CDN1163 alleviates SERCA2 dysfunction-induced pulmonary vascular remodeling by inhibiting the phenotypic transition of pulmonary artery smooth muscle cells.

BACKGROUND AND PURPOSE: Substitution of Cys674 (C674) in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) causes SERCA2 dysfunction which leads to activated inositol requiring enzyme 1 alpha (IRE1α) and spliced X-box binding protein 1 (XBP1s) pathway accelerating cell proliferation of pulmonary artery smooth muscle cells (PASMCs) followed by significant pulmonary vascular remodeling resembling human pulmonary hypertension. Based on this knowledge, we intend to investigate other potential mechanisms involved in SERCA2 dysfunction-induced pulmonary vascular remodeling. EXPERIMENTAL APPROACH: Heterozygous SERCA2 C674S knock-in (SKI) mice of which half of cysteine in 674 was substituted by serine to mimic the partial irreversible oxidation of C674 were used. The lungs of SKI mice and their littermate wild-type mice were collected for PASMC culture, protein expression, and pulmonary vascular remodeling analysis. RESULTS: SERCA2 dysfunction increased intracellular Ca2+ levels, which activated Ca2+-dependent calcineurin (CaN) and promoted the nuclear translocation and protein expression of the nuclear factor of activated T-lymphocytes 4 (NFAT4) in an IRE1α/XBP1s pathway-independent manner. In SKI PASMCs, the scavenge of intracellular Ca2+ by BAPTA-AM or inhibition of CaN by cyclosporin A can prevent PASMC phenotypic transition. CDN1163, a SERCA2 agonist, suppressed the activation of CaN/NFAT4 and IRE1α/XBP1s pathways, reversed the protein expression of PASMC phenotypic transition markers and cell cycle-related proteins, and inhibited cell proliferation and migration when given to SKI PASMCs. Furthermore, CDN1163 ameliorated pulmonary vascular remodeling in SKI mice. CONCLUSIONS AND IMPLICATIONS: SERCA2 dysfunction promotes PASMC phenotypic transition and pulmonary vascular remodeling by multiple mechanisms, which could be improved by SERCA2 agonist CDN1163.

'What is already known' l The dysfunction of SERCA2 promotes PASMC hyperproliferation and pulmonary vascular remodeling through activation of the IRE1α/XBP1s pathway.'What this study adds' l The dysfunction of SERCA2 activates the Ca²⁺-dependent CaN-mediated NFAT4 pathway to promote the PASMC phenotypic transition.l Revitalization of SERCA2 suppresses PASMC phenotypic transition and pulmonary vascular remodeling caused by SERCA2 dysfunction.'Clinical significance' l SERCA2 dysfunction-induced pulmonary vascular remodeling involves more than one mechanism, implicating that more drugable targets are to be discovered.l SERCA2 is a potential therapeutic target for preventing pulmonary vascular remodeling.

Strengthen the Affinity of Element Mercury on the Carbon-Based Material by Adjusting the Coordination Environment of Single-Site Manganese.

Mercury, as a highly poisonous pollutant, poses a severe threat to the global population. However, the removal of Hg0 can only be carried out at below 100 °C due to the weak binding of the adsorbent. Herein, a series of carbon-based materials with different coordination environments and atomic dispersion of single-site manganese were prepared, and their elemental mercury removal performance was systematically investigated. It was demonstrated that the coordination environment around manganese determines its electronic structure and size, thus affecting its affinity with mercury. The obtained best adsorbents atomically dispersed Mn with atom size near 0.2 nm, achieves high Hg0 removal efficiency and over 13 mg/g Hg0 adsorption capacity at 200 °C. And the SO2 resistance performance of single atoms (∼0.2 nm) is much better than clusters (∼1-2 nm) because of its high selectivity, that the effect of SO2 is only 3%. Density functional theory (DFT) reveals that Mn with four-nitrogen atoms (Mn-N4-C═O) is more active than other number nitrogen coordination materials. Moreover, the presence of carboxyl groups around manganese also promotes affinity for Hg0. This work might shed new light on the enhancement of Hg0 affinity in carbon-based materials and the rational design of the coordination structure of the tunable Hg0 activities.

