Universal Surface Engineering of Transition Metals for Superior Electrocatalytic Hydrogen Evolution in Neutral Water

The development of low-cost hybrid water splitting-biosynthetic systems that mimic natural photosynthesis to achieve solar-to-chemical conversion is of great promise for future energy demands, but often limited by the kinetically sluggish hydrogen evolution reaction (HER) on the surface of nonprecious transition metal catalysts in neutral media. It is thus highly desirable to rationally tailor the reaction interface to boost the neutral HER catalytic kinetics. Herein, we report a general surface nitrogen modification of diverse transition metals (e.g. iron, cobalt, nickel, copper, and nickel-cobalt alloy), accomplished by a facile low-temperature ammonium carbonate treatment, for significantly improved hydrogen generation from neutral water. Various physicochemical characterization techniques including synchroton X-ray absorption spectroscopy (XAS) and theory modeling demonstrate that the surface nitrogen modification does not change the chemical composition of the underlying transition metals. Notably, the resulting nitrogen-modified nickel framework (N-Ni) exhibits an extremely low overpotential of 64 mV at 10 mA cm-2, which is, to our knowledge, the best among those nonprecious electrocatalysts reported for hydrogen evolution at pH 7. Out combined experimental results and density functional theory (DFT) calculations reveal that the surface electron-rich nitrogen simultaneously facilitates the initial adsorption of water via the electron-deficient H atom and the subsequent dissociation of the electron-rich HO-H bond via H transfer to N on the nickel surface, beneficial to the overall hydrogen evolution process

Intravenous bone marrow mononuclear cells transplantation in aged mice increases transcription of glucose transporter 1 and Na+/K+-ATPase at hippocampus followed by restored neurological functions

We recently reported that intravenous bone marrow mononuclear cell (BM-MNC) transplantation in stroke improves neurological function through improvement of cerebral metabolism. Cerebral metabolism is known to diminish with aging, and the reduction of metabolism is one of the presumed causes of neurological decline in the elderly. We report herein that transcription of glucose transporters, monocarboxylate transporters, and Na+/K+-ATPase is downregulated in the hippocampus of aged mice with impaired neurological functions. Intravenous BM-MNC transplantation in aged mice stimulated the transcription of glucose transporter 1 and Na+/K+-ATPase α1 followed by restoration of neurological function. As glucose transporters and Na+/K+-ATPases are closely related to cerebral metabolism and neurological function, our data indicate that BM-MNC transplantation in aged mice has the potential to restore neurological function by activating transcription of glucose transporter and Na+/K+-ATPase. Furthermore, our data indicate that changes in transcription of glucose transporter and Na+/K+-ATPase could be surrogate biomarkers for age-related neurological impairment as well as quantifying the efficacy of therapies

Accelerated Oxygen Atom Transfer and C−H Bond Oxygenation by Remote Redox Changes in Fe_3Mn-Iodosobenzene Adducts

We report the synthesis, characterization, and reactivity of [Lfe_3(PhPz)_3OMn(^sPhIO)][OTf]_x (3: x=2; 4: x=3), where 4 is one of very few examples of iodosobenzene–metal adducts characterized by X-ray crystallography. Access to these rare heterometallic clusters enabled differentiation of the metal centers involved in oxygen atom transfer (Mn) or redox modulation (Fe). Specifically, ^(57)Fe Mössbauer and X-ray absorption spectroscopy provided unique insights into how changes in oxidation state (Fe^(III)_2Fe^(II)Mn^(II) vs. Fe^(III)_3Mn^(II)) influence oxygen atom transfer in tetranuclear Fe_3Mn clusters. In particular, a one-electron redox change at a distal metal site leads to a change in oxygen atom transfer reactivity by ca. two orders of magnitude

Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells

Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC50 values of 540, 110, and 290 nM, respectively, against LSD1, HDAC6, and HDAC8. We compared its activity to structurally similar control probes that act by HDAC or LSD1 inhibition alone, as well as an inactive null compound. iDual inhibited the growth of leukemia cell lines at a higher level than GSK2879552 with micromolar IC50 values. Dual engagement with LSD1 and HDAC6 was supported by dose dependent increases in substrate levels, biomarkers, and cellular thermal shift assay. Both histone methylation and acetylation of tubulin were increased, while acetylated histone levels were only mildly affected, indicating selectivity for HDAC6. Downstream gene expression (CD11b, CD86, p21) was also elevated in response to iDual treatment. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated

Tetranuclear [Mn^(III)Mn_3^(IV)O_4] Complexes as Spectroscopic Models of the S_2 State of the Oxygen Evolving Complex in Photosystem II

Despite extensive biochemical, spectroscopic, and computational studies, the mechanism of biological water oxidation by the oxygen evolving complex (OEC) of Photosystem II remains a subject of significant debate. Mechanistic proposals are guided by the characterization of reaction intermediates such as the S_2 state, which features two characteristic EPR signals at g = 2 and g = 4.1. Two nearly isoenergetic structural isomers have been proposed as the source of these distinct signals, but relevant structure–electronic structure studies remain rare. Herein, we report the synthesis, crystal structure, electrochemistry, XAS, magnetic susceptibility, variable temperature CW-EPR, and pulse EPR data for a series of [Mn^(III)Mn_3^(IV)O_4] cuboidal complexes as spectroscopic models of the S_2 state of the OEC. Resembling the oxidation state and EPR spectra of the S_2 state of the OEC, these model complexes show two EPR signals, a broad low field signal and a multiline signal, that are remarkably similar to the biological system. The effect of systematic changes in the nature of the bridging ligands on spectroscopy were studied. Results show that the electronic structure of tetranuclear Mn complexes is highly sensitive to even small geometric changes and the nature of the bridging ligands. Our model studies suggest that the spectroscopic properties of the OEC may also react very sensitively to small changes in structure; the effect of protonation state and other reorganization processes need to be carefully assessed

Molecular Mixed-Metal Manganese Oxido Cubanes as Precursors to Heterogeneous Oxygen Evolution Catalysts

Well-defined mixed-metal [CoMn_3O_4] and [NiMn_3O_4] cubane complexes were synthesized and used as precursors for heterogeneous oxygen evolution reaction (OER) electrocatalysts. The discrete clusters were dropcasted onto glassy carbon (GC) and indium tin oxide (ITO) electrodes, and the OER activities of the resulting films were evaluated. The catalytic surfaces were analyzed by various techniques to gain insight into the structure-function relationships of the electrocatalysts’ heterometallic composition. Depending on preparation conditions, the Co-Mn oxide was found to change metal composition during catalysis, while the Ni–Mn oxides maintained the NiMn_3 ratio. XAS studies provided structural insights indicating that the electrocatalysts are different from the molecular precursors, but that the original NiMn_3O_4 cubane-like geometry was maintained in the absence of thermal treatment (2-Ni). In contrast, the thermally generated 3-Ni develops an oxide-like extended structure. Both 2-Ni and 3-Ni undergo structural changes upon electrolysis, but they do not convert into the same material. The observed structural motifs in these heterogeneous electrocatalysts are reminiscent of the biological oxygen-evolving complex in Photosystem II, including the MMn_3O_4 cubane moiety. The reported studies demonstrate the use of discrete heterometallic oxide clusters as precursors for heterogeneous water oxidation catalysts of novel composition and the distinct behavior of two sets of mixed metal oxides

Activation of neurogenesis in the hippocampus is a novel therapeutic target for Alzheimer's disease

Highlights: Targeting single mechanisms of physiological (aging) and pathological (neurodegeneration) loss of function in the brain may not be sufficient. Cell–cell interactions between transplanted adult stem cells and resident cells via gap junctions have the potential to support the aging or diseased brain. These cell–cell interactions can also increase hippocampal neurogenesis. This may be a novel therapeutic strategy for Alzheimer's disease and other neurodegenerative diseases that could be applied alongside any established treatments

