The therapeutic effect of glycyrrhizic acid compound ointment on imiquimod-induced psoriasis-like disease in mice.

Glycyrrhetinic acid, a drug with anti-inflammatory effects, enhanced the activity of antipsoriatic efficacy. In this research, an ointment with glycyrrhetinic acid was prepaired as the major component and several other herbal monomers (astilbin, osthole, and momordin Ic) have antipsoriatic activity as minor components. Then an Imiquimod-induced psoriasis-like mouse model was established and the damaged skin condition of the administered group, the changes in the spleen index and the secretion of inflammatory factors in mouse skin were observed. Calcipotriol ointment was used as a positive control to compare the efficacy. Glycyrrhizic acid compound ointment significantly improved imiquimod-induced psoriasis in mice and reduced the secretion of TNF-α, IL-12, IL-17, and IL-23 in mouse skin, and showed a stronger therapeutic effect than calcipotriol ointment. Calcipotriol ointment did not significantly alleviate imiquimod-induced splenomegaly and did not significantly reduce the expression of IL-17 and IL-23 in mouse skin. Glycyrrhetinic acid compound ointment was more effective than calcipotriol and was dose-dependent in the treatment of imiquimod-induced psoriatic dermatitis in mice. Meanwhile,calcipotriol was not suitable for the treatment of Imiquimod -induced psoriasis-like mice.

Corrigendum to "Neuroprotective effect of Sanqi Tongshuan Tablets on sequelae post-stroke in rats" [Chinese Herbal Medicines 11 (2019) 45-51].

[This corrects the article DOI: 10.1016/j.chmed.2018.12.002.].

A Review of the Anti-Inflammatory Effects of Rosmarinic Acid on Inflammatory Diseases.

Inflammatory diseases are caused by abnormal immune responses and are characterized by an imbalance of inflammatory mediators and cells. In recent years, the anti-inflammatory activity of natural products has attracted wide attention. Rosmarinic acid (RosA) is a water-soluble phenolic compound that is an ester of caffeic acid and 3, 4-dihydroxyphenyl lactic acid. It is discovered in many plants, like those of the Boraginaceae and Lamiaceae families. RosA has a wide range of pharmacological effects, including anti-oxidative, anti-apoptotic, anti-tumorigenic, and anti-inflammatory effects. The anti-inflammatory effects of RosA have been revealed through in vitro and in vivo studies of various inflammatory diseases like arthritis, colitis, and atopic dermatitis. This article mainly describes the preclinical research of RosA on inflammatory diseases and depicts a small amount of clinical research data. The purpose of this review is to discuss the anti-inflammatory effects of RosA in inflammatory diseases and its underlying mechanism.

Rosmarinic acid exerts an antagonistic effect on vascular calcification by regulating the Nrf2 signalling pathway.

Vascular calcification (VC) is a process in which calcium phosphate crystals deposit within the intima and middle membrane of the vascular wall. Rosmarinic acid (RA) is a common phenolic compound. It possesses antioxidation, anti-inflammatory, antimicrobial effects. Our experiment aims to investigate the role and molecular mechanism of RA in VC. Rats were fed high-fat feed and injected with vitamin D3 to establish a VC model. ß-Glyerophosphate (ß GP) was selected to stimulate rat aortic smooth muscle cells (VSMCs) in order to establish the cell calcification model. Kits were used to detect the antioxidant index and calcification index. RA significantly reduced the levels of ALP, MDA, Ca, and P but increased SOD levels. Quantitative real-time polymerase chain reaction (RT-qPCR) and western blot analysis were used to detect various antioxidant-related genes and calcified genes on an mRNA and protein level. The results showed that nuclear factor red cell-2 related factors (Nrf2), haem oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase (NQO1), and osteoprotegerin (OPG) were up regulated by RA at both the mRNA and protein levels, but kelch-like ECH-associated protein 1 (Keap1), nuclear factor kappa B(NF-κB), cadherin associated protein (ß-catenin) and osteogenic transcription factor (Runx2) expression at both the mRNA and protein levels was significantly inhibited. Microscopic examination showed that RA significantly decreased the content of calcified nodules and the production of reactive oxygen species (ROS). When Nrf2 is disturbed, the role of RA is significantly blocked. Our results showed that RA can improve VC by regulating the Nrf2 pathway.

Scutellarin exerts protective effects against atherosclerosis in rats by regulating the Hippo-FOXO3A and PI3K/AKT signaling pathways.