Atomically Dispersed Manganese on a Carbon-Based Material for the Capture of Gaseous Mercury: Mechanisms and Environmental Applications.

A novel, atomically dispersed carbon-based sorbent was synthesized by anchoring manganese atoms with N atoms for the capture of gaseous elemental Hg (Hg0). Oxygen atoms were also introduced into the synthesis process to adjust the oxidizing ability of the Mn atoms. High-valence Mn (Mn4+) anchored by the O and N atoms (Mn-O/N-C) in the carbon-based materials provided more exposed active sites. The mercury removal efficiency of the composite exceeded 99%. The composite with a Mn loading of 0.9 wt % exhibited high affinity for Hg0, and the capacity for Hg0 adsorption within 275 min at room temperature reached 16.95 mg·g-1. The Mn utilization was ∼56.61%, which is much larger than that of reported Mn-based oxide sorbents. The atomic-level distribution of Mn was well evidenced by aberration-corrected high-angle annular darkfield scanning transmission electron microscopy. Density functional theory calculations were conducted to evaluate the energy for adsorption of Hg0 on Mn-O/N-C. The results indicated that the amount of N and O atoms in the Mn coordination environment determined the Hg0 adsorption energy, and the presence of five optimized Mn adsorption structures in Mn-O/N-C was confirmed by Hg temperature-programmed desorption analysis. These materials may be utilized for mercury removal from disposal sites with high concentrations of mercury, broken mercury-containing lamps, or mercurial thermometers. The strategy of atomic dispersion during synthesis of the materials and adjusting the oxidizing ability in the single-atom strategy may be helpful for the development of environmentally benign functional materials.

Utilization of Ag nanoparticles anchored in covalent organic frameworks for mercury removal from acidic waste water.

Metal nanoparticles (NPs) have high reaction rate and atom utilization with respect to pollutants in aqueous environments. However, the aggregation and instability in acidic solution limit their practical applications. Mercury removed from acidic solution are still a big problem. In this study, we used a tunable porous covalent organic framework (COF) material as a support for in situ growth of Ag NPs via a one-step solution infiltration method, to enhance the spatial dispersion of NPs and their stability in acidic solution, and for the first time studying the mercury adsorption performance. More importantly, the Ag NPs@COF composite exhibited high removal rate (99 %), ultrahigh Ag atom utilization (150 %), high selectivity and stability, and reusability for Hg(II) removal from acidic aqueous solutions. Meantime, through common characterizations and density functional theory calculations verifying the microscopic adsorption process, we found COF material played an important role in the entire purification process because it provided some electrons to Hg(II) ions via Ag NPs, finally generating an amalgam. Therefore, the present work not only provides a COF-supported Ag NPs material for Hg(II) ions removal from acidic waste water but also opens a new field of design of functionalized COFs material for applications in environmental pollutions control.

Spin-flip reactions of Zr + C2H6 researched by relativistic density functional theory.

Density functional theory (DFT) with relativistic corrections of zero-order regular approximation (ZORA) has been applied to explore the reaction mechanisms of ethane dehydrogenation by Zr atom with triplet and singlet spin-states. Among the complicated minimum energy reaction path, the available states involves three transition states (TS), and four stationary states (1) to (4) and one intersystem crossing with spin-flip (marked by -->): (3) Zr + C 2 H 6 → (3) Zr-CH 3 -CH 3 ((3)1) → (3)TS 1/2 → (3) ZrH-CH 2 -CH 3 ((3)2) → (3) TS 2/3 --> (1) ZrH2-CH2 = CH2 ((1) 3) → (1) TS 3/4 → (1) ZrH 3 -CH = CH 2 ((1)4). The minimum energy crossing point is determined with the help of the DFT fractional-occupation-number (FON) approach. The spin inversion leads the reaction pathway transferring from the triplet potential energy surface (PES) to the singlet's accompanying with the activation of the second C-H bond. The overall reaction is calculated to be exothermic by about 231 kJ mol(-1). Frequency and NBO analysis are also applied to confirm with the experimental observed data.

On structure and bonding of lanthanoid trifluorides LnF3 (Ln = La to Lu).

