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.

Generation and enhancement of the sum sideband under double radiation pressure.

A theoretical scheme to enhance the sum sideband generation (SSG) via double radiation pressure is proposed. In this scheme, both sides of the double-cavity system are driven by red and blue detuned pump lasers and frequency components are generated at the sum sideband through optomechanical nonlinear interaction. The results show that the efficiency of SSG can be improved with orders of magnitude. We further investigate the properties of SSG in resolved and unresolved sideband regimes. The efficiencies of upper sum sideband generation (USSG) and lower sum sideband generation (LSSG) are the equivalent in the unresolved sideband regime when the threshold condition is satisfied. It is worth noting that with the increase of the ratio between the dissipation rate of the cavity field and the decay rate of the mechanical resonator (MR), the amplitude of the LSSG can be superior to that of the USSG. Our scheme may provide a potential application in realizing the measurement of high-precision weak forces and quantum-sensitive sensing.

Review of triazole scaffolds for treatment and diagnosis of Alzheimer's disease.

Triazole scaffolds, a series of 5-membered heterocycles, are well known for their high efficacy, low toxicity, and superior pharmacokinetics. Alzheimer's disease (AD) is the first neurodegenerative disorder with complex pathological mechanisms. Triazole, as an aromatic group with three nitrogen atoms, forms polar and non-polar interactions with diverse key residues in the receptor-ligand binding procedure, and has been widely used in the molecular design in the development of anti-AD agents. Moreover, considering the simple synthesis approaches, triazole scaffolds are commonly used to link two pharmacodynamic groups in one chemical molecule, forming multi-target directed ligands (MTDLs). Furthermore, the click reaction between azide- and cyano-modified enzyme and ligand provides feasibility for the new modulator discovery, compound tissue distribution evaluation, enzyme localization, and pharmacological mechanism study, promoting the diagnosis of AD course.

Medicinal Prospects of Targeting Tyrosinase: A Feature Review.

Tyrosinase is a bifunctional polyphenol oxidase (PPO), catalyzing two oxidative reactions: monophenols to o-quinones (monophenolase activity) and o-diphenols to oquinones (diphenolase activity). As tyrosinase is the rate-limiting enzyme for the melanogenesis process, it is an attractive target for melanogenesis inhibition. Aiming at skin whitening, anticancer, Parkinson's disease (PD) treatment, antibacterial, fruit and vegetable preservation and other anti-pigmentation effect, medicinal chemists have exploited diverse tyrosinase inhibitors through various approaches. In addition to discovering inhibitors with novel scaffolds, good activity and high safety, researchers also focused on developing strategies for synergistic effects of multiple inhibitors and simultaneously regulating multiple targets to treat cancer or neurodegenerative diseases. This review focused on multiple natural and synthetic tyrosinase inhibitors, which could contribute to preventing fruit and vegetable browning, skin whitening, antibacterial, anticancer, Parkinson's Disease, etc.

The effect of transcranial magnetic stimulation on the recovery of attention and memory impairment following stroke: a systematic review and meta-analysis.

BACKGROUND: Previous studies indicated inconsistent results for the treatment effect of repetitive transcranial magnetic stimulation (rTMS) on attention and memory impairment following stroke. METHODS: Randomized controlled trials (RCTs) on TMS for the treatment of stroke were retrieved from Online databases. Data were analyzed by RevMan 5.3 software. RESULTS: Ten RCTs performed in China were included, with a total of 591 younger post-stroke patients ranging in age from their 40s to their 60s. The meta-analysis indicated that TMS could significantly improve the recovery of cognitive impairment following a stroke, according to the Montreal Cognitive Assessment (MoCA) score (8 studies, MD = 2.69, 95% CI: 1.44 to 3.95, P < 0.0001), the Rivermead Behavioral Memory Test (RBMT) score (7 studies, MD = 1.74, 95% CI:1.13 to 2.34, P < 0.00001), and the Modified Barthel Index (MBI) for Activities of Daily Living (3 studies, MD = 8.83, 95% CI:5.34 to 12.32, P < 0.00001). Sub-group analysis of MoCA and RBMT suggested that a low-frequency (1 Hz) stimulation exhibited similar effect with a higher-frequency (10 Hz) treatment. DISCUSSION: TMS might effectively improve the attention and memory impairment of stroke patients without increasing side effects. But this effect needs to be verified by more multi-center, high-quality, large-sample, rigorously designed RCTs.

