Application and underlying mechanism of acupuncture for the nerve repair after peripheral nerve injury: remodeling of nerve system.

Peripheral nerve injury (PNI) is a structural event with harmful consequences worldwide. Due to the limited intrinsic regenerative capacity of the peripheral nerve in adults, neural restoration after PNI is difficult. Neurological remodeling has a crucial effect on the repair of the form and function during the regeneration of the peripheral nerve after the peripheral nerve is injured.

SF-MVPA: A from raw data to statistical results and surface space-based MVPA toolbox.

Compared with traditional volume space-based multivariate pattern analysis (MVPA), surface space-based MVPA has many advantages and has received increasing attention. However, surface space-based MVPA requires considerable programming and is therefore difficult for people without a programming foundation. To address this, we developed a MATLAB toolbox based on a graphical interactive interface (GUI) called surface space-based multivariate pattern analysis (SF-MVPA) in this manuscript.

Combinatorial Test Generation for Multiple Input Models with Shared Parameters.

Combinatorial testing typically considers a single input model and creates a single test set that achieves -way coverage. This paper addresses the problem of combinatorial test generation for multiple input models with shared parameters. We formally define the problem and propose an efficient approach to generating multiple test sets, one for each input model, that together satisfy -way coverage for all of these input models while minimizing the amount of redundancy between these test sets.

Effectiveness and safety of manual acupuncture therapy in patients with post-stroke depression: a protocol for a systematic review and meta-analysis.

Introduction: Acupuncture is widely used on the rehabilitation of stroke survivors, including hemiplegia, constipation, emotional disorders and so on. Although the effectiveness of manual acupuncture therapy on post-stroke depression (PSD) has been confirmed by multiple randomised controlled trials, there were few meta-analyses focused on the connection between different techniques, durations or other detailed operations of manual acupuncture and their effectiveness of improving the depression severity and quality of life for patients with PSD.

Methods And Analysis: A systematic search will be performed on English databases (PubMed, the Cochrane Library, Medline and Embase), Chinese databases (China National Knowledge Infrastructure, WanFang Data, VIP and Chinese biomedical databases) and Japanese databases (Japan Science and Technology Agency and CiNii).

Screening of Potential Anti-Thrombotic Ingredients from in Zebrafish and by Molecular Docking.

Background: Danshen (DS), the dry root of Bge., has been used in traditional Chinese medicine (TCM) for many years to promote blood circulation and to inhibit thrombosis. However, the active ingredients responsible for the anti-thrombotic effect and the underlying mechanisms are yet to be fully elucidated.

Effect of acupuncture treatment on post-stroke cognitive impairment: A randomized controlled trial.

Introduction: Post-stroke cognitive impairment (PSCI), which has a high morbidity, is closely associated with the recurrence and rehabilitation of ischemic stroke. There are 2 different stages of PSCI, including post-stroke cognitive impairment with no dementia (PSCIND) and post-stroke dementia (PSD). The latter has a significantly higher mortality rate than the previous one.

The comparison of different acupuncture therapies for post stroke depression: A protocol for a Bayesian network meta-analysis.

Background: Depression is a common disease which occurs after stroke, affecting approximately one third of stroke survivors at any 1 time after stroke (compared with 5%-13% of adults without stroke), with a cumulative incidence of 55%. Acupuncture, which has a long history in China, is the generic name of different kinds of acupuncture therapies, including manual acupuncture (MA), electroacupuncture (EA), fire needle (FN), dry needling (DN), and so on. Clinical studies have shown that acupuncture has a good therapeutic effect on post stroke depression (PSD), but the evidence-based medicine of it is insufficient.

PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome.

The poly(ADP-ribose) polymerase, PARP1, plays a key role in maintaining genomic integrity by detecting DNA damage and mediating repair. γH2A.X is the primary histone marker for DNA double-strand breaks and PARP1 localizes to H2A.

Thiazolidin-5-imine Formation as a Catalyst-Free Bioorthogonal Reaction for Protein and Live Cell Labeling.

A previously undescribed reaction involving the formation of a thiazolidin-5-imine linkage was developed for bioconjugation. Being highly specific and operating in aqueous media, this simple condensation reaction is used to chemoselectively label peptides, proteins, and living cells under physiological conditions without the need to use toxic catalysts or reducing reagents.

Immobilization and Intracellular Delivery of Circular Proteins by Modifying a Genetically Incorporated Unnatural Amino Acid.

Backbone-cyclic proteins are of great scientific and therapeutic interest owing to their higher stability over their linear counterparts. Modification of such cyclic proteins at a selected site would further enhance their versatility. Here we report a chemoenzymatic strategy to engineer site-selectively modified cyclic proteins by combining butelase-mediated macrocyclization with the genetic code expansion methodology.

