Radical-Induced Changes in Transition Metal Interfacial Magnetic Properties: A Blatter Derivative on Polycrystalline Cobalt.

In this work, we study the interface obtained by depositing a monolayer of a Blatter radical derivative on polycrystalline cobalt. By examining the occupied and unoccupied states at the interface, using soft X-ray techniques, combined with electronic structure calculations, we could simultaneously determine the electronic structure of both the molecular and ferromagnetic sides of the interface, thus obtaining a full understanding of the interfacial magnetic properties. We found that the molecule is strongly hybridized with the surface. Changes in the core level spectra reflect the modification of the molecule and the cobalt electronic structures inducing a decrease in the magnetic moment of the cobalt atoms bonded to the molecules which, in turn, lose their radical character. Our method allowed us to screen, beforehand, organic/ferromagnetic interfaces given their potential applications in spintronics.

Chiral π-Conjugated Double Helical Aminyl Diradical with the Triplet Ground State.

We report a neutral high-spin diradical of chiral C2-symmetric bis[5]diazahelicene with ΔEST ≈ 0.4 kcal mol-1, as determined by EPR spectroscopy/SQUID magnetometry. The diradical is the most persistent among all high-spin aminyl radicals reported to date by a factor of 20, with a half-life of up to 6 days in 2-MeTHF at room temperature. Its triplet ground state and excellent persistence may be associated with the unique spin density distribution within the dihydrophenazine moiety, which characterizes two effective 3-electron C-N bonds analogous to the N-O bond of a nitroxide radical. The enantiomerically enriched (ee ≥ 94%) (MM)- and (PP)-enantiomers of the precursors to the diradicals are obtained by either preparative chiral supercritical fluid chromatography or resolution via functionalization with the chiral auxiliary of the C2-symmetric racemic tetraamine. The barrier for the racemization of the solid tetraamine is ΔG‡ = 43 ± 0.01 kcal mol-1 in the 483-523 K range. The experimentally estimated lower limit of the barrier for the racemization of a diradical, ΔG‡ ≥ 26 kcal mol-1 in 2-MeTHF at 293 K, is comparable to the DFT-determined barrier of ΔG‡ = 31 kcal mol-1 in the gas phase at 298 K. While the enantiomerically pure tetraamine displays strong chiroptical properties, with anisotropy factor |g| = |Δε|/ε = 0.036 at 376 nm, |g| ≈ 0.005 at 548 nm of the high-spin diradical is comparable to that recently reported triplet ground-state diradical dication. Notably, the radical anion intermediate in the generation of diradical exhibits a large SOMO-HOMO inversion, SHI = 35 kcal mol-1.

From Stable Radicals to Thermally Robust High-Spin Diradicals and Triradicals.

Stable radicals and thermally robust high-spin di- and triradicals have emerged as important organic materials due to their promising applications in diverse fields. New fundamental properties, such as SOMO/HOMO inversion of orbital energies, are explored for the design of new stable radicals, including highly luminescent ones with good photostability. A relation with the singlet-triplet energy gap in the corresponding diradicals is proposed. Thermally robust high-spin di- and triradicals, with energy gaps that are comparable to or greater than a thermal energy at room temperature, are more challenging to synthesize but more rewarding. We summarize a number of high-spin di- and triradicals, based on nitronyl nitroxides that provide a relation between the experimental pairwise exchange coupling constant J/k in the high-spin species vs experimental hyperfine coupling constants in the corresponding monoradicals. This relation allows us to identify outliers, which may correspond to radicals where J/k is not measured with sufficient accuracy. Double helical high-spin diradicals, in which spin density is delocalized over the chiral π-system, have been barely explored, with the sole example of such high-spin diradical possessing alternant π-system with Kekulé resonance form. Finally, we discuss a high-spin diradical with electrical conductivity and derivatives of triangulene diradicals.

Long-Term Degradation Mechanisms in Application-Implemented Radical Thin Films.

Blatter radical derivatives are very attractive due to their potential applications, ranging from batteries to quantum technologies. In this work, we focus on the latest insights regarding the fundamental mechanisms of radical thin film (long-term) degradation, by comparing two Blatter radical derivatives. We find that the interaction with different contaminants (such as atomic H, Ar, N, and O and molecular H2, N2, O2, H2O, and NH2) affects the chemical and magnetic properties of the thin films upon air exposure. Also, the radical-specific site, where the contaminant interaction takes place, plays a role. Atomic H and NH2 are detrimental to the magnetic properties of Blatter radicals, while the presence of molecular water influences more specifically the magnetic properties of the diradical thin films, and it is believed to be the major cause of the shorter diradical thin film lifetime in air.

