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Direct electroreduction of nitric oxide offers a promising avenue to produce valuable chemicals, such as ammonia, which is an essential chemical to produce fertilizers. Direct ammonia synthesis from NO in a polymer electrolyte membrane (PEM) electrolyzer is advantageous for its continuous operation and excellent mass transport characteristics. However, at a high current density, the faradaic efficiency of NO electroreduction reaction is limited by the competing hydrogen evolution reaction (HER). Herein, we report a CO‐mediated selective poisoning strategy to enhance the faradaic efficiency (FE) towards ammonia by suppressing the HER. In the presence of only NO at the cathode, Pt/C and Pd/C catalysts showed a lower FE towards NH3 than to H2 due to the dominating HER. Cu/C catalyst showed a 78 % FE towards NH3 at 2.0 V due to the stronger binding affinity to NO* compared to H*. By co‐feeding CO, the FE of Cu/C catalyst towards NH3 was improved by 12 %. More strikingly, for Pd/C, the FE towards NH3 was enhanced by 95 % with CO co‐feeding, by effectively suppressing HER. This is attributed to the change of the favorable surface coverage resulting from the selective and competitive binding of CO* to H* binding sites, thereby improving NH3 selectivity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Butene isomerization over ferrierite requires specific types of coke deposits as active sites. • Residual organic structure direction agent (OSDA) acts as a precursor for coke-mediated reactivity. • Trace amounts of OSDA block strong acid sites preventing undesirable side reactions. • Increased accessibility of pore-mouths extends catalyst lifetime by more than two-fold. This work examines how acid site concentration (FT-IR) and strength (NH 3 -TPD) as well as pore mouth accessibility modulate the activity of the microporous zeolite ferrierite (H-FER) during the skeletal isomerization of 1-butene to iso -butene. Restricting the accessibility of catalyst pores and strong acid sites is achieved by selective oxidation of residual organic structure directing agent (OSDA) through precise control of calcination conditions. Because this reaction is mediated by catalytically active carbonaceous deposits, residual OSDA affects their formation. This work demonstrates that small amounts of residual OSDA (∼ 0.2 wt%) are beneficial to the reaction under industrially relevant reaction conditions in three ways. Selective poisoning of strong BAS with OSDA nearly halves the amount of dimerization and cracking byproducts and improves catalyst lifetime. Simultaneously, carbonaceous fragments of the OSDA act as coke precursors and help shorten the startup time. Hence, catalyst lifetime may be significantly improved through both optimal pretreatment conditions and by designing catalysts with an increased number of accessible pore mouths. [ABSTRACT FROM AUTHOR]

Resistance to alkali metal poisoning remains a challenge for Ce-based denitration (de-NO x) catalysts. In this paper, improved low-temperature performance and resistance to K poisoning were achieved by phosphorylating CeSnO x. The activity tests revealed that the phosphorylated CeSnO x (3 wt%P/CeSn) exhibited over 90 % NO conversion at 190–450 °C and >90 % NO conversion at 240–400 °C even after K poisoning. The mechanism of phosphorylation treatment against K poisoning was investigated by many characterizations and DFT calculation. The results showed that the phosphorylation treatment facilitated the interaction between Ce and Sn, and K interacts more preferentially with PO 4 3- species. This prevents K from destroying the Ce-O-Sn structure to form a Ce-O-K structure, which in turn maintained the catalyst's redox properties. Moreover, the phosphorylation treatment supplemented the acidity of 3 wt%P/CeSn compared with CeSnO x. This effectively mitigated the reduction of acidity caused by K and ensured the adsorption and activation of NH 3 on the catalyst surface. [Display omitted] • Synthesis of CeSnO x catalysts with different degrees of phosphorylation. • Excellent low-temperature NH 3 -SCR activity and K-resistance of 3 wt%P/CeSn. • Protecting Ce-O-Sn structure from K poisoning by phosphorylation treatment. • Increase in surface acid sites on 3 wt%P/CeSn due to phosphorylation treatment. • Outstanding resistance to K poisoning attributed to PO 4 3- and K interactions. [ABSTRACT FROM AUTHOR]

[Display omitted] • Plasma regeneration achieving As removal and intrinsic activity enhancement. • Enhanced intrinsic activity of vanadia resulted from polymeric VO x. • The plasma treatment process comprised three stages. • A pathway for the nitrate assisted NH 3 activation on polymeric VO x was proposed. Regeneration of highly toxic Arsenic (As) poisoned SCR catalysts is a huge challenge, because the strong interactions between As and the active component often leads to the loss or damage of active sites during the regeneration process. Herein, we develop a low-temperature plasma regeneration method that not only selectively removes As but also preserves the active components for commercial V 2 O 5 -WO 3 /TiO 2 catalyst. More intriguingly, the catalyst after plasma regeneration achieves a significant catalytic performance enhancement, far surpassing the fresh V 2 O 5 -WO 3 /TiO 2 catalyst. Under optimized regeneration conditions, the regenerated catalyst exhibits an As removal rate exceeding 99.5 ± 0.2 % within 240 s, and a reaction rate value that was 18.6 and 3.4 times of the poisoned and fresh catalyst. Structural characterization reveals that the enhanced intrinsic activity of regenerated catalyst mainly stems from the As complete removal and subsequent transformation of monomeric VO x species into polymeric ones under H 2 plasma environment. Multiple spectroscopic monitoring techniques unveil three stages in the plasma treatment process: (1) As reduction and removal, (2) surface polymerization of VO x species, and (3) vanadium embedded into TiO 2 lattice. At low temperatures, the well regenerated catalysts with abundant polymeric VOx facilitate the nitrate-assisted dehydrogenation of adsorbed NH 3 to key NH 2 intermediates, thereby achieving superior NH 3 -SCR catalytic performance. This study not only provides a rapid regeneration strategy for poison selective separation from spent catalysts but also offers new insights into the precise control and design of active sites. [ABSTRACT FROM AUTHOR]

γ-Fe2O3 has an excellent low-temperature selective catalytic reduction (SCR) deNOx performance, but its resistance to alkaline earth metal calcium (Ca) is poor. In particular, the detailed mechanism of Ca poisoning on the γ-Fe2O3 catalyst at the atomic level is not clear. Hence, the density functional theory method was used in this research to investigate the influence mechanism of Ca poisoning on the NH3-SCR over the γ-Fe2O3 catalyst surface. The findings reveal that NH3, NO, and O2 molecules can bind to the γ-Fe2O3 (001) surface to generate coordinated ammonia, monodentate nitroso, and adsorption oxygen species, respectively. The main active site is Fe1-top. For the γ-Fe2O3 with Ca poisoning, the Ca atom has a high adsorption energy on the surface of γ-Fe2O3 (001), which covers the catalyst surface and reduces the active sites. The presence of Ca atom decreases the adsorption performance of NH3, while slightly improving the NO and O2 adsorption. In particular, the Ca atom restrains the NH3 activation and NH2 formation, which is detrimental to the NH3-SCR process. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ce enhanced the pore structure of the iron catalyst, enhanced the surface acidity. • Ce inhibited the interaction between arsenic and Fe within the catalyst. • Ce-modified iron-based catalyst exhibited enhanced H 2 O resistance. • The SO 2 resistance of cerium-doped iron-based catalysts is inhibited. The mechanism of denitrification and arsenic poisoning during the selective catalytic reduction of NO x with ammonia using a cerium-modified iron-based catalyst was investigated through fixed bed activity tests and catalyst characterization. The results demonstrated that cerium formed a solid solution with Fe, and enriched the surface acid sites of the catalyst. Furthermore, cerium inhibited the arsenic-iron interaction, thereby protecting the active sites of the catalyst. After 6 h of arsenic poisoning, the NO x conversion of 0.1Ce catalyst decreased by only about 30 % of that of Fe 2 O 3 catalyst. The cerium-modified iron-based catalyst exhibited significantly better H 2 O resistance than the Fe 2 O 3 catalyst at 300 °C, and increased as the temperature rose·H 2 O adsorbed onto the Lewis acid sites on the catalyst surface, converting them into Brønsted acid sites, which promoted arsenic adsorption and oxidation on the surface, thereby greatly reducing adsorption activity of the catalyst. In the presence of SO 2 and As 2 O 3 in the flue gas, the denitrification efficiency of the catalyst further decreased, though the reduction is less pronounced than in the presence of H 2 O and As 2 O 3 alone, and shows a negative correlation with SO 2 concentration. [ABSTRACT FROM AUTHOR]

