Ginseng is commonly used as a nutritional supplement and daily wellness product due to its ability to invigorate qi. As a result, individuals with Qi-deficiency often use ginseng as a health supplement. Ginsenosides and polysaccharides are the primary components of ginseng. However, the therapeutic effects and mechanisms of action of these components in Qi-deficiency remain unclear. This study aimed to determine the modulatory effects and mechanisms of ginseng water extract, ginsenosides, and ginseng polysaccharides in a rat model of Qi-deficiency using metabolomics and network analysis. The rat model of Qi-deficiency was established via swimming fatigue and a restricted diet. Oral administration of different ginseng water extracts for 30 days primarily alleviated oxidative stress and disrupted energy metabolism and immune response dysfunction caused by Qi-deficiency in rats. Ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used for untargeted serum metabolomic analysis. Based on the analysis results, the active constituents of ginseng significantly reversed the changes in serum biomarkers related to Qi-deficiency in rats, particularly energy, amino acid, and unsaturated fatty acid metabolism. Furthermore, analysis of the metabolite-gene network suggested that the anti-Qi-deficiency effects of the ginseng components were mainly associated with toll-like receptor (TLR) signaling and inflammatory response. Additional verification revealed that treatment with the ginseng components effectively reduced the inflammatory response and activation of the myocardial TLR4/NF-κB pathway induced by Qi-deficiency, especially the ginseng water extracts. Therefore, ginseng could be an effective preventive measure against the progression of Qi-deficiency by regulating metabolic and inflammatory responses.

Diabetic nephropathy (DN) is one of the leading clinical causes of end-stage renal failure. The classical aldose reductase (AR) inhibitor epalrestat shows beneficial effect on renal dysfunction induced by DN, with metabolic profile and molecular mechanisms remains to be investigated further. In the current study, integrated untargeted metabolomics, network pharmacology and molecular dynamics approaches were applied to explore the therapeutic mechanisms of epalrestat against DN. Firstly, untargeted serum and urine metabolomics analysis based on UPLC-Q-TOF-MS was performed, revealed that epalrestat could regulate the metabolic disorders of amino acids metabolism, arachidonic acid metabolism, pyrimidine metabolism and citrate cycle metabolism pathways after DN. Subsequently, metabolomics-based network analysis was carried out to predict potential active targets of epalrestat, mainly involving AGE-RAGE signaling pathway, TNF signaling pathway and HIF-1 signaling pathway. Moreover, a 100 ns molecular dynamics approach was employed to validate the interactions between epalrestat and the core targets, showing that epalrestat could form remarkable tight binding with GLUT1 and NFκB than it with AR. Surface-plasmon resonance assay further verified epalrestat could bind GLUT1 and NFκB proteins specifically. Overall, integrated system network analysis not only demonstrated that epalrestat could attenuate DN induced metabolic disorders and renal injuries, but also revealed that it could interact with multi-targets to play a synergistic regulatory role in the treatment of DN.

Gancao Xiexin Decoction (GCXXD) is a traditional Chinese decoction that is often used in treating gastric ulcers. However, the substance basis and mechanism of action remain unclear. In this study, in vivo and in vitro components of GCXXD were analyzed by ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry. The compound Discover platform was used to ultimately enable rapid identification of compounds. Acquire X intelligent data acquisition technology software was innovatively adopted. In the process of collecting drug-containing plasma, all components detected in blank plasma samples were excluded to eliminate the interference and influence of endogenous components in plasma, making the analysis results more accurate and reliable. At the same time, the possibility of selecting precursor parent ions with low concentration levels within the chromatographic peak can be increased, improving the coverage and integrality of the detection of components in vivo. Also, the targeted network pharmacology strategy combined with molecular docking was established to explore the mechanism of GCXXD in treating gastric ulcers. As a result, 113 components were identified, 41 of which could enter the bloodstream and exert therapeutic effects in vivo. The main effective components are glycyrrhizic acid, 6-gingerol, jatrorrhizine, wogonin, palmatine, and liquiritigenin, main targets in vivo were related to ALB, IL6, and VEGF, which play an important role in anti-inflammatory and promoting angiogenesis. In summary, this study adopted a comprehensive analysis strategy to reveal the pharmacodynamic material basis and mechanism of GCXXD against gastric ulcers, providing a scientific basis for its clinical application.