Multitargeting epi-epi drugs for multidrug reistance

Epigenetic therapy is now a clinical reality with eight approved drugs that target DNA methyltransferases, histone deacetylases (HDACs) and lysine methyltransferases. A further recent development is the concept of epigenetic multitargeting through the rational design of novel agents that combine the inhibition of an epigenetic pathway with a second non-epigenetic target and five such compounds have advanced to clinical development. We are investigating the even newer concept of „epi-epi‟ drugs that inhibit two separate epigenetic pathways. Such dual targeting agents have the potential to achieve higher efficacy against proliferating cancer cells while reducing tunor resistance. In this presentation, we report a selective dual histone deacetylase and demethylase inhibitor with an IC50 LSD1 respectively. The compound was biologically profiled together with control compounds that were either single inhibitors or inactive against either enzyme. The dua inhibitor was active against a panel of leukemia cell lines at a micromolar level and induced apoptosis. Target engagement asays such as CETSA were employed to confirm the inhibition of HDAC6 and LSD1 in cells. Further experiments were carried out to identify synergistic effects with clinically approved agents and promising results were observed with doxorubicin

Постоји ли граница између цитотоксичног и антиметастатског ефекта селективних инхибитора хистон деацетилазе 6 код солидних тумора?

Academia and industry make an extensive effort to discover selective histone deacetylase 6 inhibitors (HDAC6i) which could be delivered to the patients. These attempts are partially obscured by inconsistency in preclinical data regarding the cellular and biochemical changes upon treatment of solid tumours with HDAC6i. In this study, we present computational design, synthesis of three novel HDAC6 inhibitors along with their in vitro pharmacological profile against zinc-dependent HDACs. The in vitro anticancer effects of the synthesized compounds were examined on four types of cancer cell lines, human breast cancer cell lines (MDA-MB-231 and MCF-7) as well as human melanoma cells (A-375 and 518A2). It was found that the synthesized compounds induce apoptosis in high concentrations (IC50 >30 μM) nonetheless, the observed morphological changes of studied cell lines during cell viability assay prompted us to examine their antimetastatic properties. Novel compound MBDR-4 significantly reduces migration and invasiveness of the MDA-MB-231 and A375 cancer cell lines at subapoptotic concentration (5 μM), which open new avenues for redirecting drug development of selective HDAC6 inhibitors as adjuvant chemotherapeutics, with antimetastatic effects.Истраживачи тренутно улажу велике напоре у испитивање селективних инхибитора хистон деацетилазе 6 (HDAC6i) 1,2 који би могли да нађу клиничку примену 3 . Ова истраживања су делимично отежана услед неконзистентних преклиничких резултата о ћелијским и биохемијским променама након третмана солидних тумора HDAC6i(4,5). Наша студија обухвата компјутерски дизајн и синтезу три нова HDAC6 инхибитора, заједно са in vitro ензимским испитивањем активности на сродним изоформама HDAC ензимима. Антинеопластичан ефекат синте- тисаних једињења је испитан in vitro на четири типа ћелија карцинома, хуманим ћелијама карцинома дојке (MDA-MB-231 и MCF-7) и хуманим ће- лијама меланома (A-375 и 518A2). Утврђено је да синтетисана једињења индукују апоптозу при високим концентрацијама (IC 50 >30 μM). Истовреме- но је уочено да ова једињења доводе и до морфолошких промена на тре- тираним ћелијама током извођења теста виабилности што нас је усмери- ло ка испитивању њихових антиметастатских особина. Једињење MBDR-4 снажно инхибира миграцију и инвазивност MDA-MB-231 и A375 ћелија кан- цера на субапоптотској концентрацији (5 μM), што отвара нове могућности за истраживање селективних HDAC6 инхибитора као адјувантних хемоте- рапеутика са антиметастатским ефектом.Канцеролошка секција Српског лекарског друштва Serbian Medical Society Oncology Section Београд, новембар 2019 / Belgrade, November 2019 АНАЛИ КАНЦЕРОЛОШКЕ СЕКЦИЈЕ СЛД ANNALS OF ONCOLOGY SECTION Зборник апстраката / Abstract Boo