AAZ2 induces mitochondrial-dependent apoptosis by targeting PDK1 in gastric cancer. / AAZ2可通过靶向PDK1介导线粒体依赖的凋亡.

Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-|(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.

The organic arsenical-derived thioredoxin and glutathione system inhibitor ACZ2 induces apoptosis and autophagy in gastric cancer via ROS-dependent ER stress.

Developing novel drugs for gastric cancer (GC) is greatly needed, and a reactive oxygen species (ROS)-modulating strategy has been demonstrated to be useful for cancer treatment. However, no organic arsenical-derived ROS-modulating drug has been developed in GC. Here, we constructed ACZ2 and investigated its efficacy and potential mechanism for GC in vitro and in vivo. Our data showed that ACZ2 could inhibit GC proliferation and cause G2/M phase arrest. Moreover, ACZ2 induced ROS accumulation by depleting glutathione (GSH) and TrxR1, triggering a subsequent ER stress response by activating the PERK/EIF2/ATF4/CHOP signalling pathways, which is a crucial step for ACZ2-mediated apoptosis and autophagy. Vitally, ROS scavenger (NAC) and ER stress inhibitor (4PBA) reversed ACZ2/ROS/ER stress-mediated apoptosis and autophagy. Our in vivo results clearly demonstrated that ACZ2 suppressed tumour growth in a GC xenograft model. Collectively, our data indicated that ACZ2 is a potential agent against GC.

A novel organic arsenic derivative MZ2 remodels metabolism and triggers mtROS-mediated apoptosis in acute myeloid leukemia.

PURPOSE: Acute myeloid leukemia (AML) is one of the most common neoplasms in adults, and it is difficult to achieve satisfactory results with conventional drugs. Here, we synthesized a novel organic arsenic derivative MZ2 and evaluated its ability to remodel energy metabolism to achieve anti-leukemia. METHODS: MZ2 was characterized by the average 1-min full mass spectra analysis. Biological methods such as Western blot, qPCR, flow cytometry and confocal microscopy were used to assess the mode and mechanism of MZ2-induced death. The in vivo efficacy of MZ2 was assessed by constructing a patient-derived xenograft (PDX) AML model. RESULTS: Unlike the precursor organic arsenical Z2, MZ2 can effectively reduce the level of aerobic glycolysis. Our in-depth found that MZ2 inhibited the expression of PDK2 in a dose-dependent manner and did not affect the expression of LDHA, another key enzyme of the glycolytic pathway. MZ2 reconstituted energy metabolism to induce the generation of mitochondrial ROS (mtROS) and then triggerd intrinsic apoptosis pathway. We also assessed whether MZ2 generates autophagy and results showed that MZ2 can induce autophagy of AML cells, which may be associated with the precursor organic arsenic drug. In vivo, MZ2 effectively attenuated leukemia progression in mice, and immunohistochemical results suggested its PDK2 inhibitory effect. CONCLUSION: In summary, the novel organic arsine derivative MZ2 exhibited excellent anti-tumor effects in acute myeloid leukemia, which may provide a potential strategy for the treatment of acute myeloid leukemia.

Ancient Chinese Herbal Recipe Huanglian Jie Du Decoction for Ischemic Stroke: An Overview of Current Evidence.

Ischemic stroke is a major cause of mortality and neurological morbidity worldwide. The underlying pathophysiology of ischemic stroke is highly complicated and correlates with various pathological processes, including neuroinflammation, oxidative stress injury, altered cell apoptosis and autophagy, excitotoxicity, and acidosis. The current treatment for ischemic stroke is limited to thrombolytic therapy such as recombinant tissue plasminogen activator. However, tissue plasminogen activator is limited by a very narrow therapeutic time window (<4.5 hours), selective efficacy, and hemorrhagic complication. Hence, the development of novel therapies to prevent ischemic damage to the brain is urgent. Chinese herbal medicine has a long history in treating stroke and its sequela. In the past decades, extensive studies have focused on the neuroprotective effects of Huanglian Jie Du decoction (HLJDD), an ancient and classical Chinese herbal formula that can treat a wide spectrum of disorders including ischemic stroke. In this review, the current evidence of HLJDD and its bioactive components for ischemic stroke is comprehensively reviewed, and their potential application directions in ischemic stroke management are discussed.