The dry root and rhizome of Panax ginseng C. A. Mey has garnered much interest owing to its medicinal properties against diabetes and cardiovascular diseases. In this study, an ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS)-based metabolomics approach was used to illustrate the therapeutic mechanisms of ginseng extract on the serum and urinary metabolic profiles in streptozotocin-induced type 1 diabetes mellitus (T1DM) rats. Pharmacological and renal parameters in response to the administration of ginseng were also evaluated. In total, 16 serum endogenous metabolites and 14 urine endogenous metabolites, including pyruvic acid, indoleacetic acid, and phenylacetylglycine, were identified as potential biomarkers for diabetes. Pathway enrichment and network analysis revealed that the biomarkers modulated by ginseng were primarily involved in phenylalanine and pyruvate metabolism, as well as in arginine biosynthesis. Moreover, the levels of several renal injury-related biomarkers in T1DM rats were significantly restored following treatment with ginseng. The administration of the extract helped maintain tissue structure integrity and ameliorated renal injury. The findings suggest that the regulatory effect of ginseng extract on T1DM involves metabolic management of diabetic rats, which subsequently attenuates T1DM-induced early renal dysfunction.

本研究以《药理学》课程为例,利用超星学习通网络平台自录资源和中国MOOC(慕课)平台的优质课程,对中药学专业本科生(139名)的药理学课程开展线上线下混合式教学模式,对该教学模式的实施过程进行了问卷调查,并对激发学生学习兴趣及提升自主学习的能力进行探讨.结果表明,94.4％的学生对混合教学方式满意,75％的学生认为混合教学方式能提高实践创新能力,学生期末成绩与实践技能水平显著提高.说明线上线下混合式教学模式有助于学生综合素质、创新能力及自主能力的提高,能更好地培养应用型人才.

目的 检测并比较不同栽培土壤条件下种植的灵芝经济性状、三萜及甾醇类成分、多糖类成分以及水分和浸出物含量,探讨山核桃壳、山沙土、玉米芯及玉米秸秆4种栽培土壤对灵芝质量的影响.方法 采用《中国药典》(2020版)方法,对山核桃壳、山沙土、玉米芯及玉米秸秆栽培土壤培育的灵芝中灵芝三萜及甾醇、多糖、水分及浸出物含量进行分析测定.结果 4种栽培土壤所种植的灵芝三萜及甾醇、多糖、水分及浸出物含量均符合药典要求.其中,玉米秸秆土壤栽培的灵芝样本中检测到的灵芝三萜及甾醇、多糖成分比其他三组较高,且具有较高的浸出物含量及较低的含水量.结论 山核桃壳、玉米芯及玉米秸秆土壤均可代替山沙土培育灵芝.

Focal cerebral ischemia is a major cardiovascular disease that seriously threatens human health. Its neuromodulator is sodium butyrate, whose underlying mechanisms remain unclear. This study aimed to clarify the neuronal anti-inflammatory mechanisms of sodium butyrate against focal cerebral ischemia. A rat model of focal cerebral ischemia was established by administering sodium butyrate before middle cerebral artery occlusion (MCAO) was conducted. The neuroprotective effects of sodium butyrate were evaluated 24 hours after MCAO in terms of neurological score, infarction volume, and inflammatory biomarkers. The expression levels of nuclear receptor subfamily 4 group A1 (Nur77), NOD-like receptor protein 3 (NLRP3), caspase-1, and interleukin-1 /3 (IL-1 /3) in brain tissues were also analyzed. HT22 cells stimulated with oxygen and glucose deprivation (OGD) were treated with sodium butyrate and siNur77 to explore the role of sodium butyrate in the Nur77/NLRP3-mediated inflammatory response. Sodium butyrate treatment significantly attenuated the neurological impairment and neuroinflammation induced by cerebral ischemia. In cerebral ischemia, expression of Nur77 was dysregulated as mediated by sodium butyrate, and NLRP3-related inflammatory factors were produced in vivo and in vitro . Nur77 was identified as a negative regulator of NLRP3 in HT22 cells under OGD conditions. The anti-inflammatory effect of sodium butyrate was achieved by upregulating the expression of Nur77, which subsequently suppressed the neuronal NLRP3-mediated inflammatory response. Overall, sodium butyrate elicited a neuroprotective effect against focal cerebral ischemia by modulating Nur77/NLRP3-mediated inflammatory responses.

