Structure-Based Discovery of mPGES-1 Inhibitors Suitable for Preclinical Testing in Wild-Type Mice as a New Generation of Anti-Inflammatory Drugs

Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs without the side effects of currently available anti-inflammatory drugs, and various inhibitors have been reported in the literature. However, none of the reported potent inhibitors of human mPGES-1 has shown to be also a potent inhibitor of mouse or rat mPGES-1, which prevents using the well-established mouse/rat models of inflammation-related diseases for preclinical studies. Hence, despite of extensive efforts to design and discover various human mPGES-1 inhibitors, the promise of mPGES-1 as a target for the next generation of anti-inflammatory drugs has never been demonstrated in any wild-type mouse/rat model using an mPGES-1 inhibitor. Here we report discovery of a novel type of selective mPGES-1 inhibitors potent for both human and mouse mPGES-1 enzymes through structure-based rational design. Based on in vivo studies using wild-type mice, the lead compound is indeed non-toxic, orally bioavailable, and more potent in decreasing the PGE2 (an inflammatory marker) levels compared to the currently available drug celecoxib. This is the first demonstration in wild-type mice that mPGES-1 is truly a promising target for the next generation of anti-inflammatory drugs

Adjuvant Chemotherapy Versus Adjuvant Concurrent Chemoradiotherapy After Radical Surgery for Early-Stage Cervical Cancer: A Randomized, Non-Inferiority, Multicenter Trial

We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB-IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant chemotherapy group and 164 in the adjuvant CCRT group. The median follow-up was 72.1 months. The three-year PFS rates were both 91.9%, and the five-year OS was 90.6% versus 90.0% in adjuvant chemotherapy and CCRT groups, respectively. No significant differences were observed in the PFS or OS between groups. The adjusted HR for PFS was 0.854 (95% confidence interval 0.415-1.757; P = 0.667) favoring adjuvant chemotherapy, excluding the predefined non-inferiority boundary of 1.9. The chemotherapy group showed a tendency toward good quality of life. In comparison with post-operative adjuvant CCRT, adjuvant chemotherapy treatment showed non-inferior efficacy in patients with early-stage cervical cancer having pathological risk factors. Adjuvant chemotherapy alone is a favorable alternative post-operative treatment

Friction–wear behaviors and microstructure of AlTiVCrNb lightweight refractory high-entropy alloy coating prepared by laser cladding on Ti–6Al–4V substrate

To enhance the friction and wear properties of Ti–6Al–4V, the AlTiVCrNb lightweight refractory high entropy alloy coating was applied to a Ti–6Al–4V substrate by laser cladding. The microstructure was investigated through scanning electron microscopy, X-ray diffraction, and transmission electron microscopy. The results demonstrate that the coatings are metallurgically bonded to the Ti–6Al–4V substrate, and the microstructure of the AlTiVCrNb coatings with high Ti content comprises disordered BCC phases, laves reinforced phases, and diffusely distributed Ti2AlNb nanophases. The microhardness of the coating measures 548.54 HV0.1, surpassing that of the Ti–6Al–4V substrate by 1.57 times. The wear resistance of the AlTiVCrNb HEA coating is 1.58 times higher than that of the Ti–6Al–4V alloy under a 20 N load, thereby effectively improving the wear resistance of the Ti6Al4V alloy. The main wear mechanisms of AlTiVCrNb high-entropy alloy coatings are oxidative and adhesive wear

The Effect of Repeated Electroacupuncture Analgesia on Neurotrophic and Cytokine Factors in Neuropathic Pain Rats

Chronic pain is a common disability influencing quality of life. Results of previous studies showed that acupuncture has a cumulative analgesic effect, but the relationship with spinal cytokines neurotrophic factors released by astrocytes remains unknown. The present study was designed to observe the effect of electroacupuncture (EA) treatment on spinal cytokines neurotrophic factors in chronic neuropathic pain rats. The chronic neuropathic pain was established by chronic constrictive injury (CCI). EA treatment was applied at Zusanli (ST36) and Yanglingquan (GB34) (both bilateral) once a day, for 30 min. IL-1β mRNA, TNF-α mRNA, and IL-1 mRNA were detected by quantitative real-time PCR, and the proteins of BDNF, NGF, and NT3/4 were detected by Western blot. The expression levels of cytokines such as IL-1β mRNA, TNF-α mRNA, IL-6 mRNA, and neurotrophic factors such as BDNF, NGF, and NT3/4 in the spinal cord were increased significantly after CCI. The astrocytes released more IL-1β and BDNF after CCI. Repeated EA treatment could suppress the elevated expression of IL-1β mRNA, TNFα mRNA, and BDNF, NGF, and NT3/4 but had no effect on IL-6 mRNA. It is suggested that cytokines and neurotrophic factors which may be closely associated with astrocytes participated in the process of EA relieving chronic pain