Atherosclerosis (AS), a progressive disorder, is one of the tough challenges in the clinic. Scutellarin, an extract from Herba Erigerontis, is found to have oxygen-free radicals scavenging effects and antioxidant effects. In this study, we aimed to investigate the anti-AS effects of scutellarin is related to controlling the Hippo-FOXO3A and PI3K/AKT signal pathway. To establish an AS model, the rats in the scutellarin and model groups were intraperitoneally injected with vitamin D 3 and then fed a high-fat diet for 12 weeks. In addition, in vitro angiotensin II-induced apoptosis of human aortic endothelial cells (HAECs) were used to establish models. Scutellarin significantly reduced blood lipid levels and increased antioxidase levels in both models. Additionally, scutellarin inhibited reactive oxygen species generation and apoptosis in HAECs. The impaired vascular barrier function was restored by using scutellarin in AS rats and in HAECs cells characterized by inhibiting mammalian sterile-20-like kinases 1 (Mst1) phosphorylation, Yes-associated protein (YAP) phosphorylation, forkhead box O3A (FOXO3A) phosphorylation at serine 207, nuclear translocation of FOXO3A, and upregulating protein expression of AKT and FOXO3A phosphorylation at serine 253. Scutellarin significantly reduced Bcl-2 interacting mediator of cell death (Bim), caspase-3, APO-1, CD95 (Fas), and Bax: Bcl-2-associated X (Bax) levels and activated Bcl-2: B-cell lymphoma-2 (Bcl-2). Scutellarin also significantly inhibited the expression of Mst1, YAP, FOXO3A at the messenger RNA level. When Mst1 was overexpressed or phosphoinositide 3-kinases suppressed, the effects of scutellarin were significantly blocked. In conclusion, the results of the present study suggest that scutellarin exerts protective effects against AS by inhibiting endothelial cell injury and apoptosis by regulating the Hippo-FOXO3A and PI3K/AKT signal pathways.

Effect of a new inhibitor of factor Xa zifaxaban, on thrombosis in the inferior vena cava in rabbits.

In recent years, oral factor Xa inhibitors have become a research focus as anticoagulant drugs. Zifaxaban is the first oral FXa inhibitor to enter clinical trials in China. The aim of this study was to determine the inhibitory effect of zifaxaban on thrombosisthrough a model ofinferior vena cava (IVC) thrombosis in rabbits. IVC thrombosis model was established by electrical injury and stenosis, and zifaxaban was administered (p.o.) for 5 consecutive days, then coagulation indicators and bleeding were observed. The results showed that zifaxaban had obvious inhibitory effects on FXa, and had a significant inhibitory effect on IVC thrombosis induced by electrical damage and stenosis. The effect of zifaxaban was similar to that of rivaroxaban, but the bleeding side-effects of zifaxaban were less severe than those of rivaroxaban. Zifaxaban could prolong the prothrombin time and activated partial thromboplastin time of plasma similar to that of other oral FXa inhibitors. Zifaxaban had a significant inhibitory effect on FXa, but it had no obvious effect on other coagulation factors, major anticoagulant factors or fibrinolytic indices. Our results suggest that zifaxaban had specific inhibitory effects on FXa and inhibited IVC thrombosis in rabbits with its hemorrhagic effect was less than that of rivaroxaban. Zifaxaban is ecpected to be developed as a new drug for the prevention of deep venous thrombosis, providing more medication options for patients with such disease, more research is required to support it in the future.

Pre-clinical pharmacodynamic study of a novel oral factor Xa inhibitor zifaxaban.

Zifaxaban is an orally active, direct Factor Xa (FXa) inhibitor that is in development for the prevention and treatment of arterial and venous thrombosis. This study was conducted to investigate the biochemical and pharmacological activity of zifaxaban. In vitro activity was evaluated by enzyme, platelet aggregation, and clotting assays. In vivo effects were examined in venous thrombosis, arteriovenous-shunt thrombosis, carotid thrombosis, and bleeding models in rats. Zifaxaban competitively inhibits human FXa (IC50 = 11.1 nM) with > 10,000-fold greater selectivity than other serine proteases. It did not impair platelet aggregation induced by collagen, adenosine diphosphate (ADP) or arachidonic acid. It significantly prolonged clotting time, prothrombin time (PT), and activated partial thromboplastin time (APTT) in the plasma of humans, rabbits, and rats, with a relatively weak effect on thrombin time (TT). In venous thrombosis models in rats, zifaxaban strongly suppressed thrombus formation with ED50 values of 3.09 mg/kg, and its best efficacy time occurred at 2 h after administration. In arteriovenous-shunt thrombosis and carotid thrombosis models in rats, it inhibited thrombus formation in a dose-dependent manner. And in the rat tail bleeding assay, it showed a trend of less bleeding than rivaroxaban at doses that achieved the same antithrombotic effect. In conclusion, zifaxaban is a selective and direct FXa inhibitor and a promising oral anticoagulant for the prophylaxis and treatment of thromboembolic diseases.

