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.     

Dioscin-Mediated Autophagy Alleviates MPP+-Induced Neuronal Degeneration: An In Vitro Parkinson’s Disease Model

Autophagy is a cellular homeostatic process by which cells degrade and recycle their malfunctioned contents, and impairment in this process could lead to Parkinson’s disease (PD) pathogenesis. Dioscin, a steroidal saponin, has induced autophagy in several cell lines and animal models. The role of dioscin-mediated autophagy in PD remains to be investigated. Therefore, this study aims to investigate the hypothesis that dioscin-regulated autophagy and autophagy-related (ATG) proteins could protect neuronal cells in PD via reducing apoptosis and enhancing neurogenesis. In this study, the 1-methyl-4-phenylpyridinium ion (MPP⁺) was used to induce neurotoxicity and impair autophagic flux in a human neuroblastoma cell line (SH-SY5Y). The result showed that dioscin pre-treatment counters MPP⁺-mediated autophagic flux impairment and alleviates MPP⁺-induced apoptosis by downregulating activated caspase-3 and BCL2 associated X, apoptosis regulator (Bax) expression while increasing B-cell lymphoma 2 (Bcl-2) expression. In addition, dioscin pre-treatment was found to increase neurotrophic factors and tyrosine hydroxylase expression, suggesting that dioscin could ameliorate MPP⁺-induced degeneration in dopaminergic neurons and benefit the PD model. To conclude, we showed dioscin’s neuroprotective activity in neuronal SH-SY5Y cells might be partly related to its autophagy induction and suppression of the mitochondrial apoptosis pathway.     

Spin Transport in a Rashba Ring-Quantum Dot System Pumped by Microwave Fields

We report a theoretical study on producing electrically spin-polarized current in the Rashba ring with parallel double dots embedded, which are subject to two time-dependent microwave fields. By means of the Keldysh Green's function method, we present an analytic result of the pumped current at adiabatic limit and demonstrate that the interplay between the quantum pumping effectand spin-dependent quantum interference can lead to an arbitrarily controllable spin-polarized current in the device. The magnitude and direction of the charge and spin current can be effectively modulated by system parameters such as the pumping phase difference, Rashba precession phase, and the dynamic phase difference of electron traveling in two arms of ring; moreover, thespin-polarization degree of the charge current can also be tuned in the range [-∞, +∞]. Our findings may shed light on the all-electric way to produce the controllable spin-polarized charge current in the field of spintronics.     

过模慢波结构频率反射特性及谐振腔的影响

利用有限元方法求解:S-参数矩阵,研究了过模慢波结构对圆波导TM01,TM02模的反射特性,分析了在慢波结构末端加入谐振腔后,由于两端口的不对称性而造成的对反射特性影响。结果表明,在TM01的π模频率附近,慢波结构和谐振腔组成的系统对无谐振腔一侧端口入射TM01模的反射增大,而对有谐振腔一侧端口入射TM01模的反射减小。根据计算结果,解释了普通多波切伦柯夫振荡器所用慢波结构周期数较多的原因,说明了在多波切伦柯夫振荡器中引入谐振腔后,不但可以减少所用慢波结构周期数,而且有利于提高微波输出效率。     

马克思的制度经济思想再认识

在当代经济学的语境下,本文从一种广义的制度分析新视角,首次重新解读了马克思（以及恩格斯）著作中的制度经济论述。通过深入细致的思想梳理、观点辨析、理论提炼与重构工作发现,马克思的经济学是经济思想史上第一个重要的制度经济学分析体系。这一分析体系既包含有关社会经济制度问题的基本概念与原理的“一般性分析”,也包括关于资本主义市场经济制度的历史特性的“专门性分析”。两个分析层次之间具有内在的逻辑联系,反映了从“一般”到“特殊”的创新性理论演绎思路。对马克思的制度经济学分析体系的重新发掘与提炼表明,马克思的制度经济思想不仅在制度经济思想史上占具至关重要的地位,而且对于丰富和推进当代制度经济理论发展也具有重要的学术启示与借鉴意义。