Phosphodiesterase type 10A inhibitor attenuates lung fibrosis by targeting myofibroblast activation.

Pulmonary fibrosis (PF) is a fatal and irreversible respiratory disease accompanied by excessive fibroblast activation. Previous studies have suggested that cAMP signaling pathway and cGMP-PKG signaling pathway are continuously down-regulated in lung fibrosis, whereas PDE10A has a specifically expression in fibroblasts/myofibroblasts in lung fibrosis. In this study, we demonstrated that overexpression of PDE10A induces myofibroblast differentiation, and papaverine, as a PDE10A inhibitor used for vasodilation, inhibits myofibroblast differentiation in human fibroblasts, Meanwhile, papaverine alleviated bleomycin-induced pulmonary fibrosis and amiodarone-induced oxidative stress, papaverine downregulated VASP/ß-catenin pathway to reduce the myofibroblast differentiation. Our results first demonstrated that papaverine inhibits TGFß1-induced myofibroblast differentiation and lung fibrosis by VASP/ß-catenin pathway.

Salvianolic acid A improve mitochondrial respiration and cardiac function via inhibiting apoptosis pathway through CRYAB in diabetic cardiomyopathy.

Salvianolic acid A (SAA) is a traditional Chinese medicine that has a good therapeutic effect on cardiovascular disease. However, the underlying mechanisms by which SAA improves mitochondrial respiration and cardiac function in diabetic cardiomyopathy (DCM) remain unknown. This study aims to elucidate whether SAA had any cardiovascular protection on the pathophysiology of DCM and explored the potential mechanisms. Diabetes was induced in rats by 30 mg/kg of streptozotocin (STZ) treatment. After a week of stability, 5 mg/kg isoprenaline (ISO) was injected into the rats subcutaneously. 3 mg/kg SAA was orally administered for six weeks and 150 mg/kg Metformin was selected as a positive group. At the end of this period, cardiac function was assessed by ultrasound, electrocardiogram, and relevant cardiac injury biomarkers testing. Treatment with SAA improved cardiac function, glucose, and lipid levels, mitochondrial respiration, and suppressed myocardial inflammation and apoptosis. Furthermore, SAA treatment inhibits the apoptosis pathway through CRYAB in diabetic cardiomyopathy rats. As a result, this study not only provides new insights into the mechanism of SAA against DCM but also provides new therapeutic ideas for the discovery of anti-DCM compounds in the clinic.

Dan-Shen-Yin Granules Prevent Hypoxia-Induced Pulmonary Hypertension via STAT3/HIF-1α/VEGF and FAK/AKT Signaling Pathways.

Traditional Chinese medicine (TCM) plays an important role in the treatment of complex diseases, especially cardiovascular diseases. However, it is hard to identify their modes of action on account of their multiple components. The present study aims to evaluate the effects of Dan-Shen-Yin (DSY) granules on hypoxia-induced pulmonary hypertension (HPH), and then to decipher the molecular mechanisms of DSY. Systematic pharmacology was employed to identify the targets of DSY on HPH. Furthermore, core genes were identified by constructing a protein-protein interaction (PPI) network and analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) analysis. Related genes and pathways were verified using a hypoxia-induced mouse model and hypoxia-treated pulmonary artery cells. Based on network pharmacology, 147 potential targets of DSY on HPH were found, constructing a PPI network, and 13 hub genes were predicted. The results showed that the effect of DSY may be closely associated with AKT serine/threonine kinase 1 (AKT1), signal transducer and activator of transcription 3 (STAT3), and HIF-1 signaling pathways, as well as biological processes such as cell proliferation. Consistent with network pharmacology analysis, experiments in vivo demonstrated that DSY could prevent the development of HPH in a hypoxia-induced mouse model and alleviate pulmonary vascular remodeling. In addition, inhibition of STAT3/HIF-1α/VEGF and FAK/AKT signaling pathways might serve as mechanisms. Taken together, the network pharmacology analysis suggested that DSY exhibited therapeutic effects through multiple targets in the treatment of HPH. The inferences were initially confirmed by subsequent in vivo and in vitro studies. This study provides a novel perspective for studying the relevance of TCM and disease processes and illustrates the advantage of this approach and the multitargeted anti-HPH effect of DSY.