To address water poisoning issues of Selective Catalytic Reduction (SCR) denitrification catalysts in high-humidity flue gas, this study synthesized catalysts including Co–Mn/TiO 2 , Co–Mn–Ce/TiO 2 , Co–Mn–Ce/TiO 2 –Si, and Co–Mn–Ce/TiO 2 (stearic acid). The activity of the catalysts at low temperatures and high humidity (140–180 °C, 0–35 vol%) was evaluated. Furthermore, the characterization of the most effective of these (the Co–Mn–Ce/TiO 2 (stearic acid) catalyst) was performed. The results revealed distinct mechanisms of water poisoning under high- and low-humidity conditions. Under high humidity, the dissolution of water molecules affected the catalyst structure and thereby, resulted in reduced dispersibility of the active components. Conversely, at low humidity, the dissolution effect was relatively marginal, which resulted in a more stable catalyst structure. High-humidity flue gas reduced the catalyst acidity and thereby, hindered NH 3 adsorption. Meanwhile, low-humidity flue gas had a lesser impact on the catalyst. High-humidity flue gas hinders the conversion of Co ions in Co–Mn–Ce/TiO 2 （stearic acid) to higher oxidation states and reduced Ce4+ to Ce3+. This resulted in decreased Mn4+ on the catalyst surface and reduced chemisorbed oxygen (Oa). This, in turn, affected the adsorption and storage of oxygen by the catalyst. [Display omitted] • First study on the emissions in an environment with 35 vol%-40 vol% humidity. • The denitrification efficiency of the catalyst reaches 89.81 % at 35 vol% H 2 O. • High humidity can reduce component dispersion, gas acidity, and active components. [ABSTRACT FROM AUTHOR]

[Display omitted] Lead (Pb) species trigger serious poisoning of selective catalytic reduction (SCR) catalysts. To improve the Pb resistance ability, revealing the impact mechanism of Pb species on the commercial SCR catalysts from a molecular level is of great significance. Herein, first-principles calculations were applied to unveil the Pb adsorption mechanism on the vanadium-based catalysts, the results were also compared with the previous experimental findings. The intrinsic interaction mechanism between Pb and catalyst components was interpreted by clarifying the change of the catalyst electronic structures (including charge transfer, bond formation situations, and active sites reactivities). It is found that the adsorption of Pb species belongs to chemisorption, evident electron transfer with the catalyst surface is inspected and intense charge transfer indicates strong adsorption. A remarkable interaction with the V = O active sites occurs and stable Pb-O bonds are formed, which significantly changes the electronic structures of the V = O sites and inhibits the NH 3 adsorption, thus suppressing the SCR activity. Finally, thermodynamic analysis was applied to elucidate the temperature influence on Pb adsorption. It is found that Pb adsorption on catalysts cannot proceed spontaneously over 500 K. At higher temperatures the adsorption is inhibited and the Pb species become less stable, which partially explains why the Pb-poisoning effect at high temperatures is relatively moderate than that at low temperatures. [ABSTRACT FROM AUTHOR]

Serotonin syndrome (toxicity) describes adverse drug effects from toxic amounts of intra-synaptic central nervous system serotonin. A wide range of drugs have been implicated to cause serotonin toxicity, not all justifiably. The plausible agents all have a final common pathway resulting in a substantial increase in central nervous system serotonergic neurotransmission. Serotonin toxicity is characterized by neuromuscular excitation, mental status changes, and autonomic dysregulation. Signs and symptoms represent a spectrum of toxicity (mild to life-threatening) related to increasing serotonin concentrations. As there is no consensus on the threshold for "toxicity" or diagnostic criteria, the true incidence of serotonin toxicity is unknown. The incidence in overdose is easier to quantify and is reasonably common in serotonergic antidepressant overdoses. In a large case series of overdoses, moderate serotonin toxicity occurred in 14% of poisonings with a selective serotonin reuptake inhibitor. While half those ingesting a monoamine oxidase inhibitor in combination with a serotonergic agent in overdose exhibit at least moderately severe serotonin toxicity. In contrast, the incidence of serotonin toxicity in those on therapeutic serotonergic agents appears to be very low. To provide a narrative review of the current diagnostic criteria, utilizing case reports of fatalities to evaluate how many meet the various diagnostic criteria and propose practical solutions to resolve controversies in diagnosis. A review of serotonin toxicity diagnostic criteria in the English literature was completed by searching Embase and PubMed from January 1990 to July 2021 for the keywords "serotonin syndrome/toxicity" paired with "diagnostic criteria" or "diagnosis." Also, fatal cases of serotonin toxicity identified from a recent systematic review were independently examined to determine what diagnostic criteria were met and whether serotonin toxicity or another cause was most likely. Serotonin toxicity is a clinical diagnosis, four diagnostic criteria (Sternbach, Serotonin Syndrome Scale, Radomski, and Hunter) have been proposed. However, the Serotonin Syndrome Scale has not been validated in patients with serotonin toxicity and only utilized in those on a serotonergic agent. The remaining three criteria are utilized more widely but have undergone little refinement or validation. Shortfalls with diagnostic criteria can be illustrated by examining case fatalities. Of 55 fatal cases reviewed, 12 (22%) were unlikely to be serotonin toxicity. Sternbach and Radomski criteria were met by 25 (45%), 20 (36%) had insufficient data reported and 10 (18%) met an exclusion criterion. Few had sufficient information reported to determine whether Hunter Criteria were met, with only 13 (24%) documented as meeting the criteria, the remaining 42 (76%) had insufficient data. As serotonin toxicity is a clinical diagnosis, issues arise when basing the diagnosis on symptom criteria alone, without considering whether the drug/s ingested increase central nervous system serotonin or whether there is an alternative diagnosis. This has resulted in case reports and government warnings for drugs that cannot plausibly cause significant serotonin toxicity (e.g., ondansetron and antipsychotics). We propose when assessing for a serotonin toxidrome, both the causative agent(s) and clinical scenario is considered to determine the likelihood of serotonin toxicity. Then the clinical features assessed, those with a moderate to high prior probability (e.g., serotonergic drug–drug interaction, overdose, recent initiation or increase in dose of serotonergic agent/s) could be diagnosed based on the Hunter criteria. However, those with a low probability (e.g., stable therapeutic doses of a serotonergic agent) require more specific and stringent criteria. Finally, we propose a minimum dataset for case reports/series of serotonin toxicity. More complete and accurate reporting of serotonin toxicity cases is required in the future, to avoid further misleading associations that are physiologically implausible. [ABSTRACT FROM AUTHOR]

Hydrogen storage and transport via Liquid Organic Hydrogen Carriers (LOHC) is gaining increasing attention. In this study, we present catalytically activated stainless steel plates as a promising alternative to the commonly used pellet catalysts for the dehydrogenation of perhydro dibenzyltoluene (H18-DBT). These plate catalysts promise better heat transport to the active sites. For improved performance, we modified our Pt/alumina plate catalysts by using i) platinum sulfite impregnation and ii) post-treatment with (NH 4) 2 SO 4. Post-treatment with (NH 4) 2 SO 4 resulted in a less active catalyst with lower formation of high-boiling side products compared to the S-free plate catalyst. Catalysts prepared with platinum sulfite showed both >35% higher activities and 90% reduction in high-boiler formation compared to the S-free plate catalysts. Our findings pave the way for the development of catalytically activated heat transfer plates that would allow the incorporation of LOHC dehydrogenation units into the geometry of future high temperature fuel cell stacks. [Display omitted] • Coated plate catalysts show high activity for H 2 release from perhydro dibenzyltoluene. • Direct coating onto heated surface enhances the heat supply to the catalyst. • Selective sulfide poisoning strongly reduces by-product formation. [ABSTRACT FROM AUTHOR]