Bioactive constituents of animal-derived traditional Chinese medicinal materials for breast cancer: opportunities and challenges.

Breast cancer is globally the most common invasive cancer in women and remains one of the leading causes of cancer-related deaths. Surgery, radiotherapy, chemotherapy, immunotherapy, and endocrine therapy are currently the main treatments for this cancer type. However, some breast cancer patients are prone to drug resistance related to chemotherapy or immunotherapy, resulting in limited treatment efficacy. Consequently, traditional Chinese medicinal materials (TCMMs) as natural products have become an attractive source of novel drugs. In this review, we summarized the current knowledge on the active components of animal-derived TCMMs, including Ophiocordycepssinensis-derived cordycepin, the aqueous and ethanolic extracts of O.sinensis, norcantharidin (NCTD), Chansu, bee venom, deer antlers, Ostreagigas, and scorpion venom, with reference to marked anti-breast cancer effects due to regulating cell cycle arrest, proliferation, apoptosis, metastasis, and drug resistance. In future studies, the underlying mechanisms for the antitumor effects of these components need to be further investigated by utilizing multi-omics technologies. Furthermore, large-scale clinical trials are necessary to validate the efficacy of bioactive constituents alone or in combination with chemotherapeutic drugs for breast cancer treatment.

Neuroprotective Mechanisms of Puerarin in Central Nervous System Diseases: Update.

Due to global population aging and modern lifestyle changes, the incidence of central nervous system (CNS) disorders, such as neurodegenerative diseases, neuropsychiatric disorders, and cerebrovascular diseases, is increasing and has become a major public health challenge. Current medications commonly used in the clinic are far from satisfactory and may cause serious side effects. Therefore, the identification of novel drugs for the effective management of CNS diseases is very urgent. Puerarin, a highly bioactive ingredient isolated from Pueraria lobata, is known to possess a broad spectrum of pharmacological properties including anti-diabetic, anti-inflammatory, anti-antioxidant, neuroprotective, and cardioprotective features. However, its clinical application is limited due to its poor water solubility. Since puerarin has demonstrated a wide range of neuroprotective functions in various CNS diseases, such as Alzheimer's disease, Parkinson's disease, cerebral ischemia, depression, and spinal cord injury, it has been attracting increasingly intense attention worldwide. In this review, we intend to extensively summarize the research progress on neuroprotective mechanisms of puerarin in recent years and discuss the future directions of its application in CNS disease treatment.

Active Components of Traditional Chinese Medicinal Material for Multiple Myeloma: Current Evidence and Future Directions.

Multiple myeloma (MM) is a hematological malignancy characterized by clonal expansion of plasma cells in bone marrow, leading to the overproduction of monoclonal immunoglobulins. The clinical manifestations resulting from monoclonal proteins and malignant cells include signs of end-organ damage, such as hypercalcemia, renal failure, anemia, and bone lesions. Despite improvement in the survival of MM patients with use of myeloma-targeted and immunomodulatory therapies, MM remains an incurable disease. Moreover, patients with relapsed or refractory MM show poor survival outcomes. In recent years, there has been a growing interest in the use of traditional Chinese medicinal materials (TCMMs) for management of a wide spectrum of diseases. The bioactive ingredients derived from TCMMs hold great potential for the development of anticancer drugs. Here we summarize the evidence of the pharmacological effects of the active components in TCMMs on MM, including curcumin, resveratrol, baicalein, berberine, bufalin, cinobufagin, gambogic acid, ginsenoside, icariin, daidzin, formononetin, polysaccharides extracts from Hedyotis difus, and scutellarein. Available evidence indicates that the anti-MM effects of these bioactive ingredients are mediated via regulation of proliferation, apoptosis, autophagy, cell cycle, osteogenic differentiation, and drug resistance. In the future, the underlying mechanisms of the anti-MM effects of these components should be further investigated. Large-scale and well-designed clinical trials are also required to validate the efficacy of these bioactive constituents for MM.

