IAVPGEVA: Orally Available DPP4-Targeting Soy Glycinin Derived Octapeptide with Therapeutic Potential in Nonalcoholic Steatohepatitis.

IAVPGEVA, an octapeptide derived from soybean 11S globulin hydrolysis, also known as SGP8, has exhibited regulatory effects on lipid metabolism, inflammation, and fibrosis in vitro. Studies using MCD and HFD-induced nonalcoholic steatohepatitis (NASH) models in mice show that SGP8 attenuates hepatic injury and metabolic disorders. Mechanistic studies suggest that SGP8 inhibits the JNK-c-Jun pathway in L02 cells and liver tissue under metabolic stress and targets DPP4 with DPP4 inhibitory activity. In conclusion, the results suggest that SGP8 is an orally available DPP4-targeting peptide with therapeutic potential in NASH.

Synergistic interface between metal Cu nanoparticles and CoO for highly efficient hydrogen production from ammonia borane.

The development of efficient non-noble metal catalysts for the dehydrogenation of hydrogen (H2) storage materials is highly desirable to enable the global production and storage of H2 energy. In this study, Cu x -(CoO)1-x /TiO2 catalysts with a Cu-CoO interface supported on TiO2 are shown to exhibit high catalytic efficiency for ammonia borane (NH3BH3) hydrolysis to generate H2. The best catalytic activity was observed for a catalyst with a Cu : Co molar ratio of 1 : 1. The highest dehydrogenation turnover frequency (TOF) of 104.0 molH2 molmetal -1 min-1 was observed in 0.2 M NaOH at room temperature, surpassing most of the TOFs reported for non-noble catalysts for NH3BH3 hydrolysis. Detailed characterisation of the catalysts revealed electronic interactions at the Cu-CoO heterostructured interface of the catalysts. This interface provides bifunctional synergetic sites for H2 generation, where activation and adsorption of NH3BH3 and H2O are accelerated on the surface of Cu and CoO, respectively. This study details an effective method of rationally designing non-noble metal catalysts for H2 generation via a metal and transition-metal oxide interface.

Structural Evolution of Anatase-Supported Platinum Nanoclusters into a Platinum-Titanium Intermetallic Containing Platinum Single Atoms for Enhanced Catalytic CO Oxidation.

Strong metal-support interactions characteristic of the encapsulation of metal particles by oxide overlayers have been widely observed on large metal nanoparticles, but scarcely occur on small nanoclusters (<2 nm) for which the metal-support interactions remain elusive. Herein, we study the structural evolution of Pt nanoclusters (1.5 nm) supported on anatase TiO2 upon high-temperature H2 reduction. The Pt nanoclusters start to partially evolve into a CsCl-type PtTi intermetallic compound when the reduction temperature reaches 400 °C. Upon 700 °C reduction, the PtTi nanoparticles are exclusively formed and grow epitaxially along the TiO2 (101) crystal faces. The thermodynamics of the formation of PtTi via migration of reduced Ti atoms into Pt cluster is unraveled by theoretical calculations. The thermally stable PtTi intermetallic compound, with single-atom Pt isolated by Ti, exhibits enhanced catalytic activity and promoted catalytic durability for CO oxidation.

Optimizing the synergy between alloy and alloy-oxide interface for CO oxidation in bimetallic catalysts.

Creating synergetic metal-oxide interfaces is a promising strategy to promote the catalytic performance of heterogeneous catalysts. However, this strategy has been mainly applied to monometallic catalysts, while scarcely applied to alloy catalysts. In this work, we present a comprehensive study on the synergetic alloy-oxide interfaces in the bimetallic Pt-Co/Al2O3 catalysts for CO oxidation. A series of Pt1Cox/Al2O3 catalysts with various Co/Pt molar ratios with x ranging from 0.5 to 3.8 was synthesized via a facile wet-chemistry strategy. Among them, the Pt1Co0.5/Al2O3 catalyst exhibits the best catalytic performance for CO oxidation, with the lowest CO complete conversion temperature of -10 °C and the highest mass specific rate of 2.61 (mol CO) h-1 (g Pt)-1. From in situ X-ray absorption fine structure and diffuse reflectance infrared Fourier-transform spectroscopy studies, the superior catalytic performance of Pt1Co0.5/Al2O3 originates from the optimal length of the three-dimensional alloy-oxide perimeter sites. We further extended this strategy to other bimetallic systems of Pt-Fe and Pt-Ni, which also show similar structural properties and remarkable promotional effects on the catalytic activity.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2.

