Role of Natural Compounds and Target Enzymes in the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurological condition. The rising prevalence of AD necessitates the rapid development of efficient therapy options. Despite substantial study, only a few medications are capable of delaying the disease. Several substances with pharmacological activity, derived from plants, have been shown to have positive benefits for the treatment of AD by targeting various enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase, γ-secretase, and monoamine oxidases (MAOs), which are discussed as potential targets. Medicinal plants have already contributed a number of lead molecules to medicine development, with many of them currently undergoing clinical trials. A variety of medicinal plants have been shown to diminish the degenerative symptoms associated with AD, either in their raw form or as isolated compounds. The aim of this review was to provide a brief summary of AD and its current therapies, followed by a discussion of the natural compounds examined as therapeutic agents and the processes underlying the positive effects, particularly the management of AD.     

The Relationship between Procyanidin Structure and Their Protective Effect in a Parkinson’s Disease Model

This study evaluated the effect of grape seed-derived monomer, dimeric, and trimeric procyanidins on rat pheochromocytoma cell line (PC12) cells and in a zebrafish Parkinson’s disease (PD) model. PC12 cells were cultured with grape seed-derived procyanidins or deprenyl for 24 h and then exposed to 1.5 mm 1-methyl-4-phenylpyridinium (MPP⁺) for 24 h. Zebrafish larvae (AB strain) 3 days post-fertilization were incubated with deprenyl or grape seed-derived procyanidins in 400 µM 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 4 days. The results showed that the procyanidin dimers procyanidin B1 (B1), procyanidin B2 (B2), procyanidin B3 (B3), procyanidin B4 (B4), procyanidin B1-3-O-gallate (B1-G), procyanidin B2-3-O-gallate (B2-G), and the procyanidin trimer procyanidin C1 (C1) had a protective effect on PC12 cells, decreasing the damaged dopaminergic neurons and motor impairment in zebrafish. In PC12 cells and the zebrafish PD model, procyanidin (B1, B2, B3, B4, B1-G, B2-G, C1) treatment decreased the content of reactive oxygen species (ROS) and malondialdehyde (MDA), increased the activity of antioxidant enzymes glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD), and upregulated the expression of nuclear factor-erythroid 2-related factor (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1). These results suggest that in PC12 cells and the zebrafish PD model, the neuroprotective effects of the procyanidins were positively correlated with their degree of polymerization.     

Neuroprotective Effect of Caffeine in Alzheimer’s Disease

Alzheimer’s disease (AD) is the leading cause of dementia, predicted to be the most significant health burden of the 21st century, with an estimated 131.5 million dementia patients by the year 2050. This review aims to provide an overview of the effect of caffeine on AD and cognition by summarizing relevant research conducted on this topic. We searched the Web of Science core collection and PubMed for studies related to the effect of caffeine on AD and cognition using title search terms: caffeine; coffee; Alzheimer’s; cognition. There is suggestive evidence from clinical studies that caffeine is neuroprotective against dementia and possibly AD (20 out of 30 studies support this), but further studies, such as the “ideal” study proposed in this review, are required to prove this link. Clinical studies also indicate that caffeine is a cognitive normalizer and not a cognitive enhancer. Furthermore, clinical studies suggest the neuroprotective effect of caffeine might be confounded by gender. There is robust evidence based on in vivo and in vitro studies that caffeine has neuroprotective properties in AD animal models (21 out of 22 studies support this), but further studies are needed to identify the mechanistic pathways mediating these effects.     

The Fight against Infection and Pain: Devil’s Claw (Harpagophytum procumbens) a Rich Source of Anti-Inflammatory Activity: 2011–2022

Harpagophytum procumbens subsp. procumbens (Burch.) DC. ex Meisn. (Sesame seed Family—Pedaliaceae) is a popular medicinal plant known as Devil’s claw. It is predominantly distributed widely over southern Africa. Its impressive reputation is embedded in its traditional uses as an indigenous herbal plant for the treatment of menstrual problems, bitter tonic, inflammation febrifuge, syphilis or even loss of appetite. A number of bioactive compounds such as terpenoids, iridoid glycosides, glycosides, and acetylated phenolic compounds have been isolated. Harpagoside and harpagide, iridoid glycosides bioactive compounds have been reported in countless phytochemical studies as potential anti-inflammatory agents as well as pain relievers. In-depth studies have associated chronic inflammation with various diseases, such as Alzheimer’s disease, obesity, rheumatoid arthritis, type 2 diabetes, cancer, and cardiovascular and pulmonary diseases. In addition, 60% of chronic disorder fatalities are due to chronic inflammatory diseases worldwide. Inflammation and pain-related disorders have attracted significant attention as leading causes of global health challenges. Articles published from 2011 to the present were obtained and reviewed in-depth to determine valuable data findings as well as knowledge gaps. Various globally recognized scientific search engines/databases including Scopus, PubMed, Google Scholar, Web of Science, and ScienceDirect were utilized to collect information and deliver evidence. Based on the literature results, there was a dramatic decrease in the number of studies conducted on the anti-inflammatory and analgesic activity of Devil’s claw, thereby presenting a potential research gap. It is also evident that currently in vivo clinical studies are needed to validate the prior massive in vitro studies, therefore delivering an ideal anti-inflammatory and analgesic agent in the form of H. procumbens products.     