Epigenetic Modulation of Microglia Function and Phenotypes in Neurodegenerative Diseases.

Microglia-mediated neuroinflammation is one of the most remarkable hallmarks of neurodegenerative diseases (NDDs), including AD, PD, and ALS. Accumulating evidence indicates that microglia play both neuroprotective and detrimental roles in the onset and progression of NDDs. Yet, the specific mechanisms of action surrounding microglia are not clear. Modulation of microglia function and phenotypes appears to be a potential strategy to reverse NDDs. Until recently, research into the epigenetic mechanisms of diseases has been gradually developed, making it possible to elucidate the molecular mechanisms underlying the epigenetic regulation of microglia in NDDs. This review highlights the function and phenotypes of microglia, elucidates the relationship between microglia, epigenetic modifications, and NDDs, as well as the possible mechanisms underlying the epigenetic modulation of microglia in NDDs with a focus on potential intervention strategies.

Preventive electroacupuncture ameliorates D-galactose-induced Alzheimer's disease-like inflammation and memory deficits, probably via modulating the microbiota-gut-brain axis.

OBJECTIVES: We aimed to observe the effects of preventive electroacupuncture (EA) on the microbiota-gut-brain axis and spatial learning and memory deficits and to investigate the possible mechanism using D-galactose (D-gal)-induced aging rats. MATERIALS AND METHODS: D-gal was intraperitoneally injected to establish the aging model. We used Morris water maze to detect spatial learning and memory function of rats. RT-PCR was applied to test targeted gut microbes. The expression of zonula occludens-1 (ZO-1) and Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway proteins were detected by Western blotting. ELISA was employed to evaluate the level of lipopolysaccharides (LPS), diamine oxidase (DAO) and S-100ß. Additionally, we observed ionized calcium-binding adapter molecule-1 (Iba-1) expression in the hippocampal CA1 area by immunofluorescence. RESULTS: Morris water maze test showed decreased mean escape latency and increased target quadrant time after EA treatment. The gut microbiota composition has been modified in EA treated rats. Molecular examination indicated that expression of ZO-1 was improved and the the concentration of LPS in blood and hippocampus were reduced in EA treated rats. Further, we observed an inhibition of activated microglia and TLR4/NF-κB pathway in EA groups. CONCLUSION: Preventive EA may alleviate the impairments of the microbiota-gut-brain axis and spatial learning and memory in aging, and the mechanism may be related to the inhibition of TLR4/NF-kB signaling pathway. The combination of acupoints GV20 and ST36 can enhance the therapeutic effect in aging rats.

Mechanism of Action of Acupuncture in Obesity: A Perspective From the Hypothalamus.

Obesity is a prevalent metabolic disease caused by an imbalance in food intake and energy expenditure. Although acupuncture is widely used in the treatment of obesity in a clinical setting, its mechanism has not been adequately elucidated. As the key pivot of appetite signals, the hypothalamus receives afferent and efferent signals from the brainstem and peripheral tissue, leading to the formation of a complex appetite regulation circuit, thereby effectively regulating food intake and energy homeostasis. This review mainly discusses the relationship between the hypothalamic nuclei, related neuropeptides, brainstem, peripheral signals, and obesity, as well as mechanisms of acupuncture on obesity from the perspective of the hypothalamus, exploring the current evidence and therapeutic targets for mechanism of action of acupuncture in obesity.

Acupuncture and Related Therapies for the Cognitive Function of Alzheimer's Disease: A Network Meta-Analysis.

