Strong Intrinsic Activity Research Articles

Synergistic sulfur-doped tri-metal phosphide electrocatalyst for efficient hydrazine oxidation in water electrolysis: Toward high-performance hydrogen fuel generation

Replacing the slow anodic oxygen evolution reaction with the hydrazine (N2H4) oxidation reaction (HzOR) is a promising strategy for achieving energy-efficient hydrogen (H2) fuel production in water electrolyzer systems. Therefore, developing efficient electrocatalysts for the HzOR, in combination with the cathodic hydrogen evolution reaction, is essential for achieving high H2 fuel generation rates and advancing N2H4 fuel cell technology. In this study, we fabricated NiCoFe oxide derived from a metal-organic framework, followed by the physical mixing and carbonization of S and P. The strong intrinsic activity of S-doped tri-metal phosphide (TMP) against the HzOR is evidenced by its role in the chemisorption of N2H4 on its surface, where a dative link is formed between the electrons of the lone pair of nitrogen atoms in N2H4 and the empty orbitals of the metals in the TMP alloy. Using this process, we demonstrated the high performance of flow cell electrolysis for overall water and hydrazine oxidation by assembling the S-TMP||S-TMP electrode as both the anode and cathode of the electrolyzer. The resulting cell voltage was 0.35 V for HzOR and 1.53 V for overall water splitting, and the electric current density reached 10 mA·cm−2, with high stability over 20 h. The electrolyzer efficiency was significantly superior to that of electrolyzers constructed using other types of dual-purpose electrocatalysts as catalyst pairs. Furthermore, the overall effectiveness of the electrolyzer was comparable to that of electrolyzers incorporating two distinct, well-established, single-purpose electrocatalyst pairs for the water and hydrazine splitting reactions.

Curcumin derivatives for Type 2 Diabetes management and prevention of complications.

Type 2 diabetes Mellitus (T2DM) is characterized by chronically increased blood glucose levels, which is associated with impairment of the inflammatory and oxidative state and dyslipidaemia. Although it is considered a world heath concern and one of the most studied diseases, we are still pursuing an effective therapy for both the pathophysiological mechanisms and the complications. Curcumin, a natural compound found in the rhizome of Curcuma longa, is well known for its numerous biological activities, as demonstrated by several studies supporting that curcumin possesses hypoglycaemic, hypolipidemic, anti-inflammatory and antioxidant properties, among others. These effects have been explored to the attenuation of hyperglycaemia and progression of DM complications, being appointed as a potential therapeutic approach. Besides its strong intrinsic activity, the polyphenol has low bioavailability, compromising its therapeutic efficacy. In order to overcome this limitation, several chemical strategies have been applied to curcumin, such as drug delivery systems, chemical manipulation and the use of adjuvant therapies. Given the promising results obtained with curcumin derivative, in this review we discuss not only the therapeutic targets of curcumin, but also its most recently developed analogues and their efficacy in the management of T2DM pathophysiology and complications.

Synthesis and biological activity of analogs of the antifungal antibiotic UK-2A. III. Impact of modifications to the macrocycle isobutyryl ester position.

Fenpicoxamid (Inatreq™ active), a new fungicide under development by Corteva Agriscience™, Agriculture Division of DowDuPont, is an isobutyryl acetal derivative of the antifungal antibiotic UK-2A. SAR studies around the picolinamide ring and benzyl substituents attached at positions 3 and 8, respectively, of the UK-2A bislactone macrocycle have recently been documented. This study focuses on replacement of the isobutyryl ester group in the 7 position. Thirty analogs, predominantly esters and ethers, were prepared and evaluated for inhibition of mitochondrial electron transport and in vitro growth of Zymoseptoria tritici, Leptosphaeria nodorum, Pyricularia oryzae and Ustilago maydis. Aliphatic substituents containing four to six carbon atoms deliver strong intrinsic activity, the pivaloate ester (IC50 1.44 nM) and the n-butyl, 1-Me-propyl, 3,3-diMe-propyl and 2-c-propyl propyl ethers (IC50 values = 1.08, 1.14, 1.15 & 1.32 nM, respectively) being the most active derivatives. QSAR modelling identified solvation energy (Esolv ) and critical packing parameters (vsurf_CP) as highly significant molecular descriptors for explaining relative intrinsic activity of analogs. Activity translation to fungal growth inhibition and disease control testing was significantly influenced by intrinsic activity and physical properties, the cyclopropanecarboxylate ester (log D 3.67, IC50 3.36 nM, Z. tritici EC50 12 μg L-1 ) showing the strongest Z. tritici activity in protectant tests. Substitution of the isobutyryl ester group of UK-2A generates analogs that retain strong antifungal activity against Z. tritici and other fungi. © 2019 Society of Chemical Industry.

Molecular mechanisms of the antispasticity effects of baclofen on spinal ventral horn neurons.