The trends in the series of lanthanoid (lanthanide) trifluoride molecules LnF3 (Ln = La to Lu) are governed by the valence-active Ln(4f,5d,5p,6s) shells. The series is investigated by quasi-relativistic density functional theory at both the scalar and spin-orbit-coupled levels. Integrating many of the previous experimental and theoretical deductions, we obtain the following comprehensive picture: (1) The comparatively small Ln-F bond length contraction of 14 pm from La to Lu is rather smooth but weakly modulated by spin-orbit coupling. (2) From La to Lu the floppy structure becomes more quasi-planar. (3) The heterolytic LnF bond energies (⅓LnF3→⅓Ln(3+) + F(-)) at the spin-orbit averaged level increase smoothly from 15.3 to 16.3 eV for La to Lu, only the 'divalent' lanthanoids Eu and Yb are outliers with 0.2 eV higher bond energies. (4) The homolytic LnF bond energies (⅓LnF3→⅓Ln + F) however show an overall W-shaped double-periodicity with maxima for LaF3, GdF3 and LuF3, decreasing from La to Eu and from Gd to Yb, the large individual variations being caused by different spin-orbit coupling and Coulomb interaction effects in Ln(0) and LnF3. (5) The Ln-F interaction is basically ionic (increasing with decreasing ionic radii) with some dative Ln(3+)← F(-) bonding. (6) The latter is of the Ln(5d)-F(2p) type with a rather constant bond order from La to Lu, with small Ln(5p) and very small Ln(4f) semi-core contributions decreasing from La to Lu. All these trends are rationalized.

Investigation of spin-flip reactions of Zr + CH3CN by relativistic density functional theory.

To explore the details of the reaction mechanisms of Zr atoms with acetonitrile molecules, the triplet and singlet spin-state potential energy surfaces have been investigated. Density functional theory (DFT) with the relativistic zero-order regular approximation at the PW91/TZ2P level has been applied. The complicated minimum energy reaction path involves four transition states (TS), stationary states 1-5 and one spin inversion (indicated by ⇒): (3)Zr + NCCH(3) → (3)Zr-η(1)-NCCH(3) ((3)1) → (3)TS(1/2) → (3)Zr-η(2)-(NC)CH(3) ((3)2) → (3)TS(2/3) → (3)ZrH-η(3)-(NCCH(2)) ((3)3) → (3)TS(3/4) → CNZrCH(3) ((3)4) ⇒ (1)TS(4/5) → CN(ZrH)CH(2) ((1)5). The minimum energy crossing point was determined with the help of the DFT fractional-occupation-number approach. The spin inversion leading from the triplet to the singlet state facilitates the activation of a C-H bond, lowering the rearrangement-barrier by 78 kJ/mol. The overall reaction is calculated to be exothermic by about 296 kJ/mol. All intermediate and product species were frequency and NBO analyzed. The species can be rationalized with the help of Lewis type formulas.

Investigation of spin-flip reactions of Nb + CH3CN by relativistic density functional theory.

In order to explore the details of the reaction mechanisms of Nb atoms with acetonitrile molecules, the sextet, quartet, and doublet spin state potential energy surfaces have been investigated. Density functional theory (DFT) with the relativistic zero-order regular approximation at the PW91/TZ2P level has been applied. The complicated minimum energy reaction path involves four transition states (TS), stationary states (1) to (5) and two intersystem crossings from spin sextets to quartets to doublets (indicated by ⇒): (6)Nb + NCCH3→(6)Nb η(1)-NCCH3 ((6)1) →(6)TS1/2⇒(4)Nb η(2)-(NC)CH3 ((4)2) →(4)TS2/3→(4)NbH η(3)-(NCCH2) ((4)3) →(4)TS3/4→ CNNbCH3 ((4)4) ⇒(2)TS4/5→ CN(NbH)CH2 ((2)5). The minimum energy crossing points were determined with the help of the DFT fractional-occupation-number approach. The first spin inversion leads from the sextet to an energetically low intermediate quartet ((4)2) with final insertion of Nb into the C-C bond. The second one from the quartet to the doublet state facilitates the activation of a C-H bond, lowering the rearrangement-barrier by 44 kJ mol(-1). The overall reaction is calculated to be exothermic by about 170-180 kJ mol(-1). All intermediate and product species were frequency and NBO analyzed. The species can be rationalized with the help of Lewis type formulas.

