RESUMEN
Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment, and there is a lack of effective drugs to treat AD clinically. Existing medications for the treatment of AD, such as Tacrine, Donepezil, Rivastigmine, and Aducanumab, only serve to delay symptoms and but not cure disease. To add insult to injury, these medications are associated with very serious adverse effects. Therefore, it is urgent to explore effective therapeutic drugs for AD. Recently, studies have shown that a variety of enzyme inhibitors, such as cholinesterase inhibitors, monoamine oxidase (MAO)inhibitors, secretase inhibitors, can ameliorate cholinergic system dysfunction, Aβ production and deposition, Tau protein hyperphosphorylation, oxidative stress damage, and the decline of synaptic plasticity, thereby improving AD symptoms and cognitive function. Some plant extracts from natural sources, such as Umbelliferone, Aaptamine, Medha Plus, have the ability to inhibit cholinesterase activity and act to improve learning and cognition. Isochromanone derivatives incorporating the donepezil pharmacophore bind to the catalytic active site (CAS) and peripheral anionic site (PAS) sites of acetylcholinesterase (AChE), which can inhibit AChE activity and ameliorate cholinergic system disorders. A compound called Rosmarinic acid which is found in the Lamiaceae can inhibit monoamine oxidase, increase monoamine levels in the brain, and reduce Aβ deposition. Compounds obtained by hybridization of coumarin derivatives and hydroxypyridinones can inhibit MAO-B activity and attenuate oxidative stress damage. Quinoline derivatives which inhibit the activation of AChE and MAO-B can reduce Aβ burden and promote learning and memory of mice. The compound derived from the combination of propargyl and tacrine retains the inhibitory capacity of tacrine towards cholinesterase, and also inhibits the activity of MAO by binding to the FAD cofactor of monoamine oxidase. A series of hybrids, obtained by an amide linker of chromone in combine with the benzylpiperidine moieties of donepezil, have a favorable safety profile of both cholinesterase and monoamine oxidase inhibitory activity. Single domain antibodies (such as AAV-VHH) targeted the inhibition of BACE1 can reduce Aβ production and deposition as well as the levels of inflammatory cells, which ultimately improve synaptic plasticity. 3-O-trans-p-coumaroyl maslinic acid from the extract of Ligustrum lucidum can specifically inhibit the activity of γ-secretase, thereby rescuing the long-term potentiation and enhancing synaptic plasticity in APP/PS1 mice. Inhibiting γ-secretase activity which leads to the decline of inflammatory factors (such as IFN-γ, IL-8) not only directly improves the pathology of AD, but also reduces Aβ production. Melatonin reduces the transcriptional expression of GSK-3β mRNA, thereby decreasing the levels of GSK-3β and reducing the phosphorylation induced by GSK-3β. Hydrogen sulfide can inhibitGSK-3β activity via sulfhydration of the Cys218 site of GSK-3β, resulting in the suppression of Tau protein hyperphosphorylation, which ameliorate the motor deficits and cognitive impairment in mice with AD. This article reviews enzyme inhibitors and conformational optimization of enzyme inhibitors targeting the regulation of cholinesterase, monoamine oxidase, secretase, and GSK-3β. We are hoping to provide a comprehensive overview of drug development in the enzyme inhibitors, which may be useful in treating AD.
RESUMEN
Objective:To investigate the changes of the functional connectivity of hypothalamus and the whole brain anisotropy in patients with dysphagia after stroke using magnetic resonance imaging. Methods:From December, 2018 to December, 2019, 14 patients with dysphagia after stroke and 15 healthy controls matched in age, sex and dominant hemisphere were selected. The functional connections from bilateral hypothalamus were researched with resting-state functional nuclear magnetic resonance, and the correlation between functional connection and scores of Eating Assessment Tool-10 (EAT-10) was analyzed. Meanwhile, the whole brain white matter integrity was observed with diffusion tensor imaging, and the fraction anisotropy (FA) was compared. Results:Compared with the controls, the functional connections from left hypothalamus to left precentral gyrus, left postcentral gyrus, left marginal lobe, left parietal lobe and left occipital lobe decreased in the patients; while the functional connections to left thalamus, left midbrain and right occipital lobe increased; the functional connections from right hypothalamus to right precentral gyrus, bilateral marginal lobe, bilateral superior temporal gyrus and right parietal lobe decreased; the functional connection to bilateral parietal lobe and bilateral occipital lobe increased. There was negative correlation of EAT-10 scores to functional connection from left hypothalamus to left precentral gyrus (r = -0.595, P = 0.025) and left postcentral gyrus (r = -0.934, P < 0.001), and positive correlation to functional connections from left hypothalamus to left parietal lobe (r = 0.583, P = 0.028) and from right hypothalamus to left occipital lobe (r = 0.630, P = 0.016). Compared with the controls, FA decreased in bilateral precentral gyrus, bilateral postcentral gyrus, bilateral frontal lobe, bilateral parietal lobe, bilateral occipital lobe, bilateral caudate nucleus, bilateral thalamus, right medulla, right superior temporal gyrus, right pontine and left posterior cerebellar lobe in the patients; while FA increased in bilateral anterior lobe of cerebellum and right cingulate gyrus. Conclusion:The motor and sensory cortices are important for swallowing. Patients with dysphagia after stroke may spend more attention and visual compensation. Impairment of white matter is found in swallowing cortex, subcortical structure and brainstem swallowing center in patients with dysphagia after stroke.
RESUMEN
Alisol A 24-acetate, a triterpenoid extracted from Alisma orientale, has shown anti-atherosclerotic actions and many studies have proved that oxidized low density lipoprotein (Ox-LDL) could promote proliferation of aorta smooth muscle cells (VSMCs) which are closely related to atherosclerosis (AS). The purpose of this study was to evaluate the effect of alisol A 24-acetate on the proliferation of VSMCs isolated from the thoracic aorta of rats induced by ox-LDL. VSMCs were induced by ox-LDL(50 mg·L⁻¹) to establish the proliferation model and intervened by alisol A 24-acetate (5, 10, 20 mg·L⁻¹) for 12, 24 and 48 h. Then the proliferation of VSMCs was detected by MTT assay; protein expression levels of VSMCs PCNA, cyclinD1, cyclinE, p21, p27 and VSMCs PCNA, p21and p27 mRNA expression levels were detected by Western blot and Real-time polymerase chain reaction (RT-PCR) respectively. The results showed that ox-LDL could induce the proliferation of VSMCs (<0.05), increase the protein expression levels of PCNA, cyclinD1 and cyclinE in the VSMCs (<0.05) and inhibit the protein and mRNA expression levels of p21 and p27 (<0.05). As compared with the model group, alisol A 24-acetate inhibited the proliferation of VSMCs in rats induced by ox-LDL and inhibited the protein expression of VSMCs PCNA, cyclinD1, cyclinE and enhanced the protein and mRNA p21 and p27 expression levels (<0.05). The effect was more obvious with the increase of concentration of alisol A 24-acetate. These data indicate that alisol A 24-acetate can inhibit the proliferation of VSMCs induced by ox-LDL and the mechanism may be associated with inhibiting expression of cyclin protein, including cyclinD1, cyclinE, p21, p27 and so on.