[Display omitted] • SO 2 poisons the SCR catalysts and lead to the catalyst deactivation. • This paper reviews sulfur poisoning mechanism of SCR catalysts and anti-sulfur measures. • Formation of sulfates block catalyst pore and cover active sites, causing sulfur poisoning. • Doping element and modifying morphology protect active sites and alleviate sulfate deposition. • Thermal regeneration and water-washing regeneration are most common regeneration methods. Selective catalytic reduction (i.e., SCR) denitrification has become the most popularly used denitrification technique owing to its high denitrification efficiency, clean process, and mature reliability. However, SO 2 in the flue gas stream can poison catalysts and lead to catalyst deactivation. Thus, it is of great significance to investigate the poisoning mechanisms and anti-sulfur poisoning measures of the catalysts. This paper systematically reviews the sulfur poisoning mechanisms of several SCR catalysts (e.g., vanadium-based, cerium-based, manganese-based, copper-based, and iron-based), anti-sulfur measures (including doping of metal and non-metal elements, the use of carriers, and the control of catalyst morphology and structure). Results showed that the sulfur poisoning mechanisms of SCR catalyst mainly includes formation of ammonium sulfates and metal sulfates to block the catalyst pore and cover the active sites, competitive adsorption of SO 2 and NO x , and the consumption of active components caused by SO 2. Doping other elements and modifying morphology and structure of catalyst can protect the active sites of catalysts and alleviate the sulfate deposition and pore blockage issues. Doping elements can raise the denitrification efficiency of the catalyst by more than 20–70%, and modifying morphology and structure of catalyst can increase the denitrification efficiency by about 20%. Besides, regeneration of sulfur-poisoning catalyst was also reviewed. The most common methods of sulfur-poisoning catalysts regeneration are thermal regeneration and water-washing regeneration. Finally, some suggestions and prospects for design and development of anti-sulfur poisoning SCR catalyst in the future are commented. [ABSTRACT FROM AUTHOR]

The cleavage of C−O linkages in aryl ethers in biomass‐derived lignin compounds without hydrogenation of the aromatic rings is a major challenge for the production of sustainable mono‐aromatics. Conventional strategies over the heterogeneous metal catalysts require the addition of homogeneous base additives causing environmental problems. Herein, we propose a heterogeneous Ru/C catalyst modified by Br atoms for the selective direct cleavage of C−O bonds in diphenyl ether without hydrogenation of aromatic rings reaching the yield of benzene and phenol as high as 90.3 % and increased selectivity to mono‐aromatics (97.3 vs. 46.2 % for initial Ru) during depolymerization of lignin. Characterization of the catalyst indicates selective poisoning by Br of terrace sites over Ru nanoparticles, which are active in the hydrogenation of aromatic rings, while the defect sites on the edges and corners remain available and provide higher intrinsic activity in the C−O bond cleavage. [ABSTRACT FROM AUTHOR]

• Ni species with different dispersion could be precisely obtained. • The obtained Ni single atom catalyst displayed 100% yield for cinnamyl alcohol. • The synergistic effect between metal Ni SAs and acid–base sites was revealed. Catalytic Transfer Hydrogenation (CTH) of unsaturated functional groups to obtain high value-added products has attracted considerable attention in heterogeneous catalysis. Herein, we report a Ni single atoms (SAs) catalyst anchoring to Mg Al mixed metal oxide (MMO) based on structural topotactic transformation from hydrotalcite precursor, which displays an excellent catalytic behavior toward CTH of cinnamaldehyde (CAL) to cinnamyl alcohol (COL) (conversion: 100%; selectivity: 100%; 2 h). A combination research including AC-STEM, XAFS and in situ CO-IR demonstrates that Ni species anchored by Ni O coordination with different dispersion could be precisely obtained by tuning the reduction temperature: the Ni SAs (only Ni O coordination) were obtained below 450 °C, and the Ni Ni coordination appears and increases gradually with the rise of the reduction temperature. The selective poisoning experiment, kinetic isotope effect (KIE), in situ FT-IR measurement and DFT calculation reveal the synergistic effect between metal Ni SAs and acid–base sites toward CTH of CAL. Specifically, the Ni SAs play a crucial role in dehydrogenation reaction of 2-propanol (2-POL) to supply activated H, the base sites induce α -C H cleavage in 2-POL (the rate-determining step), and the Lewis acid sites serve as the active center for C O adsorption in CAL molecule. This work demonstrates a synergetic effect between Ni SAs and acid–base sites, which would pave the way in the rational design and synthesis of high-performance SAs materials used in CTH reactions. [ABSTRACT FROM AUTHOR]

• Sulfur species inactivate Cu ions and lead to inferior SCR activity below 400 °C; • Copper bisulfate and ammonium bisulfate can be inter-transformed; • NO+O 2 convert ammonium bisulfate to copper bisulfate, which is difficult in recovery; • NH 3 adsorption helps to decompose sulfate species and recover SCR activity easily. In order to investigate sulfate poisoning of Cu/SSZ-13 catalysts used for NO x removal by selective catalytic reduction with ammonia (NH 3 -SCR), they were exposed to SO 2 at different temperatures in the presence and absence of NH 3. Standard physicochemical characterization and density functional theory calculations were performed to probe the nature of the sulfate species formed on the catalyst and the corresponding effects. The results showed that sulfate poisoning has little effect on the chabazite structure of the catalyst, but the sulfate species formed blocks the Cu/SSZ-13 pores. For sulfation with pure SO 2 , copper bisulfate forms and its content increases with sulfation temperature. However, in the presence of NH 3 , the major sulfate formed is ammonium bisulfate (~80%). Moreover, the total sulfate contents are lower for higher sulfation temperatures because of difficulties in ammonium bisulfate formation. Regardless of the kind of sulfate species formed, the poisoning leads to lower availability of active sites, causing inferior NOx conversion. Importantly, as copper bisulfate and ammonium bisulfate on Z-Cu(OH)+ are interconvertible, our study reveals that using NH 3 to promote the transformation from copper bisulfate to ammonium bisulfate is a viable method to improve the recovery effect of sulfated Cu/SSZ-13. The schematic diagram in the effect of sulfate species formation and transformation on and SCR activity and regeneration over Cu/SSZ-13 catalysts Image, graphical abstract [ABSTRACT FROM AUTHOR]

Selective inhibition of microRNAs (miRNAs) offers a new avenue for cancer therapeutics. While most of the current anti-miRNA (antimiR) reagents target full length miRNAs, here we investigate novel nanoparticle-delivered short PNA probes containing cationic domains targeting the seed region of the miRNA for effective antimiR therapy. For proof of concept, we tested PNAs targeting miRNA-155 and employed poly(lactic- co -glycolic acid) (PLGA)-based nanoparticle formulation for delivery. A comprehensive evaluation of PLGA nanoparticles (NPs) containing short PNA probes showed significantly superior loading, release profile, and uniform size distribution, compared to conventional non-cationic PNA probes. Confocal microscopy and flow cytometry analyses showed efficient transfection efficiency and uniform distribution of PLGA NPs containing short PNA probes in the cytoplasm. Functional analysis also confirmed efficient miRNA-155 inhibition including an effect on its downstream target proteins. Further, reduced tumor growth was observed after systemic delivery of PLGA nanoparticles containing short PNA probes in vivo in a xenograft mouse model following inhibition of miR-155. There was no evidence of acute or chronic toxicity associated with systemic delivery of PLGA NPs containing short PNA probes in the mice. Overall, in this paper we present a novel antimiR strategy based on PLGA nanoparticle delivered short PNA probes for potential cancer therapy. Unlabelled Image • Short cationic anti-seed PNAs can efficiently inhibit the action of target oncomiRs. • PLGA NPs containing short arginine-PNAs exhibit superior transfection efficiency. • Short anti-seed PNA loaded PLGA NPs prevents tumor growth in a xenograft mice model of lymphoma. • Proposed anti-seed PNA strategy is cost effective and clinically translatable. [ABSTRACT FROM AUTHOR]