Baclofen is a lipophilic γ-aminobutyric acid (GABA) derivative that exhibits strong intrinsic activity and a high affinity for GABAB receptors. Intrathecal baclofen therapy has been used as an antispasticity and muscle relaxant drug in the clinical treatment of patients with severe spasticity. However, the cellular mechanisms of the antispasticity effects of baclofen on the ventral horn neurons of the spinal cord are unknown. We examined the action of baclofen on excitatory synaptic transmission in ventral horn neurons in the rat spinal cord by whole-cell patch-clamp recordings. Baclofen significantly reduced the frequency and amplitude of miniature excitatory postsynaptic currents. The reduction in miniature excitatory postsynaptic current frequency was particularly strong, indicating presynaptic inhibition by baclofen. Moreover, baclofen-induced outward currents in all neurons tested. The baclofen-induced outward currents persisted in the presence of tetrodotoxin and glutamate receptor antagonists and were diminished in the presence of the postsynaptic intracellular K channel blocker cesium sulfate and the G-protein inhibitor guanosine 5'-(β-thio)diphosphate trilithium salt. These results indicate direct postsynaptic depression mediated by G-protein-activated K channels by GABAB receptors on ventral horn neurons. The baclofen-induced outward currents and the inhibitory effects on spontaneous excitatory postsynaptic currents were blocked by the selective GABAB receptor antagonist CGP35348. Baclofen may have both presynaptic and postsynaptic capacity to inhibit synaptic transmission in ventral horn neurons by GABAB receptors. These cellular mechanisms may induce the antispasticity effects of intrathecal baclofen therapy in the spinal cord.

Assessment of selection and resistance risk for demethylation inhibitor fungicides in Aspergillus fumigatus in agriculture and medicine: a critical review

An increasing number of publications have claimed that demethylation inhibitor (DMI) fungicides are confronted with resistance development in the fungus Aspergillus fumigatus and that the origin of resistant isolates may also be outside the medical area. For resistance risk assessment and sourcing the origin of DMI resistance, the primary exposure events ofA. fumigatus with DMI treatments have been analysed case by case, resulting in the pathogen exposure risk (PER). The calculated maximum exposure concentrations (MEC) are highest during medical treatments (human and veterinary), certain fruit and seed treatments and wood preservation, and are much lower for crop protection applications. Most agricultural DMIs are intrinsically ∼10-100 times less active than medical DMIs for A. fumigatus control and potential resistance selection. However, imazalil is used in agriculture and veterinary medicine (as enilconazole) expressing strong intrinsic activity against A. fumigatus. The majority of mutations in the target gene, cyp51, of DMI-resistant isolates are different in A. fumigatus(e.g. TR34/L98H) in comparison with plant pathogens (e.g. A379G, I381V). The assumed selection risk, ASR (MEC × PER) for resistance evolution to DMIs in A. fumigatus is estimated to be highest for human and veterinary applications. However, environmental origin of DMI-resistant spores from certain sites cannot be ruled out.

HdaA, a Major Class 2 Histone Deacetylase of Aspergillus nidulans , Affects Growth under Conditions of Oxidative Stress

Histone deacetylases (HDACs) catalyze the removal of acetyl groups from the epsilon-amino group of distinct lysine residues in the amino-terminal tail of core histones. Since the acetylation status of core histones plays a crucial role in fundamental processes in eukaryotic organisms, such as replication and regulation of transcription, recent research has focused on the enzymes responsible for the acetylation/deacetylation of core histones. Very recently, we showed that HdaA, a member of the Saccharomyces cerevisiae HDA1-type histone deacetylases, is a substantial contributor to total HDAC activity in the filamentous fungus Aspergillus nidulans. Now we demonstrate that deletion of the hdaA gene indeed results in the loss of the main activity peak and in a dramatic reduction of total HDAC activity. In contrast to its orthologs in yeast and higher eukaryotes, HdaA has strong intrinsic activity as a protein monomer when expressed as a recombinant protein in a prokaryotic expression system. In vivo, HdaA is involved in the regulation of enzymes which are of vital importance for the cellular antioxidant response in A. nidulans. Consequently, deltahdaA strains exhibit significantly reduced growth on substrates whose catabolism generates molecules responsible for oxidative stress conditions in the fungus. Our analysis revealed that reduced expression of the fungal catalase CatB is jointly responsible for the significant growth reduction of the hdaA mutant strains.

In vitro activity of β-lactamase inhibitors against clinical isolates of Acinetobacter species

Acinetobacter is an important cause of nosocomial infections, and it is often resistant to many antibiotics. In a search for alternative agents, three β-lactamase inhibitors (sulbactam, clavulanate, and tazobactam) and five β-lactam antibiotics (imipenem, ceftazidime, ceftriaxone, cefotaxime, and piperacillin) were tested against 68 unique clinical isolates of Acinetobacter species. Minimum inhibitory concentrations were determined by a broth microdilution method. Using temperature sensitivity testing, we identified 59 strains as Acinetobacter baumannii, one as Acinetobacter haemolyticus, and eight as indeterminate biotype species. We demonstrated 41 of 59 (70%) strains of A. baumannii to be multiply resistant (susceptible only to amikacin and imipenem), whereas all the non- baumannii strains were not. Imipenem was the most active agent among the compounds investigated. All three β-lactamase inhibitors had strong intrinsic activity, with sulbactam being the most active agent among the β-lactamase inhibitors studied.