Lignans from Schisandra chinensis (Turcz.) Baill (LFS) has been proved to improve impaired cognitive ability thereby show potential in treating Alzheimer's disease (AD). In this study, UHPLC-Q-TOF-MS and UHPLC-QQQ-MS were adopted cooperatively to establish a method synchronously detecting 10 kinds of LFS monomers in rat plasma samples. And this method was further applied for pharmacokinetic study to compare the metabolism of LFS in normal and AD rats. The results indicated that AD rats showed an observably better absorption of LFS compared to normal rats. Based on time-varying plasma concentration of LFS, metabolomics was used to establish a plasma concentration-time-endogenous metabolite connection. In total 54 time-varying endogenous metabolites were screened and most of which were closely associated with AD. And LFS exerted a concentration dependent regulating effect to most of these metabolites. Through biomarker related pathways and biological function analysis, LFS might treat AD through neuroprotection, antioxidant damage and regulating the metabolism of unsaturated fatty acids. This is the first study connecting LFS absorbtion and endogenous metabolite changes with the time lapse. The pharmacokinetics and metabolic profile differences between normal and AD rats were firstly investigated as well. This study provides a novel perspective in exploring the effect and mechanism of LFS in treating AD.

Scutellaria baicalensis Georgi (S. baicalensis) is a traditional Chinese medicine that has been used in the treatment of diabetes for centuries. Although it has curative effects on diabetic nephropathy (DN), the critical role and mechanisms of S. baicalensis in the prevention and management of DN have not been fully elucidated. Thus, in the current study, metabolomics was integrated with a network pharmacology approach to explore the mechanisms of S. baicalensis against DN. To illustrate the metabolic alterations regulated by S. baicalensis during DN progression, an untargeted serum metabolomics approach using ultra-high- performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was developed. It revealed that 14 serum metabolic biomarkers identified in DN rats were partially reversed by S. baicalensis treatment, which was primarily involved in glycerophospholipid metabolism, arachidonic acid metabolism and retinol metabolism pathways, with 536 extended metabolite-target genes (M-T) interactions observed. Based on network pharmacology analysis, a total of 31 active compounds and 123 compound-target genes (C-T) interactions of S. baicalensis were identified. By integrating M-T with C-T co-network analysis, 18 shared genes were identified as hub targets against DN, including MAPK14, MPO, MMP9, FN1, NOS2 and CASP3, which primarily contributed to biological processes related to inflammatory responses. The molecular docking analysis further verified the interactions between the major active compounds and six predicted proteins encoded by the hub targets, indicating that S. baicalensis may function by targeting inflammatory responses process in DN. Overall, the current work yielded new insights into the molecular mechanisms of active compounds in the action of S. baicalensis against DN progression and suggested a strategy for clarifying the treatment mechanisms of traditional herbal medicines.

The complex and dynamic population of gut microbiota exerts a marked influence on the host during homeostasis and disease. Imbalance of gut microbiota metabolites may lead to cardiac dysfunction in patients with heart failure, which is related to myocardial infarction(MI) severity. However, the role of gut microbiota in the repair process after MI has rarely been reported. To explore the role of gut microbiota in MI repair and its underlying mechanism, we mixed antibiotics in drinking water to interfere with gut microbiota in rats. Hematoxylin and eosin staining, Sirius red staining, western blotting, and immunohistochemistry were used to detect tissue repair and fibrosis. We found that the expressions of alpha-smooth muscle actin, collagen, and histone deacetylase (HDAC) activities were significantly increased. We detected gut microbiota at different time points after MI using 16S ribosomal RNA sequencing and detected that Prevotellaceae, Clostridiaceae, and Lachnospiraceae were significantly altered among the butyric acid producers. We administered sodium butyrate via drinking water and discovered that sodium butyrate reduced HDAC activities and adverse repair. Therefore, we speculated that gut microbiota influences the acetylation level and tissue repair process after MI by affecting butyric acid production.