In Silico Analysis of PORD Mutations on the 3D Structure of P450 Oxidoreductase

Cytochrome P450 oxidoreductase (POR) is a membrane-bound flavoprotein that helps in transferring electrons from its NADPH domain to all cytochrome P450 (CYP450) enzymes. Mutations in the POR gene could severely affect the metabolism of steroid hormones and the development of skeletal muscles, a condition known as Cytochrome P450 oxidoreductase deficiency (PORD). PORD is associated with clinical presentations of disorders of sex development, Antley and Bixler’s syndrome (ABS), as well as an abnormal steroid hormone profile. We have performed an in silico analysis of POR 3D X-ray protein crystal structure to study the effects of reported mutations on the POR enzyme structure. A total of 32 missense mutations were identified, from 170 PORD patients, and mapped on the 3D crystal structure of the POR enzyme. In addition, five of the missense mutations (R457H, A287P, D210G, Y181D and Y607C) were further selected for an in-depth in silico analysis to correlate the observed changes in POR protein structure with the clinical phenotypes observed in PORD patients. Overall, missense mutations found in the binding sites of POR cofactors could lead to a severe form of PORD, emphasizing the importance of POR cofactor binding domains in transferring electrons to the CYP450 enzyme family.     

Friedelin Attenuates Neuronal Dysfunction and Memory Impairment by Inhibition of the Activated JNK/NF-κB Signalling Pathway in Scopolamine-Induced Mice Model of Neurodegeneration

Oxidative stress (OS) and c-Jun N-terminal kinase (JNK) are both key indicators implicated in neuro-inflammatory signalling pathways and their respective neurodegenerative diseases. Drugs targeting these factors can be considered as suitable candidates for treatment of neuronal dysfunction and memory impairment. The present study encompasses beneficial effects of a naturally occurring triterpenoid, friedelin, against scopolamine-induced oxidative stress and neurodegenerative pathologies in mice models. The treated animals were subjected to behavioural tests i.e., Y-maze and Morris water maze (MWM) for memory dysfunction. The underlying mechanism was determined via western blotting, antioxidant enzymes and lipid profile analyses. Molecular docking studies were carried out to predict the binding modes of friedelin in the binding pocket of p-JNK protein. The results reveal that scopolamine caused oxidative stress by (1) inhibiting catalase (CAT), peroxidase enzyme (POD), superoxide dismutase (SOD), and reduced glutathione enzyme (GSH); (2) the up-regulation of thiobarbituric acid reactive substances (TBARS) in mice brain; and (3) affecting the neuronal synapse (both pre- and post-synapse) followed by associated memory dysfunction. In contrast, friedelin administration not only abolished scopolamine-induced oxidative stress, glial cell activation, and neuro-inflammation but also inhibited p-JNK and NF-κB and their downstream signaling molecules. Moreover, friedelin administration improved neuronal synapse and reversed scopolamine-induced memory impairment accompanied by the inhibition of β-secretase enzyme (BACE-1) to halt amyloidogenic pathways of amyloid-β production. In summary, all of the results show that friedelin is a potent naturally isolated neuro-therapeutic agent to reverse scopolamine-induced neuropathology, which is characteristic of Alzheimer’s disease.     