Background: Acupuncture and acupuncture-related therapies are effective for Alzheimer's disease (AD), therefore, we aimed to compare and rank the interventions that mainly focus on acupuncture-related therapies in the treatment of patients with mild to moderate AD. Methods: We used network meta-analysis to evaluate the direct and indirect evidence shown in randomized controlled trials of AD. The data were analyzed using RavMan manager, Stata, and WinBUGS software after two researchers independently screened the literature, extracted the data, and assessed the risk of bias in the included studies. Results: We analyzed a total of 36 eligible studies, including 2712 patients, involving 14 types of acupuncture-related therapies and comprehensive therapies. For Mini-Mental State Examination (MMSE), acupuncture (ACU) combined with cognitive and memory training (Training) was more effective than ACU, ACU+Chinese herb (CH), ACU+Donepezil (DON), CH, DON, DON+Nimodipine (NIM), Music therapy (Music), NIM, Placebo, and Training (P<0.05), while ACU+CH was batter than CH (P<0.05), and ACU+DON+NIM was better than DON+NIM (P<0.05). For Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-cog), ACU was more effective than DON and placebo (P<0.05). For Activities of Daily Living (ADL), ACU+DON was better than CH, DON, NIM, and Placebo (P<0.05). For the clinical effectiveness rate, ACU, ACU+CH, ACU+CH+DON, ACU+CH+DON+NIM, ACU+DON, CH, NIM were all more effective than DON+NIM (P<0.05), while ACU and ACU+CH were better than DON (P<0.05). The comprehensive ranking results show that ACU+training and ACU have the highest ranking probability. Conclusion: ACU+Training and ACU may be the best therapies to improve the cognitive function of patients with mild to moderate AD, while the combination of acupuncture-related therapies and other therapies has a higher overall benefit.

Preventive electroacupuncture reduces cognitive deficits in a rat model of D-galactose-induced aging.

Acupuncture can reduce cognitive deficits in Alzheimer's disease. However, whether electroacupuncture can prevent or alleviate the cognitive deficits in animal models of aging remains poorly understood. Studies have shown that disordered epigenetic modifications play a critical role in age-related cognitive decline. Therefore, we hypothesized that preventive electroacupuncture might improve cognitive functions during aging by regulating epigenetic modifications. A rat model of aging was produced by intraperitoneal injection of 120 mg/kg D-galactose for 8 weeks. Baihui and Shenshu acupoints were stimulated by electroacupuncture for 8 weeks from the first day of D-galactose administration. Preventive electroacupuncture alleviated memory impairment, decreased tau hyperphosphorylation, and reduced glycogen synthase kinase-3ß protein and mRNA expression levels in the brainstem dorsal raphe nucleus, where intracellular neurofibrillary tangle lesions first occur. In addition, the DNA methylation level in the promoter region of the glycogen synthase kinase-3ß gene was increased. The effects of preventive electroacupuncture were stronger than those of preventive acupuncture. Intraperitoneal injection of 0.4 mg/kg 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferase that blocks epigenetic modifications, antagonized the effects of preventive electroacupuncture. Our results suggest that preventive electroacupuncture treatment alleviates cognitive impairment in aging rats probably by affecting the epigenetic modification of the glycogen synthase kinase-3ß gene in the dorsal raphe nucleus. This study was approved by the Animal Ethics Committee of Hubei University of Chinese Medicine, China (approval No. HUCMS201712001) on November 28, 2017.

Ag nanoparticles-decorated CoAl-layered double hydroxide flower-like hollow microspheres for enhanced energy storage performance.