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC50 of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

LOX inhibitor HOEC interfered arachidonic acid metabolic flux in collagen-induced arthritis rats.

Arachidonic acid (AA) metabolic network generates a variety of products that mediate or modulate inflammatory reactions. (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), isolated from Incarvillea mairei var. granditlora (Wehrhahn) Grierson, was found as an inhibitor of 5-LOX and 15-LOX in vitro. When evaluated in collagen-induced arthritis (CIA) rats, however, lowdose of HOEC (1 mg/kg) showed better efficacy than that of high dose (10 mg/kg). To study how HOEC interfered the AA metabolic pathway, in this study, we dynamically observed the changes of plasma AA metabolites (LTB4, LTC4, 15-HETE, PGE2, TXB2 and PGD2) in the CIA rats treated with different doses of HOEC by using enzyme-linked immunosorbent assay (ELISA). The results showed that eicosanoids were elevated synchronously at three time points in different treated rats. The incidence of arthritis had a higher correlation with LOX pathway while the COX pathway might be more important in the severity of arthritis. HOEC in all doses could inhibit LOX pathway in the beginning of arthritis while highdose of HOEC could induce the increase of COX metabolites in the later stage of disease. These dynamic changes of eicosanoids, depending on the regulation of metabolic flux, can be interfered by HOEC and thus affect the output of efficacy.

Chemiluminescence of off-line and on-line gold nanoparticle-catalyzed luminol system in the presence of flavonoid.

It was found that flavonoids could remarkably inhibit the chemiluminescence (CL) intensity of an off-line gold nanoparticle (AuNP)-catalyzed luminol-H2 O2 CL system. By contrast, flavonoids enhanced the CL intensity of an on-line AuNP-catalyzed luminol-H2 O2 CL system. In the off-line system, the AuNPs were prepared beforehand, whereas in the on-line system, AuNPs were produced by on-line mixing of luminol prepared in a buffer solution of NaHCO3  - Na2 CO3 and HAuCl4 with no need for the preliminary preparation of AuNPs. The on-line system had prominent advantages over the off-line system, namely a lowering of the background noise and improvements in the stability of the CL system. The results show that differences in the signal suppression effect of flavonoids on the off-line AuNP-catalyzed CL system are influenced by the combined action of a free radical scavenging effect and occupy-sites function; the latter was proved to be predominant using controlled experiments. Enhancement of the on-line system was ascribed to the presence of flavonoids promoting the on-line formation of AuNPs, which better catalyzed the luminol-H2 O2 CL reaction, and the enhancement activity of the six flavonoids increased with the increase in reducibility. This work broadens the scope of practical applications of an AuNP-catalyzed CL system.

Rational Design of Benzylidenehydrazinyl-Substituted Thiazole Derivatives as Potent Inhibitors of Human Dihydroorotate Dehydrogenase with in Vivo Anti-arthritic Activity.

Human dihydroorotate dehydrogenase (hDHODH) is an attractive therapeutic target for the treatment of rheumatoid arthritis, transplant rejection and other autoimmune diseases. Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range. Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo. Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold. This work not only elucidates promising scaffolds targeting hDHODH for the treatment of rheumatoid arthritis, but also demonstrates that the water-mediated hydrogen bond interaction is an important factor in molecular design and optimization.

Neuroprotection of (+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Against Hydrogen Peroxide and Lipopolysaccharide Induced Injury via Modulating Arachidonic Acid Network and p38-MAPK Signaling.