The Influence of Tyrosol-Enriched Rhodiola sachalinensis Extracts Bioconverted by the Mycelium of Bovista plumbe on Scopolamine-Induced Cognitive,Behavioral, and Physiological Responses in Mice

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by cognitive deficits, which are accompanied by memory loss and cognitive disruption. Rhodiola sachalinensis (RSE) is a medicinal plant that has been used in northeastern Asia for various pharmacological activities. We attempted to carry out the bioconversion of RSE (Bio-RSE) using the mycelium of Bovista plumbe to obtain tyrosol-enriched Bio-RSE. The objective of this study was to investigate the effects of Bio-RSE on the activation of the cholinergic system and the inhibition of oxidative stress in mice with scopolamine (Sco)-induced memory impairment. Sco (1 mg/kg body weight, i.p.) impaired the mice’s performance on the Y-maze test, passive avoidance test, and water maze test. However, the number of abnormal behaviors was reduced in the groups supplemented with Bio-RSE. Bio-RSE treatment improved working memory and avoidance times against electronic shock, increased step-through latency, and reduced the time to reach the escape zone in the water maze test. Bio-RSE dramatically improved the cholinergic system by decreasing acetylcholinesterase activity and regulated oxidative stress by increasing antioxidant enzymes (superoxide dismutase (SOD) and catalase (CAT)). The reduction in nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling in the brain tissue due to scopolamine was restored by the administration of Bio-RSE. Bio-RSE also significantly decreased amyloid-beta 1–42 (Aβ1–42) and amyloid precursor protein (APP) expression. Moreover, the increased malondialdehyde (MDA) level and low total antioxidant capacity in Sco-treated mouse brains were reversed by Bio-RSE, and an increase in Nrf2 and HO-1 was also observed. In conclusion, Bio-RSE protected against Sco-induced cognitive impairment by activating Nrf2/HO-1 signaling and may be developed as a potential beneficial material for AD.     

Folding Free Energy Determination of an RNA Three-Way Junction Using Fluctuation Theorems

Nonequilibrium work relations and fluctuation theorems permit us to extract equilibrium information from nonequilibrium measurements. They find application in single-molecule pulling experiments where molecular free energies can be determined from irreversible work measurements by using unidirectional (e.g., Jarzynski’s equality) and bidirectional (e.g., Crooks fluctuation theorem and Bennet’s acceptance ratio (BAR)) methods. However, irreversibility and the finite number of pulls limit their applicability: the higher the dissipation, the larger the number of pulls necessary to estimate ΔG within a few kBT. Here, we revisit pulling experiments on an RNA three-way junction (3WJ) that exhibits significant dissipation and work-distribution long tails upon mechanical unfolding. While bidirectional methods are more predictive, unidirectional methods are strongly biased. We also consider a cyclic protocol that combines the forward and reverse work values to increase the statistics of the measurements. For a fixed total experimental time, faster pulling rates permit us to efficiently sample rare events and reduce the bias, compensating for the increased dissipation. This analysis provides a more stringent test of the fluctuation theorem in the large irreversibility regime.     

基于热图像的种蛋气室变化监测算法

种蛋气室的大小是监测种蛋孵化过程的重要指标之一。根据种蛋的热力学结构,种蛋在孵化过程中,包裹气室部分蛋壳会与其他部分蛋壳产生温差,从而可通过热红外图像进行观察。针对在种蛋孵化过程中,人工照蛋检测气室效率低的问题,探索设计了一种基于热图像的种蛋气室变化俯视监测算法。监测种蛋气室热图像的算法主要包括种蛋目标检测,种蛋图像分割和种蛋气室面积计算3个部分,其中种蛋的目标检测采用Faster-RCNN算法实现;种蛋图像分割采用BP神经网络算法实现;种蛋气室面积是在种蛋图像分割的基础上进行计算。使用孵化5天及以上的种蛋作为研究对象,并拍取种蛋的热图像进行试验。试验结果表明：种蛋热图像的目标检测的平均精度（mAP）为99.85%,拥有较好的检测效果。使用BP网络对种蛋进行图像分割。BP神经网络经过调参后,其网络最佳的结构为三层隐藏层,每个隐藏层拥有1 000个神经元,最优初始学习率为0.000 1,最优最大迭代次数为500。以F1-measure作为分割效果的评价指标,BP神经网络的图像分割总体结果为87.02%,Otsu算法的总体结果为65.25%。其中只有一个蛋的情况下,BP神经网络的分割结果为87.17%,Otsu算法的结果为68.86%。存在其他种蛋的干扰条件下,BP神经网络的分割结果为86.94%,Otsu算法的结果为61.64%,BP神经网络的分割效果优于Otsu分割算法,BP神经网络拥有更强的抗干扰能力。最后提取了孵化5～19 d种蛋的气室变化,通过观察种蛋气室大小曲线来监测种蛋的孵化情况,可看出随着天数的增加,气室有着明显变大的趋势。人工测量法与热红外测量法比较结果说明两者相关性为0.934 3,拥有较好的相关性。基于热图像的种蛋气室变化监测算法可在实际生产中实现种蛋的识别与气室大小的快速监测,为实现监测种蛋孵化的自动化提供了技术参考。