Puerarin-V prevents the progression of hypoxia- and monocrotaline-induced pulmonary hypertension in rodent models.

Pulmonary hypertension (PH) is a cardiopulmonary disease characterized by a progressive increase in pulmonary vascular resistance. One of the initial pathogenic factors of PH is pulmonary arterial remodeling under various stimuli. Current marketed drugs against PH mainly relieve symptoms without significant improvement in overall prognosis. Discovering and developing new therapeutic drugs that interfere with vascular remodeling is in urgent need. Puerarin is an isoflavone compound extracted from the root of Kudzu vine, which is widely used in the treatment of cardiovascular diseases. In the present study, we evaluated the efficacy of puerarin in the treatment of experimental PH. PH was induced in rats by a single injection of MCT (50 mg/kg, sc), and in mice by exposure to hypoxia (10% O2) for 14 days. After MCT injection the rats were administered puerarin (10, 30, 100 mg · kg-1 · d-1, i.g.) for 28 days, whereas hypoxia-treated mice were pre-administered puerarin (60 mg · kg-1 · d-1, i.g.) for 7 days. We showed that puerarin administration exerted significant protective effects in both experimental PH rodent models, evidenced by significantly reduced right ventricular systolic pressure (RVSP) and lung injury, improved pulmonary artery blood flow as well as pulmonary vasodilation and contraction function, inhibited inflammatory responses in lung tissues, improved resistance to apoptosis and abnormal proliferation in lung tissues, attenuated right ventricular injury and remodeling, and maintained normal function of the right ventricle. We revealed that MCT and hypoxia treatment significantly downregulated BMPR2/Smad signaling in the lung tissues and PPARγ/PI3K/Akt signaling in the lung tissues and right ventricles, which were restored by puerarin administration. In addition, we showed that a novel crystal type V (Puer-V) exerted better therapeutic effects than the crude form of puerarin (Puer). Furthermore, Puer-V was more efficient than bosentan (a positive control drug) in alleviating the abnormal structural changes and dysfunction of lung tissues and right ventricles. In conclusion, this study provides experimental evidence for developing Puer-V as a novel therapeutic drug to treat PH.

Puerarin reduces oxidative damage to vascular endothelial cells by improving mitochondrial respiratory function / 药学学报

This study investigated the effect of puerarin on human umbilical vein endothelial cells (HUVEC) injured with hydrogen peroxide (H2O2). HUVEC were divided into three groups: a control group, a model group (H2O2 400 μmol·L-1) and a puerarin-treated group (3, 10, 30 and 100 μmol·L-1). HUVEC were cultured with varied concentration of puerarin for 2 h and treated with H2O2 for another 24 h. Cell proliferation was detected by a CCK-8 assay. The mitochondrial membrane potential was measured by a JC-1 fluorescent probe. A transwell chamber assay was adopted to observe cell migration ability. Mitochondrial respiratory function was measured in a two-chamber titration injection respirometer (Oxygraph-2k). The expression of interleukin-1β (IL-1β), interleukin-18 (IL-18) and tumor necrosis factor-α (TNF-α) was detected by quantitative real-time PCR. The expression of pyroptosis-mediated proteins, including cleaved-cysteinyl aspartate-specific proteinase-1 (caspase-1), N-gasdermin D (N-GSDMD), NOD-like receptor protein 3 (NLRP3) and purinergic ligand-gated ion channel 7 receptor (P2X7R) was detected by Western blot. The results show that 400 μmol·L-1 H2O2 treatment for 24 h causes obvious damage to HUVEC. Compared with the model group, puerarin protected against cellular injury in a dose-dependent manner, with the greatest effect at a dose of 30 and 100 μmol·L-1. Puerarin significantly decreased the mitochondrial membrane potential and improved mitochondrial function. Puerarin inhibited cell migration induced by H2O2, suppressed the expression of IL-1β, IL-18 and TNF-α, and down-regulated the pyroptosis-mediated protein. These changes are statistically significant (P < 0.05). These findings demonstrate that puerarin has a protective effect against H2O2-induced oxidative damage of HUVEC by inhibiting the migration of HUVEC cells. The mechanism may be related to improved mitochondrial respiratory function and inhibition of pyroptosis.