The Discovery of N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-((6- ((methylamino)methyl)pyrimidin-4-yl)oxy)-1H-indole-1-carboxamide (Acrizanib), a VEGFR-2 Inhibitor Specifically Designed for Topical Ocular Delivery, as a Therapy for Neovascular Age-Related Macular Degeneration.

A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-molecule VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile.

Enzymatic Engineering of Live Bacterial Cell Surfaces Using Butelase 1.

Butelase-mediated ligation (BML) can be used to modify live bacterial cell surfaces with diverse cargo molecules. Surface-displayed butelase recognition motif NHV was first introduced at the C-terminal end of the anchoring protein OmpA on E. coli cells.

Peptide Weinreb amide derivatives as thioester precursors for native chemical ligation.

Peptide Weinreb amide derivatives with an N-substituted mercaptoethyl group are designed as thioester precursors for native chemical ligation. We show that these amides undergo rapid ligation with a cysteinyl peptide under normal NCL conditions to form various Xaa-Cys peptide bonds, including the difficult Val-Cys junction. Facile synthesis of the Weinreb amide linkers allows easy access to this new type of peptide thioester precursor by standard Fmoc solid phase synthesis.

Discovery of Oral VEGFR-2 Inhibitors with Prolonged Ocular Retention That Are Efficacious in Models of Wet Age-Related Macular Degeneration.

The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. We employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compound design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients.

Lack of involvement of CEP adducts in TLR activation and in angiogenesis.

Proteins that are post-translationally adducted with 2-(ω-carboxyethyl)pyrrole (CEP) have been proposed to play a pathogenic role in age-related macular degeneration, by inducing angiogenesis in a Toll Like Receptor 2 (TLR2)-dependent manner. We have investigated the involvement of CEP adducts in angiogenesis and TLR activation, to assess the therapeutic potential of inhibiting CEP adducts and TLR2 for ocular angiogenesis. As tool reagents, several CEP-adducted proteins and peptides were synthetically generated by published methodology and adduction was confirmed by NMR and LC-MS/MS analyses.

Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors.

Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure-activity relationship studies both in vitro and in vivo.

3,5-diarylazoles as novel and selective inhibitors of protein kinase D.

The synthesis and preliminary studies of the SAR of novel 3,5-diarylazole inhibitors of Protein Kinase D (PKD) are reported. Notably, optimized compounds in this class have been found to be active in cellular assays of phosphorylation-dependant HDAC5 nuclear export, orally bioavailable, and highly selective versus a panel of additional putative histone deacetylase (HDAC) kinases. Therefore these compounds could provide attractive tools for the further study of PKD/HDAC5 signaling.

Identification of potent and selective amidobipyridyl inhibitors of protein kinase D.

The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists.

Identification of orally available naphthyridine protein kinase D inhibitors.

A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure.

The discovery of potent inhibitors of aldosterone synthase that exhibit selectivity over 11-beta-hydroxylase.

Aldosterone, the final component of the renin-angiotensin-aldosterone system, plays an important role in the pathophysiology of hypertension and congestive heart failure. Aldosterone synthase (CYP11B2) catalyzes the last three steps of aldosterone biosynthesis, and as such appears to be a target for the treatment of these disorders. A sulfonamide-imidazole scaffold has proven to be a potent inhibitor of CYP11B2.

A novel kinase inhibitor establishes a predominant role for protein kinase D as a cardiac class IIa histone deacetylase kinase.

Class IIa histone deacetylases (HDACs) repress genes involved in pathological cardiac hypertrophy. The anti-hypertrophic action of class IIa HDACs is overcome by signals that promote their phosphorylation-dependent nuclear export. Several kinases have been shown to phosphorylate class IIa HDACs, including calcium/calmodulin-dependent protein kinase (CaMK), protein kinase D (PKD) and G protein-coupled receptor kinase (GRK).

Diversification of the three-component coupling of 2-aminoheterocycles, aldehydes, and isonitriles: efficient parallel synthesis of a diverse and druglike library of imidazo- and tetrahydroimidazo[1,2-a] heterocycles.

Due to their diverse range of biological activities, imidazoheterocycles are recognized as privileged structures making these structural motifs attractive targets for library preparation. We report herein the synthesis of a sizable collection of imidazo[1,2- a]heterocycle scaffolds well-suited for divergent library preparation by virtue of amine functional handles with diverse positioning and connectivities. Partial reduction of imidazo[1,2- a]pyrazines to the tetrahydroimidazo[1,2- a]pyrazines and regiospecific Mannich-type bond formation at the C-3 of imidazo[1,2- a]pyridine under mild conditions achieved additional topological and connective diversity within the scaffold collection.