Antibond breaking--the formation and decomposition of He@adamantane: descriptions, explanations, and meaning of concepts.

The reaction path from the inclusion complex He@adamantane to its two separated fragments over the transition barrier is investigated by using quantum chemistry. The changes of structure and wavefunction are intuitively anticipated, accurately computed, and qualitatively rationalized. With the help of the traditional concepts of chemical bonding and nonbonding interactions, and with numerical results from a chemically oriented energy-partitioning approach, we can rationalize the details of the chemical process, and qualitatively predict and interpret the two chosen alternative descriptions: the energy-partitioning approach and the topological electron-density analysis. The meaning of bonding within these two approaches, and unsolved aspects of the latter tool are clarified.

Spin-flip reaction of Re + CH4--a relativistic density functional theory investigation.

To explore the reaction mechanisms of methane dehydrogenation by gas-phase Re atom, the sextet, quartet, and doublet potential energy surfaces have been performed using density functional theory (DFT) and zero-order regular approximation relativistic corrections at the PW91/TZ2P level. The minimum energy reaction path is found to proceed through the following steps: (6)Re + CH(4) --> ReCH(4) ((6)1) --> H(3)CReH ((4)2) --> (4)TS2/3 --> H(2)CReH(2) ((4)3) --> (2)TS3/4 --> HCReH(3) ((2)4). Also, the reaction path involves the spin inversion twice in the different reaction steps. To better understand the spin inversion processes, the low energy crossing point is determined with the help of the density functional fractional occupation number approach. The first spin inversion, from the sextet state to the quartet state, makes the activation of the C-H bond energetically spontaneous. The second transition from the quartet state to the doublet state facilitates the cleavage of the second C-H bond, lowering the barrier from 186.1 to 24.2 kJ/mol. The overall reaction is calculated to be exothermic by 149.8 kJ/mol, and the final products in three spin states are investigated by NBO analysis, to compare the Re-C bonds and the C-H bonds.

Bonding or nonbonding? Description or explanation? "Confinement bonding" of He@adamantane.

Different insights into chemical phenomena are obtained by analyzing the whole process (comparing three or more points, thereby explaining the atomistic mechanism) or only the final product (yielding an interesting fingerprint of the result). The viewpoint depends also on whether one analyzes the wavefunctions according to notions grounded in chemical experience or along physically well-defined formal concepts. Bond energies can only be understood upon comparing both ends of the formation process from fragments to molecule. We examine the formation of the inclusion complex He@adamantane. The large antibonding energy expense is partitioned into four physical contributions according to chemical concepts. Introduction of the He atom into an undeformed adamantane cage leads to a large increase of Pauli repulsion; this is partly moderated by electrostatic overlap attraction and by electronic and nuclear relaxations. The IUPAC definition of bonding comprises this antibonding interaction, since a (meta)stable complex is formed. We call it "confinement bonding". Single-point analyses of the bond-formation product can only yield one-sided characterizations. Any analysis depends on its prescription, which should always be specified in order to avoid controversies based on a mix up of unlike concepts.

Metal-phosphorus bonding in complexes W@Au12PX3 (X = H, F, Cl, Br, I, Me, OMe) and [M@Au12](q)PH3 (M(q) = Hf2-, Ta-, W, Re+, Os2+, Ir3+, Pt4+, Au5+): relativistic DFT investigations.

Relativistic density functional theory (DFT) calculations of the geometries and Au-P bonding of W@Au(12)PX(3) (X = H, F, Cl, Br, I, Me, OMe) and [M@Au(12)](q)PH(3) (M(q) = Hf(2-), Ta(-), W, Re(+), Os(2+), Ir(3+), Pt(4+), Au(5+)) have been carried out. There are some regular changes in geometry and binding of these two kinds of complexes with the variation of the phosphanes PX(3) and transition metals M(q). The energy decomposition analysis confirms that the PX(3) ligands are sigma donors. The donor tendency (DeltaE(sigma)/DeltaE(pi)) decreases for different X with increasing electronegativity and for different M(q) from Au(5+) to Hf(2-), while the pi-back-donation increases in the same direction. The calculated P-H bond lengths show a regular decrease from Hf(2-) to Ir(3+), but have abnormal trends for Pt(4+) and Au(5+).