Viruses employ multiple strategies to inhibit host mRNA nuclear export. Distinct to the generally nonselective inhibition mechanisms, ORF10 from gammaherpesviruses inhibits mRNA export in a transcript-selective manner by interacting with Rae1 (RNA export 1) and Nup98 (nucleoporin 98). We now report the structure of ORF10 from MHV-68 (murine gammaherpesvirus 68) bound to the Rae1-Nup98 heterodimer, thereby revealing detailed intermolecular interactions. Structural and functional assays highlight that two highly conserved residues of ORF10, L60 and M413, play critical roles in both complex assembly and mRNA export inhibition. Interestingly, although ORF10 occupies the RNA-binding groove of Rae1-Nup98, the ORF10-Rae1-Nup98 ternary complex still maintains a comparable RNA-binding ability due to the ORF10-RNA direct interaction. Moreover, mutations on the RNA-binding surface of ORF10 disrupt its function of mRNA export inhibition. Our work demonstrates the molecular mechanism of ORF10-mediated selective inhibition and provides insights into the functions of Rae1-Nup98 in regulating host mRNA export. [ABSTRACT FROM AUTHOR]

The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer's disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cell types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF-1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signaling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophage populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34. Overall, our results highlight the challenges of targeting the CSF1R/IL34 axis in the systemic and central compartments, important for framing any therapeutic effort to tackle microglia/macrophage numbers during brain disease. [ABSTRACT FROM AUTHOR]

In this study, an original method of macromolecular design was used to develop a hyaluronidase‐1 (HYAL1) inhibitor from its principal substrate, hyaluronic acid (HA). HA‐based nanoparticles (HA‐NP) were obtained by copolymer self‐assembly and their effects on HYAL1 activity were investigated by combining different analytical tools. Compared to HA, HA‐NP exhibited an enhanced stability against HYAL1 degradation while maintaining its interaction with the HA receptors CD44 and aggrecan. HA‐NP displayed a strong and selective inhibition of HYAL1 activity and retarded the hydrolysis of higher‐molar‐mass HA in solution. A co‐nanoprecipitation process was used to formulate a range of hybrid nanoparticle samples, which demonstrated the specificity and efficiency of HA‐NP in HYAL1 inhibition. [ABSTRACT FROM AUTHOR]

The heterogeneously catalysed reaction of hydrogen with carbon monoxide and carbon dioxide (syngas) to methanol is nearly 100 years old, and the standard methanol catalyst Cu/ZnO/Al2O3 has been applied for more than 50 years. Still, the nature of the Zn species on the metallic Cu0 particles (interface sites) is heavily debated. Here, we show that these Zn species are not metallic, but have a positively charged nature under industrial methanol synthesis conditions. Our kinetic results are based on a self-built high-pressure pulse unit, which allows us to inject selective reversible poisons into the syngas feed passing through a fixed-bed reactor containing an industrial Cu/ZnO/Al2O3 catalyst under high-pressure conditions. This method allows us to perform surface-sensitive operando investigations as a function of the reaction conditions, demonstrating that the rate of methanol formation is only decreased in CO2-containing syngas mixtures when pulsing NH3 or methylamines as basic probe molecules. Methanol synthesis has a high potential for global CO2 reduction. Here, the authors identify the oxidation state of the zinc sites on the metallic copper particles as partially positive for an industrial Cu/ZnO/Al2O3 catalyst under high-pressure reaction conditions. [ABSTRACT FROM AUTHOR]

Blocking GSK3α in a fragile X mouse model: Fragile X syndrome is a heritable cause of autism and intellectual disability. Inhibitors of glycogen synthase kinase 3 (GSK3), including lithium, have shown promise in correcting disease phenotypes in a mouse model of fragile X syndrome, but various toxicities have precluded further development of these compounds. McCamphill et al. now report that a major toxicity of GSK3 inhibition, stabilization of β-catenin, could be avoided by selective pharmacological inhibition of the α paralog of GSK3. Furthermore, the authors found that selective inhibition of GSK3α was sufficient to correct a range of disease phenotypes in a mouse model of fragile X syndrome, whereas inhibition of GSK3β was ineffective. Fragile X syndrome is caused by FMR1 gene silencing and loss of the encoded fragile X mental retardation protein (FMRP), which binds to mRNA and regulates translation. Studies in the Fmr1−/y mouse model of fragile X syndrome indicate that aberrant cerebral protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5) signaling contributes to disease pathogenesis, but clinical trials using mGluR5 inhibitors were not successful. Animal studies suggested that treatment with lithium might be an alternative approach. Targets of lithium include paralogs of glycogen synthase kinase 3 (GSK3), and nonselective small-molecule inhibitors of these enzymes improved disease phenotypes in a fragile X syndrome mouse model. However, the potential therapeutic use of GSK3 inhibitors has been hampered by toxicity arising from inhibition of both α and β paralogs. Recently, we developed GSK3 inhibitors with sufficient paralog selectivity to avoid a known toxic consequence of dual inhibition, that is, increased β-catenin stabilization. We show here that inhibition of GSK3α, but not GSK3β, corrected aberrant protein synthesis, audiogenic seizures, and sensory cortex hyperexcitability in Fmr1−/y mice. Although inhibiting either paralog prevented induction of NMDA receptor–dependent long-term depression (LTD) in the hippocampus, only inhibition of GSK3α impaired mGluR5-dependent and protein synthesis–dependent LTD. Inhibition of GSK3α additionally corrected deficits in learning and memory in Fmr1−/y mice; unlike mGluR5 inhibitors, there was no evidence of tachyphylaxis or enhanced psychotomimetic-induced hyperlocomotion. GSK3α selective inhibitors may have potential as a therapeutic approach for treating fragile X syndrome. [ABSTRACT FROM AUTHOR]

Diabetic hearts are more susceptible to myocardial ischemia/reperfusion (I/R) injury and less sensitive to ischemic postconditioning (IPostC), but the underlying mechanisms remain unclear. PKCβ2 is preferentially overactivated in diabetic myocardium, in which autophagy status is abnormal. This study determined whether hyperglycemia-induced PKCβ2 activation resulted in autophagy abnormality and compromised IPostC cardioprotection in diabetes. We found that diabetic rats showed higher cardiac PKCβ2 activation and lower autophagy than control at baseline. However, myocardial I/R further increased PKCβ2 activation and promoted autophagy status in diabetic rats. IPostC significantly attenuated postischemic infarct size and CK-MB, accompanied with decreased PKCβ2 activation and autophagy in control but not in diabetic rats. Pretreatment with CGP53353, a selective inhibitor of PKCβ2, attenuated myocardial I/R-induced infarction and autophagy and restored IPostC-mediated cardioprotection in diabetes. Similarly, CGP53353 could restore hypoxic postconditioning (HPostC) protection against hypoxia reoxygenation- (HR-) induced injury evidenced by decreased LDH release and JC-1 monomeric cells and increased cell viability. These beneficial effects of CGP53353 were reversed by autophagy inducer rapamycin, but could be mimicked by autophagy inhibitor 3-MA. It is concluded that selective inhibition of PKCβ2 could attenuate myocardial I/R injury and restore IPostC-mediated cardioprotection possibly through modulating autophagy in diabetes. [ABSTRACT FROM AUTHOR]