Fruit of Schisandra chinensis Turcz. (Baill.) (S. chinensis) is a traditional herbal medicine widely used in China, Korea, and many other east Asian countries. At present, S. chinensis commonly forms Chinese medicinal formulae with other herbal medicines to treat liver disease and neurological disease in clinical. Modern researches indicated that lignans were the main active ingredients of S. chinensis with high content and novel dibenzocyclooctadiene skeletal structure, exhibited considerable antioxidant, anti-inflammatory, and neuroprotective properties. Additionally, some of these lignans also showed certain potentials in anti-cancer, anti-fibrosis, and other effects. In the current review, we summarize literature reported lignans from S. chinensis in the past five years, and highlight the molecular mechanisms of lignans in exerting their biological functions. Also, we point out some deficiencies of existing researches and discuss the future direction of lignans study.

Obesity is associated with an increased risk of developing cardiovascular disease (CVD), with limited alterations in cardiac genomic characteristics known. Cardiac transcriptome analysis was conducted to profile gene signatures in high-fat diet (HFD)-induced obese mice. A total of 184 differentially expressed genes (DEGs) were identified between groups. Based on the gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs, the critical role of closely interlocked glucose metabolism was determined in HFD-induced cardiac remodeling DEGs, including Nr4a1, Fgf21, Slc2a3, Pck1, Gck, Hmgcs2, and Bpgm. Subsequently, the expression levels of these DEGs were evaluated in both the myocardium and palmitic acid (PA)-stimulated H9c2 cardiomyocytes using qPCR. Nr4a1 was highlighted according to its overexpression resulting from the HFD. Additionally, inhibition of Nr4a1 by siRNA reversed the PA-induced altered expression of glucose metabolism-related DEGs and hexokinase 2 (HK2), the rate-limiting enzyme in glycolysis, thus indicating that Nr4a1 could modulate glucose metabolism homeostasis by regulating the expression of key enzymes in glycolysis, which may subsequently influence cardiac function in obesity. Overall, we provide a comprehensive understanding of the myocardium transcript molecular framework influenced by HFD and propose Nr4a1 as a key glucose metabolism target in obesity-induced CVD.

Fibroblasts mediate acute wound healing and long-term tissue remodeling with scarring after tissue injury. Following myocardial infarction (MI), necrotized cardiomyocytes become replaced by secreted extracellular matrix proteins produced by fibroblasts. Dendritic cells (DCs) can migrate from the bone marrow to the infarct areas and infarct border areas to mediate collagen accumulation after MI. Trichostatin A (TSA) is known to regulate apoptosis and proliferation in fibroblasts and affect the functions of DCs under oxygen-glucose deprivation (OGD) conditions. In this study, we used label-free quantitative proteomics to investigate the effects of TSA and bone marrow-derived dendritic cells (BMDCs) on NIH3T3 fibroblasts under OGD conditions. The results showed that the fatty acid degradation pathway was significantly upregulated in NIH3T3 cells under OGD conditions and that the fatty acid synthesis pathway was significantly downregulated in NIH3T3 cells treated with conditioned media (CM) from BMDCs treated with TSA under OGD conditions [BMDCs-CM(TSA)]. In addition, BMDCs-CM(TSA) significantly decreased the levels of triglycerides and free fatty acids and mediated fatty acid metabolism-related proteins in NIH3T3 cells under OGD conditions. In summary, this proteomics analysis showed that TSA and BMDCs affect fatty acid metabolism in NIH3T3 cells under OGD conditions.

