Discovery of novel dual Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) inhibitors as a promising strategy for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronically systemic autoimmune disorder, which is related with various cellular signal pathways. Both BTK (Bruton's Tyrosine Kinase) and JAK3 (Janus Kinase 3) play important roles in the pathogenesis of rheumatoid arthritis. Herein, we reported the discovery of dual BTK/JAK3 inhibitors through bioisosterism and computer-aided drug design based on the structure of BTK inhibitor ibrutinib. We reported the discovery of dual BTK/JAK3 inhibitors which are based on the structure of BTK inhibitor ibrutinib via the method of bioisosterism and computer-aided drug design) Most of the target compounds exhibited moderate to strong inhibitory activities against BTK and JAK3. Among them, compound XL-12 stood out as the most promising candidate targeting BTK and JAK3 with potent inhibitory activities (IC50 = 2.0 nM and IC50 = 14.0 nM respectively). In the in vivo studies, compound XL-12 (40 mg/kg) exhibited more potent antiarthritic activity than ibrutinib (10 mg/kg) in adjuvant arthritis (AA) rat model. Furthermore, compound XL-12 (LD50 > 1600 mg/kg) exerted improved safety compared with ibrutinib (LD50 = 750 mg/kg). These results indicated that compound XL-12, the dual BTK/JAK3 inhibitor, might be a potent drug candidate for the treatment of RA.

Magnetic tri-bead microrobot assisted near-infrared triggered combined photothermal and chemotherapy of cancer cells.

Magnetic micro/nanorobots attracted much attention in biomedical fields because of their precise movement, manipulation, and targeting abilities. However, there is a lack of research on intelligent micro/nanorobots with stimuli-responsive drug delivery mechanisms for cancer therapy. To address this issue, we developed a type of strong covalently bound tri-bead drug delivery microrobots with NIR photothermal response azobenzene molecules attached to their carboxylic surface groups. The tri-bead microrobots are magnetic and showed good cytocompatibility even when their concentration is up to 200 µg/mL. In vitro photothermal experiments demonstrated fast NIR-responsive photothermal property; the microrobots were heated to 50 °C in 4 min, which triggered a significant increase in drug release. Motion control of the microrobots inside a microchannel demonstrated the feasibility of targeted therapy on tumor cells. Finally, experiments with lung cancer cells demonstrated the effectiveness of targeted chemo-photothermal therapy and were validated by cell viability assays. These results indicated that tri-bead microrobots have excellent potential for targeted chemo-photothermal therapy for lung cancer cell treatment.

Discovery of novel nonpeptide small-molecule NRP1 antagonists: Virtual screening, molecular simulation and structural modification.

Multifaceted roles of vascular endothelial growth factor (VEGF)-neuropilin-1 (NRP1) interaction have been implicated in cancer, but reports on small-molecule inhibitors of VEGF-NRP1 interaction are scarce. Herein, we describe the identification of 1, a novel nonpeptide small-molecule NRP1 antagonist with moderate activity via structure-based virtual screening. Ensemble docking and molecular dynamics (MD) simulations of 1 were carried out and an interesting binding model was obtained. We found that the "aromatic box" enclosed by Tyr297, Trp301 and Tyr353 of NRP1 is critical for NRP1-1 binding. Further structure modification of 1 based on the binding model derived from MD simulations resulted in the identification of 12a with significantly improved activity.

Efficacy and adverse effects of ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis.

BACKGROUND: Research into Ginkgo biloba has been ongoing for many years, while the benefit and adverse effects of Ginkgo biloba extract EGb761 for cognitive impairment and dementia has been discussed controversially. OBJECTIVE: To discuss new evidence on the clinical and adverse effects of standardized Ginkgo biloba extract EGb761 for cognitive impairment and dementia. METHODS: MEDLINE, EMBASE, Cochrane, and other relevant databases were searched in March 2014 for eligible randomized controlled trials of Ginkgo biloba EGb761 therapy in patients with cognitive impairment and dementia. RESULTS: Nine trials met our inclusion criteria. Trials were of 22-26 weeks duration and included 2,561 patients in total. In the meta-analysis, the weighted mean differences in change scores for cognition were in favor of EGb761 compared to placebo (-2.86, 95%CI -3.18; -2.54); the standardized mean differences in change scores for activities in daily living (ADLs) were also in favor of EGb761 compared to placebo (-0.36, 95%CI -0.44; -0.28); Peto OR showed a statistically significant difference from placebo for Clinicians' Global Impression of Change (CGIC) scale (1.88, 95%CI 1.54; 2.29). All these benefits are mainly associated with EGb761 at a dose of 240 mg/day. For subgroup analysis in patients with neuropsychiatric symptoms, 240 mg/day EGb761 improved cognitive function, ADLs, CGIC, and also neuropsychiatric symptoms with statistical superiority than for the whole group. For the Alzheimer's disease subgroup, the main outcomes were almost the same as the whole group of patients with no statistical superiority. Finally, safety data revealed no important safety concerns with EGb761. CONCLUSIONS: EGb761 at 240 mg/day is able to stabilize or slow decline in cognition, function, behavior, and global change at 22-26 weeks in cognitive impairment and dementia, especially for patients with neuropsychiatric symptoms.

Efficacy of vitamins B supplementation on mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis.

Despite B vitamin supplementation playing an important role in cognitive function, the exact effect remains unknown. The aim of this study was to systematically review and quantitatively synthesize the efficacy of treatment with vitamins B supplementation in slowing the rate of cognitive, behavioral, functional and global decline in individuals with MCI or AD. A systematic literature search in PubMed, EMBASE, International Pharmaceutical Abstracts, clinicaltrials. gov, the Cochrane Controlled Trials Register, the Cochrane Database of Systematic Reviews, and the Cochrane Cognitive Improvement Group specialized registry was conducted on April 2014, with no limit of date. Five trials met the eligibility criteria and were selected for this meta-analysis. Meta-analysis showed moderate beneficial effects of vitamins B supplementation on memory (SMD 0.60, 95% CI 0.20, 1.00), whereas no significant difference on general cognitive function (WMD -0.10, 95% CI -0.80, 0.59), executive function (SMD 0.05, 95% CI -0.11, 0.21) and attention (WMD -0.03, 95% CI -1.20, 1.14) were found in MCI patients. In addition, no significantly cognitive benefits on the Alzheimer's Disease Assessment Scale (ADAS-cog) (WMD 1.01, 95% CI -0.68, 2.70) and Mini Mental State Examination (MMSE) (WMD -0.22, 95% CI -1.00, 0.57), functional (SMD 0.13, 95% CI -0.05, 0.31), behavioral (SMD 0.04, 95% CI -0.16, 0.25) or global (WMD 0.07, 95% CI -0.48, 0.62) change were observed in AD patients. Collectively, weak evidence of benefits was observed for the domains of memory in patients with MCI. Nevertheless, future standard RCTs are still needed to determine whether it was still significant in larger populations. However, the data does not yet provide adequate evidence of an effect of vitamins B on general cognitive function, executive function and attention in people with MCI. Similarly, folic acid alone or vitamins B in combination are unable to stabilize or slow decline in cognition, function, behavior, and global change of AD patients.