Layered double hydroxides (LDHs) have been considered as one class of promising active electrode materials for supercapacitors due to their tunable composition and chemical versatility. Nonetheless, the poor electrical conductivity hinders their further practical applications in supercapacitors. Herein, CoAl LDH flower-like hollow microspheres are decorated with Ag nanoparticles by a facile one-step solvothermal reaction, followed by chemical bath deposition reaction. Experimental results and theoretical calculations indicate that decorating Ag nanoparticles onto CoAl LDH not only reduces the energy band gap and enhances their electrical conductivity, but also promotes fast diffusion kinetics of electrolyte ions and electrochemical reaction activity. Consequently, the prepared Ag/CoAl LDH electrode demonstrates improved specific capacities of 1214 (825) C g-1 at 3 (30) A g-1 and 91% capacity retention over 10,000 cycles at 10 A g-1 compared to the pristine CoAl LDH electrode. Moreover, using Ag/CoAl LDH and N-doped carbon nanotubes as the positive and negative electrodes, respectively, the assembled hybrid capacitor device delivers an energy density of 61.2 Wh kg-1 at a power density of 800 W kg-1. This work may showcase a great promise of engineering conductive nanoparticles-decorated LDHs-based active materials towards high-performance supercapacitors.

Acupuncture and related therapies for hyperlipidemia: A protocol for systematic review and network meta-analysis.

OBJECTIVE: To compare and rank the clinical effects of different acupuncture and acupuncture-related therapies on patients with hyperlipidemia. METHODS: We used Network Meta-Analysis (NMA) to evaluate the direct and indirect evidence from relevant studies. Three English and 4 Chinese databases were searched to collect randomized controlled trials (RCT) of acupuncture and related therapies in the treatment of hyperlipidemia. The data were analyzed using Stata15.0 and WinBUGS1.4.3 software after 2 researchers independently screened the literature, extracted the data, and assessed the risk of bias in the included studies. RESULTS: Based on the current evidence, we comprehensively compare the pros and cons of various acupuncture-related therapies, rank the efficacy of various acupuncture-related therapies compared with statins in the treatment of hyperlipidemia, and summarize the best acupuncture intervention methods or combinations. CONCLUSION: This study will provide new evidence for the safety and effectiveness of acupuncture-related therapies in the treatment of hyperlipidemia, and may be helpful for clinicians, hyperlipidemia patients, and clinical guideline makers to choose the optimal combination of acupuncture for the treatment of hyperlipidemia. REGISTRATION NUMBER: INPLASY2020100100.

Genome-Wide Regulation of Electroacupuncture and Treadmill Exercise on Diet-Induced Obese Rats.

Acupuncture has been widely used for obesity treatment, but its mechanism is still unclear. To investigate the molecular mechanisms, we applied electroacupuncture (EA) at the Zusanli (ST36) acupoint and treadmill exercise (TE) in a diet-induced obese (DIO) rat model and used RNA sequencing (RNA-seq) to identify molecular consequences. Forty Sprague-Dawley male rats were selected and randomly divided into five groups: control (C), DIO model (M), EA, TE, and EA + TE groups. According to the results, acupuncture reduced body weight and the ratio of retroperitoneal white adipose tissue (retro-WAT) to body weight. Total RNA was extracted from the retro-WAT from five groups for RNA-seq. Differentially expressed genes (DEG) analysis showed that there were obvious differences among the four comparisons of C vs. M, M vs. EA, M vs. TE, and M vs. EA + TE, followed by 1383, 913, 3324, and 2794 DE genes. Gene ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to further classify the DEGs. Several GO terms were commonly significantly enriched in both M vs. TE and M vs. EA, such as myofibril and muscle contraction. In addition, some pathways were regulated by EA and TE, such as the peroxisome proliferator activated receptor signaling pathway and calcium signaling pathway. This study is the first to compare and analyze the differences in gene expression profiles in the retro-WAT of rats in different groups, which provide a clue for further investigation into the molecular mechanisms of obesity treatment by EA and TE.

[Effects of electroacupuncture on cognitive function and neuronal autophagy in rats with D-galactose induced Alzheimer's disease].

