A new strategy for the treatment of Parkinson's disease: Discovery and bio-evaluation of the first central-targeting tyrosinase inhibitor.

The high level of tyrosinase leads to the generation of neuromelanin, further causing the abnormality of redox-related protein level and mediating the occurrence and development of Parkinson's disease (PD). However, the existing tyrosinase inhibitors are mostly natural product extracts or polyphenolic derivatives, which hindered them from penetrating the blood-brain barrier (BBB). Herein, we obtained a novel tyrosinase inhibitor, 2-06 (tyrosinase: monophenolase IC50 = 70.44 ± 22.69 µM, diphenolase IC50 = 1.89 ± 0.64 µM), through the structure-based screening method. The compound 2-06 presented good in vitro and in vivo safety, and can inhibit the tyrosinase and melanogenesis in B16F10. Moreover, this compound showed neuroprotective effects and Parkinsonism behavior improving function. 2-06 was proved to penetrate the BBB and enter the central nervous system (CNS). The exploration of the binding mode between 2-06 and tyrosinase provided the foundation for the subsequent structural optimization. This is the first research to develop a central-targeting tyrosinase inhibitor, which is crucial for in-depth study on the new strategy for utilizing tyrosinase inhibitors to treat PD.

Opportunities and perspectives of small molecular phosphodiesterase inhibitors in neurodegenerative diseases.

Phosphodiesterase (PDE) is a superfamily of enzymes that are responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDE inhibition promotes the gene transcription by activating cAMP-response element binding protein (CREB), initiating gene transcription of brain-derived neurotrophic factor (BDNF). The procedure exerts neuroprotective profile, and motor and cognitive improving efficacy. From this point of view, PDE inhibition will provide a promising therapeutic strategy for treating neurodegenerative disorders. Herein, we summarized the PDE inhibitors that have entered the clinical trials or been discovered in recent five years. Well-designed clinical or preclinical investigations have confirmed the effectiveness of PDE inhibitors, such as decreasing Aß oligomerization and tau phosphorylation, alleviating neuro-inflammation and oxidative stress, modulating neuronal plasticity and improving long-term cognitive impairment.

Targeting glycogen synthase kinase-3ß for Alzheimer's disease: Recent advances and future Prospects.

Senile plaques induced by ß-amyloid (Aß) abnormal aggregation and neurofibrillary tangles (NFT) caused by tau hyperphosphorylation are important pathological manifestations of Alzheimer's disease (AD). Glycogen synthase kinase-3 (GSK-3) is a conserved kinase; one member GSK-3ß is highly expressed in the AD brain and involved in the formation of NFT. Hence, pharmacologically inhibiting GSK-3ß activity and expression is a good approach to treat AD. As summarized in this article, multiple GSK-3ß inhibitors has been comprehensively summarized over recent five years. However, only lithium carbonate and Tideglusib have been studied in clinical trials of AD. Besides ATP-competitive and non-ATP-competitive inhibitors, peptide inhibitors, allosteric inhibitors and other types of inhibitors have gradually attracted more interest. Moreover, considering the close relationship between GSK-3ß and other targets involved in cholinergic hypothesis, Aß aggregation hypothesis, tau hyperphosphorylation hypothesis, oxidative stress hypothesis, neuro-inflammation hypothesis, etc., diverse multifunctional molecules and multi-target directed ligands (MTDLs) have also been disclosed. We hope that these recent advances and critical perspectives will facilitate the discovery of safe and effective GSK-3ß inhibitors for AD treatment.

Mapping quantitative trait loci associated with stem-related traits in maize (Zea mays L.).

KEY MESSAGE: Mapping QTL for stem-related traits using RIL population with ultra-high density bin map can better dissect pleiotropic QTL controlling stem architecture that can provide valuable information for maize genetic improvement. The maize stem is one of the most important parts of the plant and is also a component of many agronomic traits in maize. This study aimed to advance our understanding of the genetic mechanisms underlying maize stem traits. A recombinant inbred line (RIL) population derived from a cross between Ye478 and Qi319 was used to identify quantitative trait loci (QTL) controlling stem height (SH), ear height (EH), stem node number (SN), ear node (EN), and stem diameter (SD), and two derived traits (ear height coefficient (EHc) and ear node coefficient (ENc)). Using an available ultra-high density bin map, 46 putative QTL for these traits were detected on chromosomes 1, 3, 4, 5, 6, 7, 8, and 10. Individual QTL explained 3.5-17.7% of the phenotypic variance in different environments. Two QTL for SH, three for EH, two for EHc, one for SN, one for EN, and one for SD were detected in more than one environment. QTL with pleiotropic effects or multiple linked QTL were also identified on chromosomes 1, 3, 4, 6, 8, and 10, which are potential target regions for fine-mapping and marker-assisted selection in maize breeding programs. Further, we discussed segregation of bin markers (mk1630 and mk4452) associated with EHc QTL in the RIL population. We had identified two putative WRKY DNA-binding domain proteins, AC209050.3_FG003 and GRMZM5G851490, and a putative auxin response factor, GRMZM2G437460, which might be involved in regulating plant growth and development, as candidate genes for the control of stem architecture.