic penumbra. CONCLUSIONS: Our data illustrate that TSP4-BMSCs can promote the proliferation and migration of endothelial cells and tube formation. We found that TSP4-BMSC infusion can promote the recovery of neural function post-stroke. The tsp4 gene-modified BMSCs provides a better therapeutic effect than that of wild-type BMSCs.

Stable Diindeno-Fused Corannulene Regioisomers with Open-Shell Singlet Ground States and Large Diradical Characters.

The synthesis of open-shell polycyclic hydrocarbons with large diradical characters is challenging because of their high reactivities. Herein, two diindeno-fused corannulene regioisomers DIC-1 and DIC-2, curved fragments of fullerene C104 , were synthesized that exhibit open-shell singlet ground states. The incorporation of the curved and non-alternant corannulene moiety within diradical systems leads to significant diradical characters as high as 0.98 for DIC-1 and 0.89 for DIC-2. Such high diradical characters can presumably be ascribed to the re-aromatization of the corannulene π system. Although the DIC compounds have large diradical characters, they display excellent stability under ambient conditions. The half-lives are 37 days for DIC-1 and 6.6 days for DIC-2 in solution. This work offers a new design strategy towards diradicaloids with large diradical characters yet maintain high stability.