This isoform is just right: Cancer immunotherapy, including immune checkpoint blockade, has achieved increasing prominence in recent years. Unfortunately, only a fraction of tumors respond to this treatment. Previous studies have suggested that inhibition of transforming growth factor–β (TGFβ) may help overcome resistance to immune checkpoint blockade, but it proved to be too toxic for clinical use. Martin et al. designed a more specific inhibitor, targeting only one isoform of TGFβ. The authors showed that this isoform, TGFβ1, is the most relevant one to target in tumors, then demonstrated the effectiveness and safety of their inhibitor with immune checkpoint blockade in multiple mouse models of cancer. Despite breakthroughs achieved with cancer checkpoint blockade therapy (CBT), many patients do not respond to anti–programmed cell death-1 (PD-1) due to primary or acquired resistance. Human tumor profiling and preclinical studies in tumor models have recently uncovered transforming growth factor–β (TGFβ) signaling activity as a potential point of intervention to overcome primary resistance to CBT. However, the development of therapies targeting TGFβ signaling has been hindered by dose-limiting cardiotoxicities, possibly due to nonselective inhibition of multiple TGFβ isoforms. Analysis of mRNA expression data from The Cancer Genome Atlas revealed that TGFΒ1 is the most prevalent TGFβ isoform expressed in many types of human tumors, suggesting that TGFβ1 may be a key contributor to primary CBT resistance. To test whether selective TGFβ1 inhibition is sufficient to overcome CBT resistance, we generated a high-affinity, fully human antibody, SRK-181, that selectively binds to latent TGFβ1 and inhibits its activation. Coadministration of SRK-181-mIgG1 and an anti–PD-1 antibody in mice harboring syngeneic tumors refractory to anti–PD-1 treatment induced profound antitumor responses and survival benefit. Specific targeting of TGFβ1 was also effective in tumors expressing more than one TGFβ isoform. Combined SRK-181-mIgG1 and anti–PD-1 treatment resulted in increased intratumoral CD8+ T cells and decreased immunosuppressive myeloid cells. No cardiac valvulopathy was observed in a 4-week rat toxicology study with SRK-181, suggesting that selectively blocking TGFβ1 activation may avoid dose-limiting toxicities previously observed with pan-TGFβ inhibitors. These results establish a rationale for exploring selective TGFβ1 inhibition to overcome primary resistance to CBT. [ABSTRACT FROM AUTHOR]

Butanal conversion has been studied over Zr‐BEA zeolites with different amount of partially hydrolyzed open Zr‐sites and fully condensed closed sites. The kinetic study pointed that the main reaction pathway of butanal conversion involves its self‐condensation into 2‐ethyl‐2‐hexenal (2‐EN), the selectivity to 2‐EN being within 80–85 %. Besides, small amounts of 1‐butanol and butanoic acid are formed via Cannizzaro disproportionation of butanal. Secondary reactions include butanoic acid ketonization to 4‐heptanone and esterification to butyl butanoate and tandem hydrogenation/dehydration of 2‐EN into octadienes. A number of techniques, including FTIR spectroscopy of adsorbed CO, pyridine, 2,6‐di‐tert‐butylpyridine (DTBPy), TPD of isopropylamine and selective poisoning with DTBPy were applied for characterization of Zr‐sites and elucidation of their activity. Open Zr‐sites were found to be more active with respect to closed Zr‐sites in butanal condensation: the TOF values estimated at 433 K being 1.4 s−1 for open Zr‐sites and 0.6 s−1 for closed sites. On the contrary, selectivity into 2‐EN was similar for open and closed sites. The results point that Zr‐BEA catalysts with enhanced content of open sites are perspective catalysts for the selective synthesis of 2‐EN. [ABSTRACT FROM AUTHOR]

Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) with the pharmaceutical rapamycin prolongs the lifespan and healthspan of model organisms including rodents, with evidence now emerging that rapamycin and its analogs may also have rejuvenative effects in dogs and humans. However, the side effects associated with long-term rapamycin treatment, many of which are due to inhibition of a second mTOR complex, mTORC2, have seemed to preclude the routine use of rapamycin as a therapy for age-related diseases. Here, we discuss recent findings suggesting that strong, chronic inhibition of both mTOR complexes may not be necessary to realize the geroprotective effects of rapamycin. Instead, modestly but specifically inhibiting mTORC1 via a variety of emerging techniques, including intermittent or transient treatment with rapamycin derivatives, or specific dietary regimens, may be sufficient to promote health and longevity with reduced side effects. We will also discuss prospects for the development of new molecules that, by harnessing the detailed molecular understanding of mTORC1 signaling developed over the last decade, will provide new routes to the selective inhibition of mTORC1. We conclude that therapies based on the selective inhibition of mTORC1 may soon permit the safer treatment of diseases of aging. [ABSTRACT FROM AUTHOR]

Selective inhibition (SI) has been routinely used to differentiate the contributions of bacteria and fungi to soil ecological processes. SI experiments typically measured rapid responses within hours since the addition of inhibitor, but the long-term effects of selective biocides on microbial community composition and function were largely unknown. In this study, a microcosm experiment was performed with an agricultural soil to explore the effectiveness of two bactericides (bronopol, streptomycin) and two fungicides (cycloheximide, captan), which were applied at two different concentrations (2 and 10 mg g−1). The microcosms were incubated for 6 weeks. A radiolabeled substrate, [1,2,3,4,4a,9a-14C] anthracene, was spiked to all microcosms, and the derived CO2 was monitored during the incubation. The abundance and composition of bacteria and fungi were assessed by qPCR and Miseq sequencing of ribosomal rRNA genes. It was demonstrated that only 2 mg g−1 bronopol and cycloheximide significantly changed the bacteria to fungi ratio without apparent non-target inhibition on the abundances; however, community shifts were observed in all treatments after 6 weeks incubation. The enrichment of specific taxa implicated a selection of resistant or adapted microbes by these biocides. Mineralization of anthracene was continuingly suppressed in all SI microcosms, which may result in biased estimate of bacterial and fungal contributions to pollutant degradation. These findings highlight the risks of long-term application of selective inhibition, and a preliminary assessment of biocide selection and concentration is highly recommended. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDAC) are evolutionary conserved enzymes, which catalyze removal of acetyl groups from histone and non-histone proteins, therefore, control multiple biological processes. Inhibition of their activities have been investigated to modify gene expression and/or protein functions not only for treatment of certain diseases but also for understanding functions of deacetylase isoforms. We previously synthesized aryl butenoic acid derivatives and identified their pan-HDAC inhibition activities. In this study, we investigated selective inhibition activities of these derivatives (C1, C3, C4) on class I HDACs using in silico and in vitro approaches. Molecular docking studies of the three aryl butenoic acid derivatives were performed on the crystal structures of HDAC 1, 2, 3 and 8, which were obtained from RCSB protein databank, using Glide software. In vitro inhibition activities of the compounds at two different concentrations were tested using fluorometric assay. In silico results indicated that all the compounds showed higher affinity to HDAC 1 and 8 than other class I deacetylases. In vitro analysis showed that the compounds inhibit HDAC 8 more effectively than HDAC 1. It was shown that C1 had higher binding affinity and inhibition activity to both enzymes. We concluded that, C1 inhibited both HDAC 1 and 8, however, C3 and C4 showed slight selectivity for HDAC 8 over HDAC 1, which was in agreement with the docking studies. Further cell culture studies will be valuable to determine increased acetylation on target proteins in response to compound treatment. [ABSTRACT FROM AUTHOR]