Superior treatment efficacy of neuromodulation rehabilitation for upper limb recovery after stroke: a meta-analysis.

BACKGROUND: This study aims to explore the treatment efficacy of different motor rehabilitation interventions for upper limb impairment recovery. RESEARCH DESIGN & METHODS: Publications were searched in PubMed and Embase. 4 grouped motor rehabilitation treatments (training, technological intervention, pharmacological intervention, and neuromodulation) were compared. The change of the Fugl-Meyer Assessment Scale for Upper Extremity (FMA-UE) was applied to assess upper limb function after stroke. RESULTS: 56 studies including 5292 patients were identified. A significant difference was found among the 4 groups (P = 0.02). Neuromodulation interventions had the best treatment efficacy among the 4 types of interventions (P < 0.01). Among neuromodulation interventions, acupuncture, electric, or magnetic intervention all had therapeutic efficacy for stroke upper limb recovery, without significant subgroup difference (P = 0.34). Stroke patients with mild upper limb impairment might not benefit from motor rehabilitation (P = 0.14). CONCLUSION: Neuromodulation interventions might have the best therapeutic efficacy among motor rehabilitation treatments for upper limb impairment after stroke. It is a potential treatment direction for upper limb recovery among stroke patients. However, since a large proportion of the original studies are low to very low-quality evidence, large-scale RCTs should be conducted in the future to validate current findings and assess treatment effects based on patient characteristics.

Cooling of mechanical resonator in a hybrid intracavity squeezing optomechanical system.

A hybrid intracavity squeezing optomechanical cooling system, in which an auxiliary cavity couples to an optomechanical cavity with a nonlinear medium inside it, is proposed to realize the ground state cooling of the mechanical resonator in the highly unresolved sideband regime. We demonstrate that the quantum backaction heating can be suppressed perfectly by the intracavity squeezing, and the cooling process can be further promoted by adjusting the tunnel coupling between the coupled cavities. The scheme has good performance in resisting the environmental thermal noise and better tolerance for the auxiliary cavity quality factor and provides the possibility for the quantum manipulation of the mechanical resonator with large mass and low frequency.

A highly effective and stable butyrylcholinesterase inhibitor with multi-faceted neuroprotection and cognition improvement.

Butyrylcholinesterase (BChE) has been more and more attractive for treating neurodegenerative diseases, especially Alzheimer's disease (AD). In this study, we conducted activity and druggability optimization based on the structures that were previously reported. Most compounds exhibited pronounced BChE inhibitory capacity with nanomolar IC50 values. Based on the results of inhibiting activity and cyto-safety evaluations, two compounds (7, eqBChE IC50 = 2.94 nM, hBChE IC50 = 34.6 nM, and 20, eqBChE IC50 = 0.15 nM, hBChE IC50 = 45.2 nM) have been selected as candidates. High stability of compound 20 contributed to significantly improved blood concentration and tissue exposure, resulting in a reduced administration and effective dose in pharmacodynamic experiments. Two candidates exhibited remarkable neuroprotective properties and cognition improving activity, by benefiting cholinergic system, reducing the total Aß amount and increasing the ghrelin content. Simultaneous modulation in the center and periphery greatly improves the efficiency of BChE inhibitors. Considering the regulation on ghrelin level, BChE inhibition could improve not only symptoms but also nutritional status of AD patients.

Discovery of Resorcinol-Based Polycyclic Structures as Tyrosinase Inhibitors for Treatment of Parkinson's Disease.