OBJECTIVE: To observe the effect of electroacupuncture at "Baihui"(GV20) and "Shenshu"(BL23) on the expression of autophagy-related proteins in the hippocampus of rats with Alzheimer's disease (AD)，so as to explore its underlying mechanisms on improvement of AD. METHODS: Forty-eight male SD rats were randomly divided into blank control group, model group, electroacupuncture group and sham electroacupuncture group, with 12 rats in each group. The AD rat model was establish by intraperitoneal injection of D-galactose for 6 weeks. Rats in the electroacupuncture group received electroacupuncture (50 Hz, 1 mA)at GV20 and BL23 for 20 min each time after daily intraperitoneal injection. Rats in the sham electroacupuncture group received acupuncture at the local skin of GV20 and BL23 without electricity. After the intervention, Morris water maze and open field test were used to evaluate the learning and cognitive ability of rats in each group. The transmission electron microscope was used to observe the numerical density of synaptic in hippocampus, and the immunohistochemical staining was used to observe the paired helical filament protein-1 (PHF-1) in the hippocampus. Western blot was used to detected the expression of autophagy-related proteins phosphoinositide-3-kinase (PI3K), protein kinase B (AKT), phosphorylated AKT (p-AKT), mammalian target of rapamycin (mTOR) in the hippocampus. RESULTS: Compared with the blank control group, the escape latency of the rats in the model group increased from day 2 to day 5 (P<0.01), and the ratio of the time through the quadrant of the original platform reduced （P<0.01）, in the open field test the distance of exercise, the number of uprights and the rate of exercise time in the central area decreased (P<0.01), meanwhile the density of hippocampus synapses decreased (P<0.01), the positive expression of PHF-1 and the relative expression of PI3K, AKT, p-AKT, and mTOR all increased (P<0.01). Compared with the model group, the escape latency of rats in the electroacupuncture group was shortened from day 2 to day 5 (P<0.01), and the ratio of the time through the quadrant of the original platform meanwhile, the distance of the open field test, the number of uprights, and the rate of central area exercise time up-regulated (P<0.01), the numerical density of hippocampus synatic increased (P<0.01), the positive expression of PHF-1 and the relative expression of PI3K, AKT, p-AKT, and mTOR all down-regulated (P<0.01). Compared with the model group, the expression of PI3K in the sham electroacupuncture group decreased (P<0.05). CONCLUSION: Electroacupuncture can improve learning and memory and cognitive impairment in AD rats, which may be associated with its effects in regulation of hippocampal autophagy and removal of neurofibrillary tangles by suppressing PI3K/AKT/mTOR signaling pathway.

Preventive Electroacupuncture Ameliorates D-Galactose-Induced Alzheimer's Disease-Like Pathology and Memory Deficits Probably via Inhibition of GSK3ß/mTOR Signaling Pathway.

Acupuncture has been practiced to treat neuropsychiatric disorders for a thousand years in China. Prevention of disease by acupuncture and moxibustion treatment, guided by the theory of Chinese acupuncture, gradually draws growing attention nowadays and has been investigated in the role of the prevention and treatment of mental disorders such as AD. Despite its well-documented efficacy, its biological action remains greatly invalidated. Here, we sought to observe whether preventive electroacupuncture during the aging process could alleviate learning and memory deficits in D-galactose-induced aged rats. We found that preventive electroacupuncture at GV20-BL23 acupoints during aging attenuated the hippocampal loss of dendritic spines, ameliorated neuronal microtubule injuries, and increased the expressions of postsynaptic PSD95 and presynaptic SYN, two important synapse-associated proteins involved in synaptic plasticity. Furthermore, we observed an inhibition of GSK3ß/mTOR pathway activity accompanied by a decrease in tau phosphorylation level and prompted autophagy activity induced by preventive electroacupuncture. Our results suggested that preventive electroacupuncture can prevent and alleviate memory deficits and ameliorate synapse and neuronal microtubule damage in aging rats, which was probably via the inhibition of GSK3ß/mTOR signaling pathway. It may provide new insights for the identification of prevention strategies of AD.