Estrogens are the major female sex steroid hormones, estradiol (E2) being the most potent form in humans. Disturbing the balance between E2 and its weakly active oxidized form estrone (E1) leads to diverse types of estrogen-dependent diseases such as endometriosis or osteoporosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the biosynthesis of E2 by reduction of E1 while the type 2 enzyme catalyzes the reverse reaction. Thus, 17β-HSD1 and 17β-HSD2 are attractive targets for treatment of estrogen-dependent diseases. Recently, we reported the first proof-of-principle study of a 17β-HSD2 inhibitor in a bone fracture mouse model, using subcutaneous administration. In the present study, our aim was to improve the in vitro ADME profile of the most potent 17β-HSD1 and 17β-HSD2 inhibitors described so far. The optimized compounds show strong and selective inhibition of both the human enzymes and their murine orthologs. In addition, they display good metabolic stability in human liver microsomes (S9 fraction), low in vitro cytotoxicity as well as better aqueous solubility and physicochemical properties compared to the lead compounds. These achievements make the compounds eligible for testing in preclinical in vivo animal model studies on the effects of inhibition of 17β-HSD1 and 17β-HSD2. Image 1 • Bicyclic substituted hydroxyphenylmethanones were structurally modified. • Inhibition of 17β-HSD1 & 2 was evaluated and SARs were derived. • Potent and selective 17β-HSD1 & 2 inhibitors, active on murine orthologs, were discovered. • In vitro ADME profiling and docking of a promising 17ß-HSD1 inhibitor were performed. [ABSTRACT FROM AUTHOR]

In multiple myeloma (MM), homeostasis is largely maintained by misfolded protein clearance via the proteasomal and aggresomal pathways. Histone deacetylase 6 (HDAC6) binds polyubiquitinated proteins and dynein motors and transports this protein cargo to the aggresome for further degradation. Accordingly, a combination of an HDAC6 inhibitor and bortezomib (BTZ) could increase ubiquitinated protein accumulation, leading to further apoptosis. Here we evaluated the anti-MM activity of MPT0G413, a novel specific HDAC6 inhibitor, using in vitro and in vivo models. MPT0G413 treatment more significantly inhibited cell growth in MM cells than in normal bone marrow cells. Furthermore, the combination of MPT0G413 and BTZ enhanced polyubiquitinated protein accumulation and synergistically reduced MM viability, increased caspase-3, caspase-8, caspase-9 levels, and cleaved poly (ADP) ribosome polymerase and also inhibited adherence of MM cells to bone marrow stromal cells (BMSC) and reduced VEGF and IL-6 levels and cell growth in a co-culture system. The combination treatment disturbed the bone marrow microenvironment and induced synergic, caspase-dependent apoptosis. Xenograft tumor growth significantly decreased in combination-treated SCID mice. In conclusion, MPT0G413 and BTZ synergistically inhibit MM viability, providing a framework for the clinical evaluation of combined therapies for MM. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A stereoselective synthesis of the ITK inhibitor GNE-6688 has been accomplished. • An enantioselective transfer hydrogenation was used to prepare the Western fragment. • An enantioselective allylboration, and a directed cyclopropanation were key steps for the Eastern fragment. Abstract An enantioselective synthesis of the previously-disclosed ITK inhibitor GNE-6688 is described. Synthesis of the nitropyrazole fragment is highlighted by a Ru-catalyzed transfer hydrogenation using the Wills tethered ligand system. Synthesis of the pyrazole carboxylic acid fragment features an allylboration catalyzed by a chiral diol-SnCl 4 complex, followed by a highly diastereoselective directed cyclopropanation. [ABSTRACT FROM AUTHOR]

Abstract Triple-negative breast cancer (TNBC) shows highly aggressive clinical behaviors and poor prognosis compared to other breast cancer subtypes. Histone deacetylases (HDACs) can regulate the progression of various cancers, but the role of HDAC8 in TNBC remains unexplored. Here, we found that HDAC8 enhanced the in vitro migration abilities of breast cancer cells. Targeted inhibition of HDAC8 via si-HDAC8 and its selective inhibitor PCI34051 could suppress the migration of cells. In TNBC cells, HDAC8 stabilized the expression and increased the nuclear localization of YAP, a major downstream effector of Hippo pathway. While silencing YAP could attenuate HDAC8 triggered migration of TNBC cells. Mechanistically, HDAC8 suppressed the phosphorylation of YAPSer127, which was related to its cytoplasmic sequestration degradation. Our data revealed that HDAC8 could trigger the migration of TNBC cells via regulation of Hippo-YAP signals, suggesting that HDAC8 might be a potential target for TNBC therapy. [ABSTRACT FROM AUTHOR]

• Heavy metals in flue gas can result in deactivation and deterioration of SCR catalysts by poisoning the active sites on catalyst. • The paper reviews the new research progress of the poisoning mechanism of different heavy metals on SCR catalysts. • Various anti-heavy metal poisoning measures and mechanisms were summarized. • Anti-poisoning ability of SCR catalysts can be effectively improved using various measures. Selective catalytic reduction (SCR) denitrification technology is the most widely used, mature and efficient flue gas denitrification technology because of its high denitrification efficiency, good selectivity and clean process. However, heavy metals in flue gas can result in deactivation and deterioration of SCR catalysts by poisoning active sites on catalyst. Therefore, it is necessary to study the heavy metal poisoning mechanism and anti-heavy metal poisoning measures of SCR catalyst for reducing the operating cost of SCR denitrification system. This paper reviews the new research progress of the poisoning mechanism of different heavy metals on SCR catalysts (including vanadium-based catalysts, manganese-based catalysts, cerium-based catalysts). Various anti-heavy metal poisoning measures and mechanisms (e.g., doping metal and nonmetal elements, etc.) were summarized. Results show that the deposition of heavy metals on SCR catalyst causes the catalyst pores to be blocked, which reduces the specific surface area and pore volume of the catalyst and destroys the active sites on catalyst surface, thereby eventually leading to physical or/and chemical poisoning of catalyst. The anti-poisoning ability of SCR catalysts can be effectively improved by doping with metals or non-metals and using and synthesizing of carrier materials. Besides, the regeneration measures of SCR catalysts poisoning by heavy metals were also reviewed systematically. Solution wet washing, thermal reduction method and composite method are the common methods for the regeneration of heavy metal-poisoning SCR catalysts. Finally, the prospects and future directions for the development of heavy metal poisoning of selective catalytic reduction (SCR) denitration catalyst are presented. [ABSTRACT FROM AUTHOR]

Cu-CHA catalysts for NH 3 -SCR in exhaust after treatment systems of heavy-duty vehicles, are constantly exposed to SO 2 during their lifetime of about 10,000 h. In order to study the development of deactivation by SO 2 , a Cu-CHA catalyst was exposed to SO 2 at 200, 300, 400 and 500 °C for different durations up to 120 h, resulting in total SO 2 exposures that are comparable to that of the lifetime of a Cu-CHA catalyst in an after treatment system. The measured deactivation increases very fast to a steady level in the range 0.85–0.95, dependent on the exposure temperature, which shows the need for frequent regeneration of the catalyst. Regeneration at 550 °C can restore the activity of the catalyst to 80% of its fresh activity level even after 120 h exposure, suggesting frequent regeneration as a feasible method for overcoming SO 2 -poisoning. ICP analyses showed that SO 2 exposure led to S/Cu ratios in the range 0.5–1, indicating that sulfur is associated with Cu. After regeneration the S/Cu ratios did not exceed 0.2, suggesting that only certain Cu sites are able to form Cu,S species that are thermally stable above 550 °C. This together with the observations that the deactivation before and after regeneration impact differently on the activation energy of the SCR reaction, and that the deactivation never exceeded 0.95, suggests that SO 2 -poisoning of Cu-CHA depends on the structural properties of this material. TGA measurements of the mass uptake during SO 2 exposure was consistent with a process where SO 2 is initially adsorbed on Cu, and then slowly oxidized to SO 3 at 200 °C, whereas the mass uptake at 500 °C was consistent with an immediate adsorption of SO 3 , which is accredited to a faster oxidation rate at higher temperature. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3-dioxygenase 1 (IDO1) activity links to immune escape of cancers. Inhibition of IDO1 provides a new approach for cancer treatment. Most clinical IDO1 drugs show marginal efficacy as single agents. On basis of molecular docking and pharmacophore modelling, a novel inhibitor Roxyl-WL was discovered with a half maximal inhibitory concentration (IC50) value of 1 nM against IDO1 and 10-100-fold increased potent activity compared with IDO1 drugs in clinical trials. Roxyl-WL displayed excellent kinase spectrum selectivity with no activity out of the 337 protein kinases. In vitro, Roxyl-WL effectively augmented the proliferation of T cells and reduced the number of regulatory T cell (Tregs).When administered to melanoma (B16F10) tumor-bearing mice orally, Roxyl-WL significantly suppressed tumor growth and induced immune response. [ABSTRACT FROM AUTHOR]