Oxidative stress and neuroinflammation are highly relevant to the pathological processes of various neurodegenerative diseases including Alzheimer's disease (AD). (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), a novel 5-lipoxygenase inhibitor, was isolated from the whole plant of Incarvillea mairei var granditlora (Wehrhahn) Grierson. In this study, we investigated the protective effect of HOEC on hydrogen peroxide (H2O2) and lipopolysaccharide (LPS) -induced cytotoxicity and neuroinflammation in vitro and in vivo. MTT assay, LDH release assay, morphological observation and Hoechst 33342/PI dual staining followed by EIA, immunofluorescence staining and Western Blotting analysis were performed to elucidate the neuroprotective effect of HOEC. Treatment with HOEC at various concentrations prior to H2O2 exposure significantly enhanced cell viability, decreased LDH release, prevented cell morphologic changes and apoptosis. Instead of PGE2 reduction, HOEC markedly inhibited the production of LTB4 and suppressed the macrophage-mediated neurotoxicity. Western blotting and immunofluorescence staining showed that HOEC inhibited H2O2-induced p38 phosphorylation and NF-κB activation. Neuroprotective effect of HOEC was abolished by a p38 inhibitor. Further in vivo studies of LPS-induced neuroinflammation confirmed the anti-inflammatory effects of HOEC. These findings that HOEC protects SH-SY5Y cells from H2O2 and LPS-induced injury via arachidonic acid network modulation followed by p38 MAPK and NF-κB signaling, might make HOEC be considered as a therapeutic candidate for prevention and treatment of neurodegenerative diseases involving oxidative stress or/and inflammation.

Design, synthesis, X-ray crystallographic analysis, and biological evaluation of thiazole derivatives as potent and selective inhibitors of human dihydroorotate dehydrogenase.

Human dihydroorotate dehydrogenase (HsDHODH) is a flavin-dependent mitochondrial enzyme that has been certified as a potential therapeutic target for the treatment of rheumatoid arthritis and other autoimmune diseases. On the basis of lead compound 4, which was previously identified as potential HsDHODH inhibitor, a novel series of thiazole derivatives were designed and synthesized. The X-ray complex structures of the promising analogues 12 and 33 confirmed that these inhibitors bind at the putative ubiquinone binding tunnel and guided us to explore more potent inhibitors, such as compounds 44, 46, and 47 which showed double digit nanomolar activities of 26, 18, and 29 nM, respectively. Moreover, 44 presented considerable anti-inflammation effect in vivo and significantly alleviated foot swelling in a dose-dependent manner, which disclosed that thiazole-scaffold analogues can be developed into the drug candidates for the treatment of rheumatoid arthritis by suppressing the bioactivity of HsDHODH.

Synthesis and effects of new caffeic acid derivatives on nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages.

In this study, 20 new derivatives of caffeic acid esters were synthesized and their inhibitory activities against the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages were determined. Compounds 3l, 3r, 3s and 3t were found to decrease nitrite levels in a dose-dependent manner in LPS-induced cells and showed potent inhibitory activities against the NO production in RAW264.7 macrophages with IC50 values of 7.4, 5.9, 3.3 and 2.2 µM, respectively. They could be selected as compromising compounds for the later pharmacological study.

[Cyclooxygenases, lipoxygenases, their targeted drugs and the prevention of Alzheimer's disease].

Many studies have shown that chronic inflammation occurs in the brain of patients with Alzheimer's disease (AD). It is well known that long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) can alleviate the cognitive decline of AD patient and elderly. Several inflammatory cytokines produced in the metabolism of arachidonic acid (AA) are closely related to inflammatory diseases. Lipoxygenases (LOXs) and cyclooxygenases (COXs) play a crucial role in the AA network, the products eicosanoids have an important impact on the progression of AD. Although there are many arguments and conflicting evidence, currently LOXs and COXs are still the hot topics in the research on AD pathogenesis and drug development. Here, we review the progress in research on COXs and LOXs, including their actions on CNS and their association with AD, and explore the feasibility of LOXs and COXs as targets for the drugs to prevent and/or treat AD.