Experimental Evidence of the Benefits of Acupuncture for Alzheimer's Disease: An Updated Review.

As the global population ages, the prevalence of Alzheimer's disease (AD), the most common form of dementia, is also increasing. At present, there are no widely recognized drugs able to ameliorate the cognitive dysfunction caused by AD. The failure of several promising clinical trials in recent years has highlighted the urgent need for novel strategies to both prevent and treat AD. Notably, a growing body of literature supports the efficacy of acupuncture for AD. In this review, we summarize the previously reported mechanisms of acupuncture's beneficial effects in AD, including the ability of acupuncture to modulate Aß metabolism, tau phosphorylation, neurotransmitters, neurogenesis, synapse and neuron function, autophagy, neuronal apoptosis, neuroinflammation, cerebral glucose metabolism, and brain responses. Taken together, these findings suggest that acupuncture provides therapeutic effects for AD.

Epigenetic Regulation of Amyloid-beta Metabolism in Alzheimer's Disease.

Senile plaques (SPs) are one of the pathological features of Alzheimer's disease (AD) and they are formed by the overproduction and aggregation of amyloid-beta (Aß) peptides derived from the abnormal cleavage of amyloid precursor protein (APP). Thus, understanding the regulatory mechanisms during Aß metabolism is of great importance to elucidate AD pathogenesis. Recent studies have shown that epigenetic modulation-including DNA methylation, non-coding RNA alterations, and histone modifications-is of great significance in regulating Aß metabolism. In this article, we review the aberrant epigenetic regulation of Aß metabolism.

[Effect of pretreatment of acupuncture on learning-memory ability and related protein of NLRP3 inflammasome in hippocampus in Alzheimer's disease like rats].

OBJECTIVE: To observe the effect of pretreatment of acupuncture on the expression of nucleotide-binding oligomerization domain-like receptor 3(NLRP3), Caspase-1, interleukin1ß(IL-1ß) and the number of activated microglia (MG) in the hippocampus in Alzheimer's disease (AD) like rats, so as to explore the mechanism of pretreatment of acupuncture in preventing and treating AD. METHODS: A total of 36 SD rats were randomly divided into a blank group, a model group and an electroacupuncture (EA) group, 12 rats in each group. The AD like rat model was established by 8-week continuous intraperitoneal injection of D-galactose (120 mg·kg-1·d-1) in the model group and the EA group. The rats in the EA group were intervened with EA at "Baihui" (GV 20) and "Zusanli" (ST 36), continuous wave, 5 Hz in frequency, 1 mA in intensity, 20 min each intervention, once a day, for 8 weeks. After the intervention, the spatial learning-memory ability was evaluated by the Morris water maze test. The expression levels of NLRP3, Caspase-1 and IL-1ß protein in hippocampus were detected by Western blot method. The number of activated MG in hippocampus was detected by immunofluorescence labeling method. RESULTS: Compared with the blank group, the average escape latency was prolonged (P<0.01), the number of platform crossing was reduced (P<0.01), and the exploration time of target quadrant was shortened (P<0.01) in the model group. Compared with the model group, the average escape latency was shortened (P<0.01), the number of platform crossing was increased (P<0.01), and the exploration time of target quadrant was prolonged (P<0.01) in the EA group. Compared with the blank group, the expression levels of NLRP3, Caspase-1, IL-1ß protein in hippocampus were increased (P<0.01), and the number of activated MG was increased (P<0.01) in the model group. Compared with the model group, the expression levels of NLRP3, Caspase-1, IL-1ß protein in hippocampus were decreased (P<0.01), and the number of activated MG was decreased (P<0.05) in the EA group. CONCLUSION: Pretreatment of acupuncture could prevent and treat the learning-memory dysfunction in AD like rats, and its mechanism may be related to the inhibition of NLRP3 inflammatsome related protein and MG activation.