Selective inhibition with sulphonamides of carbonic anhydrase (CA) IX reduces cell proliferation and induces apoptosis in human cancer cells. The effect on CA IX expression of seven previously synthesised sulphonamide inhibitors, with high affinity for CA IX, as well as their effect on the proliferation/apoptosis of cancer/normal cell lines was investigated. Two normal and three human cancer cell lines were used. Treatment resulted in dose- and time-dependent inhibition of the growth of various cancer cell lines. One compound showed remarkably high toxicity towards CA IX-positive HeLa cells. The mechanisms of apoptosis induction were determined with Annexin-V and AO/EB staining, cleaved caspases (caspase-3, caspase-8, caspase-9) and cleaved PARP activation, reactive oxygen species production (ROS), mitochondrial membrane potential (MMP), intracellular pH (pHi), extracellular pH (pHe), lactate level and cell cycle analysis. The autophagy induction mechanisms were also investigated. The modulation of apoptotic and autophagic genes (Bax, Bcl-2, caspase-3, caspase-8, caspase-9, caspase-12, Beclin and LC3) was measured using real time PCR. The positive staining using γ-H2AX and AO/EB dye, showed increased cleaved caspase-3, caspase-8, caspase-9, increased ROS production, MMP and enhanced mRNA expression of apoptotic genes, suggesting that anticancer effects are also exerted through its apoptosis-inducing properties. Our results show that such sulphonamides might have the potential as new leads for detailed investigations against CA IX-positive cervical cancers. [ABSTRACT FROM AUTHOR]

Pyridinium containing sulfonamides have been largely investigated as carbonic anhydrase inhibitors (CAIs), showing interesting selectivity features. Nevertheless, only few structural studies are so far available on adducts that these compounds form with diverse CA isoforms. In this paper, we report the structural characterization of the adduct that a triphenylpyridinium derivative forms with hCA II, showing that the substitution of the pyridinium ring plays a key role in determining the conformation of the inhibitor in the active site and consequently the binding affinity to the enzyme. These findings open new perspectives on the basic structural requirements for designing sulfonamide CAIs with a selective inhibition profile. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Twenty-eight coumarin-dithiocarbamate hybrids were designed and synthesized. • 8g was identified as a potent and balanced inhibitor for AChE and MAO-B. • 8g showed no acute toxicity in mice and could penetrate the BBB. • 8g could significantly reverse scopolamine-induced memory deficit in vivo. Abstract A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC 50 values of 0.0068 μM and 0.0089 μM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 µM for hAChE; 0.101 µM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold. [ABSTRACT FROM AUTHOR]

In a recent study, the differential effects of prolonged physiologically challenging exercise upon two executive processes (cognitive control and working memory) were investigated. However, the impact of exercise on the selective inhibition task employed was debatable and needed further analysis to dissociate the effects induced by exercise intensity from those induced by the time spent on task upon cognitive control outcomes. In this study, we propose a thorough analysis of these data, using a generalized mixed model on a trial-by-trial basis and a new measure of the strength of the automatic response based on reaction time distribution, to disentangle the effect of physical fatigue from cognitive fatigue. Despite the prolonged duration of exercise, no decline in cognitive performance was found in response to physical fatigue. The only change observed during 60-min exercise was an acceleration of the correct trials and an increase of errors for incompatible trials. This pattern, shown during low and physiologically challenging exercise, supports the occurrence of cognitive fatigue induced by the repetition of the cognitive tasks over time. [ABSTRACT FROM AUTHOR]

N-(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine [ASP2905] is a potent and selective inhibitor of the potassium voltage-gated channel subfamily H member 3 (KCNH3) that was originally identified in our laboratory. KCNH3 is concentrated in the forebrain, and its overexpression in mice leads to cognitive deficits. In contrast, Kcnh3 knockout mice exhibit enhanced performance in cognitive tasks such as attention. These data suggest that KCNH3 plays important roles in cognition. Here we investigated the neurochemical and neurophysiological profiles of ASP2905 as well as its effects on cognitive function, focusing on attention. ASP2905 (0.0313 and 0.0625 mg/kg, po) improved the latent learning ability of mice, which reflects attention. Microdialysis assays in rats revealed that ASP2905 increased the efflux of dopamine and acetylcholine in the medial prefrontal cortex (0.03, 0.1 mg/kg, po; 0.1, 1 mg/kg, po, respectively). The activities of these neurotransmitters are closely associated with attention. We used a multiple-trial passive avoidance task to investigate the effects of ASP2905 on inattention and impulsivity in juvenile stroke-prone spontaneously hypertensive rats. ASP2905 (0.1 and 0.3 mg/kg, po) significantly prolonged cumulative latency as effectively as methylphenidate (0.1 and 0.3 mg/kg, sc), which is the gold standard for treating ADHD. Further, ASP2905, amphetamine, and methylphenidate significantly increased the alpha-band power of rats, suggesting that ASP2905 increases arousal, which is a pharmacologically important activity for treating ADHD. In contrast, atomoxetine and guanfacine did not significantly affect power. Together, these findings suggest that ASP2905, which acts through a novel mechanism, is as effective for treating ADHD as currently available drugs such as methylphenidate. [ABSTRACT FROM AUTHOR]

Abstract: Lysine‐specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A‐tri‐/di‐methylated histone 3 protein–protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple‐negative breast cancer (TNBC) cell lines, MDA‐MB‐231 and 4T1. Finally, 1 exhibited potent anti‐tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal‐based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC. [ABSTRACT FROM AUTHOR]

Introduction: Acute kidney injury (AKI), which is based on ischemic-reperfusion damage, is a widespread life-threatening condition and remains a serious public health problem with a high mortality rate among patients. Despite significant advances in various areas of medicine, the prevention and correction of ischemic-reperfusion kidney damage are still far from being at the desired level. Pharmacological preconditioning and the use of endothelioprotectors are promising areas in this field, therefore the purpose of this study was to analyze the nephroprotective properties of asialoerythropoietin and selective inhibitor of arginase II KUD975 in ischemic kidney damage in the experiment. Materials and methods: The study was performed on 260 white adult male Wistar rats, each weighing 180-220 g. Ischemic- reperfusion damage was simulated by applying a clamp on the renal leg for 40 minutes. To determine a degree of correction caused by morphofunctional disorders traditional functional, biochemical and morphological criteria were used. Results and discussion: When administering asialoerythropoietin and selective inhibitor of arginase II KUD975, there is observed an improvement in the glomerular filtration and microcirculation in the kidneys, decrease in the concentration of creatinine and urea, a decrease in fractional excretion of sodium and improvement in the histological pattern at different periods. The most pronounced nephroprotective effects are observed in the combined use of the test pharmacological agents, which are superior to such used in a monotherapy. The use of glibenclamide and L-NAME against the background of the correction of the pathology caused by asialoerythropoietin completely eliminates its positive effects. When glibenclamide and L-NAME are used against the background of correction of the pathology caused by the selective inhibitor of arginase II KUD975, its positive effects are completely eliminated by L-NAME. Glibenclamide does not eliminate positive effects. Conclusions: The results of the experiment prove the presence of pronounced nephroprotective properties of asialoerythropoietin and selective inhibitor of arginase II KUD975 in ischemic kidney damage in the experiment. The most pronounced effects are observed in the combined use of these pharmacological agents. The leading role in causing the positive effects from asialoerythropoietin is played by the activation of K+ATP channels and the activation of eNOS. The leading role in causing the positive effects from the selective inhibitor of arginase II KUD975 is played by the activation of eNOS. [ABSTRACT FROM AUTHOR]