Tyrosinase is involved in the synthesis of neuromelanin in the substantia nigra, which is closely correlated with the pathogenesis of Parkinson's disease. Herein, we identified S05014 (l-Tyr, IC50 = 6.25 ± 1.43 nM; l-Dopa, IC50 = 0.64 ± 0.40 µM) as a highly effective tyrosinase inhibitor. It could inhibit the tyrosinase function from different origins and decrease the expression of tyrosinase. S05014 presented good medication safety and inhibited melanogenesis in a dose-dependent manner. Moreover, as a resorcinol derivative, S05014 could scavenge the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical and significantly reduce the overproduction of LPS-induced reactive oxidative species (ROS), indicating its antioxidative profile. S05014 exhibited an excellent neuroprotective effect against methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) impairment in vitro and could remarkably alleviate movement abnormalities and exploratory activities in vivo. Altogether, S05014 is considered as a promising inhibitor for tyrosinase, melanogenesis, and oxidative stress and has great potential to be utilized in anti-Parkinsonian syndrome. From this point of view, tyrosinase inhibition has been further confirmed to be a novel strategy to improve locomotor capacity and treat Parkinson's disease.

Strategies for Structural Modification of Small Molecules to Improve Blood-Brain Barrier Penetration: A Recent Perspective.

In the development of central nervous system (CNS) drugs, the blood-brain barrier (BBB) restricts many drugs from entering the brain to exert therapeutic effects. Although many novel delivery methods of large molecule drugs have been designed to assist transport, small molecule drugs account for the vast majority of the CNS drugs used clinically. From this perspective, we review studies from the past five years that have sought to modify small molecules to increase brain exposure. Medicinal chemists make it easier for small molecules to cross the BBB by improving diffusion, reducing efflux, and activating carrier transporters. On the basis of their excellent work, we summarize strategies for structural modification of small molecules to improve BBB penetration. These strategies are expected to provide a reference for the future development of small molecule CNS drugs.

Highly Potent and Selective Butyrylcholinesterase Inhibitors for Cognitive Improvement and Neuroprotection.

Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Aß deposit. Here, we identified S06-1011 (hBChE IC50 = 16 nM) and S06-1031 (hBChE IC50 = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Aß1-42 peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.

Discovery and Biological Evaluation of a Novel Highly Potent Selective Butyrylcholinsterase Inhibitor.

To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound 8012-9656 (eqBChE IC50 = 0.18 ± 0.03 µM, hBChE IC50 = 0.32 ± 0.07 µM) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with 8012-9656 could almost entirely recover the Aß1-42 (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Aß1-42 total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood-brain barrier (BBB) penetrating ability, a long T1/2, and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.

Design, synthesis and biological evaluation of novel carboline-cinnamic acid hybrids as multifunctional agents for treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease with multiple pathological features. Multifunctional compounds able to simultaneously interact with several pathological components have been considered as a solution to treat the complex pathologies of neurodegenerative diseases. ß-carboline and cinnamic acid have been extensively studied for their widespread biological effects in treatment of AD, further application is limited due to its poor solubility and high toxicity. Herein, a series of carboline-cinnamic acid hybrids was designed and synthesized to obtain new multifunctional molecules with low toxicity and good physicochemical properties. In particular, e3 and e12 exhibited significant inhibition of Aß aggregation (inhibitory rate at 25 µM: 65% and 72% respectively), moderate BuChE inhibition, excellent neuroprotective effects and low neurotoxicity. Furthermore, in the AD mice model, e3 and e12 could restore learning and memory function to a comparable level to that of the control and did not exhibit any acute toxicity in vivo at a relatively high dose of 600 mg/kg. Thus, these new compounds can be further studied as multifunctional molecules for AD.

Transparency and tunable slow-fast light in a hybrid cavity optomechanical system.