The transcriptional regulator VarN contributes to Salmonella Typhimurium growth in macrophages and virulence in mice.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a major intracellular pathogen of humans and animals and its survival and growth in macrophages is essential for its pathogenicity. The S. Typhimurium genome encodes more than 50 putative regulatory proteins, but their involvement in pathogenicity and their regulatory roles are largely unknown. In this study, we investigated the biological function of the S. Typhimurium STM4320 gene (named varN), which encodes a putative MerR family transcriptional regulator. We found that varN is upregulated 2.6- to 6.8-fold after S. Typhimurium enters murine macrophages. A varN mutant reduced S. Typhimurium growth in murine macrophages and attenuated virulence in mice. Moreover, we showed that deletion of varN decreased the transcription of Salmonella pathogenicity island-2 (SPI-2) genes, which are required for S. Typhimurium growth in macrophages, indicative of the positive regulation of SPI-2 by VarN. We confirmed that the virulence defects of the varN mutant are entirely dependent on its regulation of SPI-2. Thus, our results revealed that VarN is a novel activator of the expression of SPI-2 genes and contributes to S. Typhimurium growth in macrophages and virulence in mice. Our findings provide a significant example of how a putative regulatory protein facilitates S. Typhimurium pathogenicity.

Procaterol but not dexamethasone protects 16HBE cells from H2O2-induced oxidative stress.

Oxidative stress is an important pathophysiological factor of asthma and chronic obstructive pulmonary disease (COPD). We hypothesized that procaterol and dexamethasone might treat inflammation through inhibiting oxidative stress in vitro. This study evaluated procaterol and dexamethasone in the hydrogen peroxide (H2O2)-induced immortal human bronchial epithelial cell model of oxidative stress and investigated the underlying mechanisms. Results showed that exposure to 125 µM H2O2 for 2 h led to a 50% reduction in the cell viability, significantly increased the percentage of apoptosis, and elevated levels of malondialdehyde and reactive oxygen species. Pretreatment with procaterol (25 - 200 nM) could reduce these effects in a dose-dependent manner. In contrast, pretreatment with dexamethasone (100 nM, 1000 nM) was inefficient. Pretreatment with procaterol plus dexamethasone (100 nM procaterol + 1000 nM dexamethasone) was effective, but the combined effect was not more effective than the sole pretreatment with 100 nM procaterol. The nuclear factor kappa-B (NF-κB) pathway was involved in the pathogenic mechanisms of H2O2. Procaterol may indirectly inhibit H2O2-induced activation of the NF-κB pathway due to its capability of antioxidation. Glucocorticoids may be not recommended to treat asthma or COPD complicated with severe oxidative stress.

Long-range balanced electron- and hole-transport lengths in organic-inorganic CH3NH3PbI3.

Low-temperature solution-processed photovoltaics suffer from low efficiencies because of poor exciton or electron-hole diffusion lengths (typically about 10 nanometers). Recent reports of highly efficient CH3NH3PbI3-based solar cells in a broad range of configurations raise a compelling case for understanding the fundamental photophysical mechanisms in these materials. By applying femtosecond transient optical spectroscopy to bilayers that interface this perovskite with either selective-electron or selective-hole extraction materials, we have uncovered concrete evidence of balanced long-range electron-hole diffusion lengths of at least 100 nanometers in solution-processed CH3NH3PbI3. The high photoconversion efficiencies of these systems stem from the comparable optical absorption length and charge-carrier diffusion lengths, transcending the traditional constraints of solution-processed semiconductors.

Treatment responses of procaterol and CD38 inhibitors in an ozone-induced airway hyperresponsiveness mice model.

Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of many respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). To evaluate the treatment responses of procaterol and CD38 inhibitors in an ozone-induced AHR mice model, we hypothesized that procaterol and two synthetic CD38 inhibitors (Compounds T and H) might have therapeutic effects on the ozone-induced AHR mice model, and the nuclear factor-kappaB (NF-κB) pathway and the CD38 enzymatic activity might be involved in the mechanisms. With the exception of the Control group, ozone exposure was used to establish an AHR model. Male Kunming mice in the Procaterol and CD38 inhibitors groups were treated with an emulsifier of procaterol hydrochloride, Compound T or H. Results indicated that (1) no drug showed severe toxicity in this study; (2) ozone exposure induced airway inflammation and AHR; (3) intragastric treatment with procaterol and Compound T achieved potent therapeutic effects, but Compound H did not show any therapeutic effect; (4) the NF-κB pathway was involved in both the pathogenic mechanisms of ozone and therapeutic mechanisms of procaterol and Compound T; (5) however, the in vivo effect of Compound T was not caused by its inhibitory activity on CD38. Taken together, procaterol and Compound T are potentially good drugs to treat asthma and COPD complicated with ozone exposure.

DJ-1 protein protects dopaminergic neurons against 6-OHDA/MG-132-induced neurotoxicity in rats.

Parkinson disease (PD) is the second most common neurodegenerative disease, and it cannot be completely cured by current medications. In this study, DJ-1 protein was administrated into medial forebrain bundle of PD model rats those had been microinjected with 6-hydroxydopamine (6-OHDA) or MG-132. We found that DJ-1 protein could reduce apomorphine-induced rotations, inhibit reduction of dopamine contents and tyrosine hydroxylase levels in the striatum, and decrease dopaminergic neuron death in the substantia nigra. In 6-OHDA lesioned rats, uncoupling protein-4, uncoupling protein-5 and superoxide dismutase-2 (SOD2) mRNA and SOD2 protein were increased when DJ-1 protein was co-injected. Simultaneously, administration of DJ-1 protein reduced α-synuclein and hypoxia-inducible factor 1α mRNA and α-synuclein protein in MG-132 lesioned rats. Therefore, DJ-1 protein protected dopaminergic neurons in two PD model rats by increasing antioxidant capacity and inhibiting α-synuclein expression.

Solution-processed nanocrystalline TiO2 buffer layer used for improving the performance of organic photovoltaics.

In this study, we use solution-processable crystalline TiO(2) nanoparticles as a buffer layer between the active layer and aluminum cathode to fabricate the P3HT:PCBM-based bulk heterojunction (BHJ) organic photovoltaic (OPV) devices. The employment of the presynthesized TiO(2) nanoparticles simplifies the fabrication of OPV devices because of the elimination of an additional hydrolysis step of precursors in air. The fabricated OPV devices with the thermally stable TiO(2) buffer layer are subjected to the further postdeposition thermal annealing, resulting in a power conversion efficiency (PCE) as high as 3.94%. The improved device performance could be attributed to the electron transporting and hole blocking capabilities due to the introduced TiO(2) buffer layer.

Design, synthesis and biological characterization of novel inhibitors of CD38.

Human CD38 is a novel multi-functional protein that acts not only as an antigen for B-lymphocyte activation, but also as an enzyme catalyzing the synthesis of a Ca(2+) messenger molecule, cyclic ADP-ribose, from NAD(+). It is well established that this novel Ca(2+) signaling enzyme is responsible for regulating a wide range of physiological functions. Based on the crystal structure of the CD38/NAD(+) complex, we synthesized a series of simplified N-substituted nicotinamide derivatives (Compound 1-14). A number of these compounds exhibited moderate inhibition of the NAD(+) utilizing activity of CD38, with Compound 4 showing the highest potency. The crystal structure of CD38/Compound 4 complex and computer simulation of Compound 7 docking to CD38 show a significant role of the nicotinamide moiety and the distal aromatic group of the compounds for substrate recognition by the active site of CD38. Biologically, we showed that both Compounds 4 and 7 effectively relaxed the agonist-induced contraction of muscle preparations from rats and guinea pigs. This study is a rational design of inhibitors for CD38 that exhibit important physiological effects, and can serve as a model for future drug development.

Organic photovoltaic devices using highly flexible reduced graphene oxide films as transparent electrodes.

The chemically reduced graphene oxide (rGO) was transferred onto polyethylene terephthalate (PET) substrates and then used as transparent and conductive electrodes for flexible organic photovoltaic (OPV) devices. The performance of the OPV devices mainly depends on the charge transport efficiency through rGO electrodes when the optical transmittance of rGO is above 65%. However, if the transmittance of rGO is less than 65%, the performance of the OPV device is dominated by the light transmission efficiency, that is, the transparency of rGO films. After the tensile strain (∼2.9%) was applied on the fabricated OPV device, it can sustain a thousand cycles of bending. Our work demonstrates the highly flexible property of rGO films, which provide the potential applications in flexible optoelectronics.