All cellular processes, including those involved in normal cell metabolism to those responsible for cell proliferation or death, are finely controlled by cell signaling pathways, whose core proteins constitute the family of phosphatidylinositol 3-kinase-related kinases (PIKKs). Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia and Rad3 related (ATR) are two important PIKK proteins that act in response to DNA damage, phosphorylating a large number of proteins to exert control over genomic integrity. The genus Leishmania belongs to a group of early divergent eukaryotes in evolution and has a highly plastic genome, probably owing to the existence of signaling pathways designed to maintain genomic integrity. The objective of this study was to evaluate the use of specific human inhibitors of ATR and ATM in Leishmania major. Bioinformatic analyses revealed the existence of the putative PIKK genes ATR and ATM, in addition to mTOR and DNA-PKcs in Leishmania spp. Moreover, it was possible to suggest that the inhibitors VE-821 and KU-55933 have binding affinity for the catalytic sites of putative L. major ATR and ATM, respectively. Promastigotes of L. major exposed to these inhibitors show slight growth impairment and minor changes in cell cycle and morphology. It is noteworthy that treatment of promastigotes with inhibitors VE-821 and KU-55933 enhanced the oxidative damage caused by hydrogen peroxide. These inhibitors could significantly reduce the number of surviving L. major cells following H2O2 exposure whilst also decreasing their evaluated IC50 to H2O2 to less than half of that observed for non-treated cells. These results suggest that the use of specific inhibitors of ATR and ATM in Leishmania interferes in the signaling pathways of this parasite, which can impair its tolerance to DNA damage and affect its genome integrity. ATR and ATM could constitute novel targets for drug development and/or repositioning for treatment of leishmaniases. [ABSTRACT FROM AUTHOR]

We report herein the synthesis and biological evaluation of a new series of 2,4,6-trisubstituted 1,3,5-triazines as reversible inhibitors of human cysteine cathepsins. The desired products bearing morpholine and N -Boc piperidine, respectively, were obtained in three to four steps from commercially available trichlorotriazine. Seventeen hitherto unknown compounds were evaluated in vitro against various cathepsins for their inhibitory properties. Among them, compound 7c (4-(morpholin-4-yl)-6-[4-(trifluoromethoxy)anilino]-1,3,5-triazine-2-carbonitrile) was identified as the most potent and selective inhibitor of cathepsin S (Ki  =  2  ±  0.3 nM). Also 7c impaired the autocatalytic maturation of procathepsin S. Molecular docking studies support that 7c bound within the active site of cathepsin S, by interacting with Gly23, Cys25 and Trp26 (S1 subsite), with Asn67, Gly69 and Phe70 (S2 subsite) and with Gln19 (S1′ pocket). [ABSTRACT FROM AUTHOR]

The rapid growth of antibiotic-resistant bacterial infections is of major concern for human health. Therefore, it is of great importance to characterize novel targets for the development of antibacterial drugs. One promising protein target is MraY (UDP- N -acetylmuramyl-pentapeptide: undecaprenyl phosphate N -acetylmuramyl-pentapeptide-1-phosphate transferase or MurNAc-1-P-transferase), which is essential for bacterial cell wall synthesis. Here, we summarize recent breakthroughs in structural studies of bacterial MraYs and the closely related human GPT (UDP- N -acetylglucosamine: dolichyl phosphate N -acetylglucosamine-1-phosphate transferase or GlcNAc-1-P-transferase). We present a detailed comparison of interaction modes with the natural product inhibitors tunicamycin and muraymycin D2. Finally, we speculate on possible routes to design an antibacterial agent in the form of a potent and selective inhibitor against MraY. [ABSTRACT FROM AUTHOR]

Background and Purpose: Cyclin D-dependent kinases 4 and 6 (CDK4/6) are crucial regulators of the G1 to S phase transition of the cell cycle and are actively pursued as therapeutic targets in cancer. We sought to discover a novel series of orally bioavailable and highly selective small molecule inhibitors of CDK4/6.Experimental Approach: The discovery of pharmacological inhibitors and optimization for potency, selectivity and drug properties were achieved by iterative chemical synthesis, biochemical screening against a panel of kinases, cell-based assays measuring cellular viability, cell cycle distribution, induction of apoptosis and the level of retinoblastoma tumour suppressor protein (Rb) phosphorylation and E2 factor (E2F)-regulated gene expression and in vitro biopharmaceutical and in vivo pharmacokinetic profiling.Key Results: We discovered several lead compounds that displayed >1000-fold selectivity for CDK4/6 over other members of the CDK family. The lead compounds, 82, 91 and 95, potently inhibited the growth of cancer cells by inducing G1 arrest with a concomitant reduction in the phosphorylation of Rb at S780 and in E2F-regulated gene expression. With a remarkable selectivity for CDK4 over 369 human protein kinases, 91 was identified as a highly potent and orally bioavailable drug candidate.Conclusions and Implications: We have identified unique and new inhibitors of CDK4/6 as potential drug candidates. Compound 91 represents an ideal candidate for further development as targeted cancer therapy. [ABSTRACT FROM AUTHOR]

A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with ∼15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members. In addition, 8b, 8k and 8m also demonstrate selectivity over PARP1. Together, this study identified novel, potent and metabolically stable derivatives to use as chemical probes for these biologically interesting therapeutic targets. [ABSTRACT FROM AUTHOR]

Neuronal α3-containing nicotinic acetylcholine receptors (nAChRs) in the peripheral nervous system (PNS) and non-neuronal tissues are implicated in a number of severe disease conditions ranging from cancer to cardiovascular diseases and chronic pain. However, despite the physiological characterization of mouse models and cell lines, the precise pathophysiology of nAChRs outside the CNS remains not well understood, in part because there is a lack of subtype-selective antagonists. α-Conotoxins isolated from cone snail venom exhibit characteristic individual selectivity profiles for nAChRs and, therefore, are excellent tools to study the determinants for nAChR-antagonist interactions. Given that human α3β4 subtype selective α-conotoxins are scarce and this is a major nAChR subtype in the PNS, the design of new peptides targeting this nAChR subtype is desirable. Recent studies using α-conotoxins RegIIA and AuIB, in combination with nAChR site-directed mutagenesis and computational modelling, have shed light onto specific nAChR residues, which determine the selectivity of the α-conotoxins for the human α3β2 and α3β4 subtypes. Publications describing the selectivity profile and binding sites of other α-conotoxins confirm that subtype-selective nAChR antagonists often work through common mechanisms by interacting with the same structural components and sites on the receptor.Linked Articles: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase-12 (MMP-12) selective inhibitors could play a role in the treatment of lung inflammatory and cardiovascular diseases. In the present study, the previously reported 4-methoxybiphenylsulfonyl hydroxamate and carboxylate based inhibitors (1b and 2b) were modified to enhance their selectivity for MMP-12. In the newly synthesized thioaryl derivatives, the nature of the zinc binding group (ZBG) and the sulfur oxidation state were changed. Biological assays carried out in vitro on human MMPs with the resulting compounds led to identification of a sulfide, 4a, bearing an N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. Compound 4a is a promising hit compound since it displayed a nanomolar affinity for MMP-12 with a marked selectivity over MMP-9, MMP-1, and MMP-14. Solution complexation studies with Zn2+ were performed to characterize the chelating abilities of the new compounds and confirmed the bidentate binding mode of HPD derivatives. X-ray crystallography studies using MMP-12 and MMP-9 catalytic domains were carried out to rationalize the biological results. [ABSTRACT FROM AUTHOR]

Protein kinase C iota (PKC-ι) is an atypical kinase implicated in the promotion of different cancer types. A biochemical screen of a fragment library has identified several hits from which an azaindole-based scaffold was chosen for optimization. Driven by a structure-activity relationship and supported by molecular modeling, a weakly bound fragment was systematically grown into a potent and selective inhibitor against PKC-ι. [ABSTRACT FROM AUTHOR]