采用基于超高效液相色谱与串联四极杆飞行时间质谱仪(Ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry,UHPLC-Q-TOF MS)联用的代谢组学方法,通过分析大鼠尿液内源性代谢物的变化,研究黄岑-桅子药对治疗糖尿病肾病的作用机制.利用高脂高糖饲料喂养并腹腔注射链脲佐菌素(STZ)建立糖尿病大鼠模型.给药12周后,采用UHPLC-Q-TOF MS对正常对照组、模型组、黄岑-桅子药对治疗组的尿液样品进行代谢轮廓分析.利用正交偏最小二乘判别分析(Orthogonal partial least squares discriminant analysis,OPLS-DA)对实验数据进行分析,挑选出对各组分分离贡献较大(VIP＞1,p＜0.05)的化合物在Human Metabolome Database(HMDB)等数据库进行质谱信息匹配,共鉴定出糖尿病肾病潜在生物标记物31个,给药后回调生物标记物16个.研究结果表明,黄岑-桅子药对通过影响胆汁酸的合成与代谢、尿毒素代谢、能量代谢、色氨酸代谢、苯丙氨酸代谢、酪氨酸代谢等通路对糖尿病肾病起到治疗作用,其中胆汁酸的合成与代谢、尿毒素代谢和能量代谢可能是黄岑-桅子药对发挥治疗作用的主要途径.与单味药相比,配伍后的药对具有了新的药理作用.

Gancao Fuzi decoction (GFD) is a classic Chinese medicine formula for the treatment of rheumatic and rheumatoid arthritis. The main active components of GFD are alkaloids, flavonoids and saponins. This study aimed to clarify the pharmacodynamic effects of the active components in GFD and investigate the mechanism of them treating rheumatoid arthritis rats by the method of metabonomics. Seven groups were studied, named as the normal group (NG), the model group (MG), the Gancao Fuzi decoction treatment group (GFDe), the alkaloids group (ALK), the compatibility of alkaloids with flavonoids group (AF), the compatibility of alkaloids with saponins group (AS) and the compatibility of alkaloids with flavonoids and saponins group (AFS), respectively. Firstly, the anti-inflammatory and analgesic effects of these groups were studied. Besides, urinary metabonomics based on ultra high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was employed for delineation of metabolic alterations in the rats. Based on our results, it is concluded that AFS showed better anti-inflammatory and analgesic activities in GFD. Urinary metabonomic study and multivariate statistical analyses were used to investigate the mechanism of different groups. 26 potential biomarkers have been identified. By the analysis of heat map combined with score plot, the AFS group was the closest group to the NG group after treatment in GFD. The changes of urinary endogenous metabolites showed that AFS exhibited better effect on regulating the taurine and hypotaurine metabolism, phenylalanine metabolism, TCA cycle, tryptophan metabolism, fatty acid metabolism, vitamin B6 metabolism, arginine and proline metabolism and purine metabolism pathways. The pharmacodynamics results showed that three components of flavonoids, saponins and alkaloids in GFD played an overall efficacy. Metabonomics studies showed that the compatibility of three components in GFD achieved the therapeutic effect by regulating the perturbations of multiple metabolic pathways.

Modern studies have indicated Gardenia jasminoides Ellis (G. jasminoides) showed positive effect in treating type 2 diabetes mellitus (T2DM). In this study, 60 streptozotocin-induced T2DM rats were divided into four groups: type 2 diabetes control group, geniposide-treated group, total iridoid glycosides-treated group, and crude extraction of gardenlae fructus-treated group. The other ten healthy rats were the healthy control group. During 12 weeks of treatment, rat's feces samples were collected for the metabolomics study based on mass spectrometry technique. On the basis of the fecal metabolomics method, 19 potential biomarkers were screened and their relative intensities in each group were compared. The results revealed G. jasminoides mainly regulated dysfunctions in phenylalanine metabolism, tryptophan metabolism, and secondary bile acid biosynthesis pathways induced by diabetes. The current study provides new insight for metabonomics methodology toward T2DM, and the results show that feces can preferably reflect the liver and intestines disorders.