Evolution of Dislocation Loops Induced by Different Hydrogen Irradiation Conditions in Reduced-Activation Martensitic Steel

Hydrogen can be induced in various ways into reduced-activation ferritic/martensitic (RAFM) steels when they are used as structural materials for advanced nuclear systems. However, because of the fast diffusion of hydrogen in metals, the effect of hydrogen on the evolution of irradiation-induced defects was almost neglected. In the present work, the effect of hydrogen on the evolution of dislocation loops was investigated using a transmission electron microscope. Specimens of reduced-activation ferritic/martensitic (RAFM) steels were irradiated with hydrogen ions to 5 × 1020 H+ • m−2 at 523⁻823 K, and to 1 × 1020 H+ • m−2 − 5 × 1020 H+ • m−2 at 723 K. The experimental results reveal that there is an optimum temperature for dislocation loop growth, which is ~723 K, and it is greater than the reported values for neutron irradiations. Surprisingly, the sizes of the loops produced by hydrogen ions, namely, 93 nm and 286 nm for the mean and maximum value, respectively, at the peak dose of 0.16 dpa under 723 K, are much larger than that produced by neutrons and heavy ions at the same damage level and temperature. The results indicate that hydrogen could enhance the growth of loops. Moreover, 47.3% 1 2   a0 <111> and 52.7% a0 <100> loops were observed at 523 K, but 1 2   a0 <111> loops disappeared and only a0 <100> loops existed above 623 K. Compared with the neutron and ion irradiations, the presence of hydrogen promoted the formation of a0 <100> loops

<i>De Novo</i> Design of Multitarget Ligands with an Iterative Fragment-Growing Strategy

The discovery of multitarget drugs has recently attracted much attention. Most of the reported multitarget ligands have been serendipitous discoveries. Although a few methods have been developed for rational multitarget drug discovery, there is a lack of elegant methods for <i>de novo</i> multitarget drug design and optimization, especially for multiple targets with large differences in their binding sites. In this paper, we report the first <i>de novo</i> multitarget ligand design method, with an iterative fragment-growing strategy. Using this method, dual-target inhibitors for COX-2 and LTA₄H were designed, with the most potent one inhibiting PGE₂ and LTB₄ production in the human whole blood assay with IC₅₀ values of 7.0 and 7.1 μM, respectively. Our strategy is generally applicable in rational and efficient multitarget drug design, especially for the design of highly integrated inhibitors for proteins with dissimilar binding pockets

Electroacupuncture Reduces the Effects of Acute Noxious Stimulation on the Electrical Activity of Pain-Related Neurons in the Hippocampus of Control and Neuropathic Pain Rats

To study the effects of acupuncture analgesia on the hippocampus, we observed the effects of electroacupuncture (EA) and mitogen-activated protein kinase (MEK) inhibitor on pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal area CA1 of sham or chronic constrictive injury (CCI) rats. The animals were randomly divided into a control, a CCI, and a U0126 (MEK1/2 inhibitor) group. In all experiments, we briefly (10-second duration) stimulated the sciatic nerve electrically and recorded the firing rates of PENs and PINs. The results showed that in both sham and CCI rats brief sciatic nerve stimulation significantly increased the electrical activity of PENs and markedly decreased the electrical activity of PINs. These effects were significantly greater in CCI rats compared to sham rats. EA treatment reduced the effects of the noxious stimulus on PENs and PINs in both sham and CCI rats. The effects of EA treatment could be inhibited by U0126 in sham-operated rats. The results suggest that EA reduces effects of acute sciatic nerve stimulation on PENs and PINs in the CA1 region of the hippocampus of both sham and CCI rats and that the ERK (extracellular regulated kinase) signaling pathway is involved in the modulation of EA analgesia