We theoretically investigate the optomechanically induced transparency (OMIT) phenomenon in a hybrid optomechanical system composing of an optomechanical cavity and a traditional one. A Kerr medium is inserted in the optomechanical cavity and the other traps the atomic ensemble. We demonstrate the appearance of electromagnetically and optomechanically induced transparency when there is only Kerr medium or atoms in the system. We give an explicit explanation for the mechanism of the transparency. Moreover, we set up new scheme for the measurement of Kerr coefficient and the single atom-photon coupling strength. It is shown that Kerr nonlinearity can inhibit the normal mode splitting (NMS) when the tunnel strength is strong coupling. Furthermore, in the output field, slow light and fast light are converted to realize the tunable switch from slow light to fast light. This study has some important guiding significance in the fields of the high precision measurement and quantum information processing.

Reasonably activating Nrf2: A long-term, effective and controllable strategy for neurodegenerative diseases.

Neurodegenerative diseases are a variety of debilitating and fatal disorder in central nervous system (CNS). Besides targeting neuronal activity by influencing neurotransmitters or their corresponding receptors, modulating the underlying processes that lead to cell death, such as oxidative stress and mitochondrial dysfunction, should also be emphasized as an assistant strategy for neurodegeneration therapy. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been closely verified to be related to anti-inflammation and oxidative stress, rationally regulating its belonging pathway and activating Nrf2 is emphasized to be a potential treatment approach. There have existed multiple Nrf2 activators with different mechanisms and diverse structures, but those applied for neuro-disorders are still limited. On the basis of research arrangement and compound summary, we put forward the limitations of existing Nrf2 activators for neurodegenerative diseases and their future developing directions in enhancing the blood-brain barrier permeability to make Nrf2 activators function in CNS and designing Nrf2-based multi-target-directed ligands to affect multiple nodes in pathology of neurodegenerative diseases.

Dynamic generation of multi-qubit entanglement in the ultrastrong-coupling regime.

We propose a dynamic evolution protocol for generating multi-qubit GHZ states in the ultrastrong-coupling regime of circuit QED. By varying the time length of sequences, the protocol works for any coupling strength g/ωr ≥ 0.25. The time for generating the GHZ states in our protocol can be in the subnanoseconds. By taking into account realistic parameters of circuit QED, the degeneracy of fidelity due to decoherence can be as low as 0.02%.

Design, synthesis and evaluation of novel bivalent ß-carboline derivatives as multifunctional agents for the treatment of Alzheimer's disease.

To develop potent multi-target ligands against Alzheimer's disease (AD), a series of novel bivalent ß-carboline derivatives were designed, synthesized, and evaluated. In vitro studies revealed these compounds exhibited good multifunctional activities. In particular, compounds 8f and 8g showed the good selectivity potency on BuChE inhibition (IC50 = 1.7 and 2.7 µM, respectively), Aß1-42 disaggregation and neuroprotection. Compared with the positive control resveratrol, 8f and 8g showed better activity in inhibiting Aß1-42 aggregation, with inhibitory rate 82.7% and 85.7% at 25 µM, respectively. Moreover, compounds 8e, 8f and 8g displayed excellent neuroprotective activity by ameliorating the impairment induced by H2O2, okadaic acid (OA) and Aß1-42 without cytotoxicity in SH-SY5Y cells. Thus, the present study evidently showed that compounds 8f and 8g are potent multi-functional agents against AD and might serve as promising lead candidates for further development.

High-speed quantum-random number generation by continuous measurement of arrival time of photons.

We demonstrate a novel high speed and multi-bit optical quantum random number generator by continuously measuring arrival time of photons with a common starting point. To obtain the unbiased and post-processing free random bits, the measured photon arrival time is converted into the sum of integral multiple of a fixed period and a phase time. Theoretical and experimental results show that the phase time is an independent and uniform random variable. A random bit extraction method by encoding the phase time is proposed. An experimental setup has been built and the unbiased random bit generation rate could reach 128 Mb/s, with random bit generation efficiency of 8 bits per detected photon. The random numbers passed all tests in the statistical test suite.