Rheumatoid arthritis (RA) is a chronic disease with pain, swelling, and limitation in the motion and function of multiple joints thus leading to high disability. Previous studies have shown that flavonoids and saponins are the most abundant and active constituents in Glycyrrhiza, which possess a wide range of pharmacological effects such as anti-inflammatory, antioxidant and anti-bacteria. But the mechanisms of those actions are not entirely clear. In order to clarify the mechanisms of those actions, the pharmacodynamical assessments of extraction of water-soluble components and flavonoids and saponins obtained from Glycyrrhiza were investigated. Combining the pharmacodynamical researches, we found that flavonoids obtained from Glycyrrhiza had more significant therapeutic effects on acute inflammation, chronic inflammation and inflammatory pain than that of extraction of water-soluble components and saponins obtained from Glycyrrhiza. The results indicated that flavonoids are the main medicinal ingredients in Glycyrrhiza. In order to further investigate the mechanism of the action of flavonoids in Glycyrrhiza on treating RA, a urine metabolomics method based on ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was established to observe the metabolic variations in adjuvant-induced arthritis (AIA) rats and investigate the therapeutic effect of flavonoids in Glycyrrhiza on RA. As a result, twenty potential biomarkers were found by comparison with the model group (MG) and flavonoid treated group (FG). We associated these compounds with related metabolic pathways, the results showed that these biomarkers were mainly associated with purine metabolism, taurine and hypotaurine metabolism, tryptophan metabolism, phenylalanine metabolism, tricarboxylic acid cycle (TCA cycle), pantothenate and coenzyme A (CoA) biosynthesis. The results about the pharmacodynamics and metabolomics provided a theoretical basis for clarifying the mechanism of flavonoids in Glycyrrhiza in the treatment of RA.

Estrogens are biologically active steroid hormones mainly released from the ovary by ovarian secretion of estrogen into the circulating blood to regulate or function at the distal target. Estrogens play an important role in the central nervous system, cardiovascular system and immune system, especially for post-menopausal women. Panax ginseng Mayer has been reported to relieve women's menopausal symptoms and affect estrogen activities. However, the mechanism of its estrogen regulation has not yet been clearly investigated. In this work, ovariectomized rats were administered a P. ginseng decoction intragastrically for 8 weeks. Urine samples were analyzed by ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) to identify metabolites. The estrous cycle, body weight, uterine weight index and serum hormone levels were measured. The results showed that P. ginseng significantly prolonged the estrus stage, decreased the body weight and serum luteinizing hormone (LH) levels and increased the uterine weight index and serum estradiol (E2) levels of ovariectomized rats. A total of twelve potential biomarkers for which levels changed markedly upon treatment have been identified based on metabolomics. A systematic network analysis of their corresponding pathways indicates that the antagonistic effect of P. ginseng on ovariectomized rats occurs mainly through regulating steroid hormone metabolism, fatty acid biosynthesis, the citric acid cycle and tryptophan metabolism. In conclusion, this study validated the antagonistic effect of P. ginseng in rats with estrogen decline and explored the metabolic and biochemical mechanisms involved.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with no effective method for its treatment so far. The pathogenesis of AD has been reported, but the endogenous metabolic profile and disease-related biomarkers are still not clear. To better understand AD, an AD model induced by injecting beta-amyloid 25-35 (A beta 25-35) solution into bilateral hippocampus was developed on Sprague-Dawley rats. After 8 weeks of modeling, the impairment of spatial learning and memory ability in AD rats were assessed by Morris water maze task. Hematoxylin and eosin staining and immunohistochemistry were used to investigate the pathological changes of hippocampus. The neurotransmitter concentrations in the hippocampus were measured using UHPLC-TQ-MS. Urinary metabolomics based on UHPLC-Q-TOF-MS was established to delineate the alterations of endogenous metabolites in AD rats. The results showed that compared with healthy control rats, AD rats suffered from cognitive dysfunction, hippocampus damage, A beta formation and tau phosphorylation at 8 weeks after surgery, suggesting that the A beta 25-35-induced AD model was successfully established. In addition, the levels of gamma-aminobutyric acid, acetylcholine, glycine, norepinephrine, serotonin, taurine and dopamine decreased and glutamate and aspartic acid increased in hippocampal tissue of AD rats. 45 altered metabolites mainly involved in 8 metabolic pathways were identified as the endogenous biomarkers of AD. According to the analysis of the biological significance of metabolic profiles, the pathogenesis of AD was mainly due to gut microbiome dysbiosis, inhibition of energy metabolism, oxidative stress injury and loss of neuronal protective substances. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.