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Ginsenoside RK1 improves cognitive impairments and pathological changes in Alzheimer's disease via stimulation of the AMPK/Nrf2 signaling pathway
... Nrf2 is the "smashing door" to tightly regulate the antioxidant system (She et al. 2024). When cells are stimulated by ROS, Nrf2's conformation changes and it moves from the cytoplasm to the nucleus. ...
Varicellovirus bovinealpha 1 (BoAHV-1) is a significant pathogen responsible for respiratory disease in cattle, capable of inducing lung damage independently or co-infection with bacteria. The widespread spread of BoAHV-1 in cattle herds has caused substantial economic losses to the cattle industry. The pathogenic mechanisms of BoAHV-1 are often relevant to robust inflammatory responses, increased oxidative burden, and the initiation of apoptosis. Glycyrrhizin (GLY) is a small-molecule triterpenoid saponin compound obtained from the herb liquorice, which has a broad spectrum of pharmacological properties such as antiviral, anti-inflammatory, and antioxidant effects. Furthermore, GLY regulates lung physiology by modulating oxidative stress, inflammatory response, and cell apoptosis through interference with the NF-κB/NLRP3 and Nrf2/HO-1 Signaling pathways. However, the potential of GLY to mitigate lung injury induced by BoAHV-1 and its underlying mechanism remains unclear. Therefore, in this study, we investigated the protective effect of GLY against pulmonary injury induced by BoAHV-1 in a guinea pig model by reducing viral load and suppressing the inflammatory response, oxidative stress, and apoptosis. The results of this study demonstrated that GLY exerted a protective effect against BoAHV-1-induced lung injury in guinea pigs. Specifically, GLY reduced the levels of pro-inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and interleukin (IL)-8 in guinea pig tissues while suppressing the expression of Caspase-1. Additionally, GLY reduced BoAHV-1 load and the number of TUNEL-positive lung cells in guinea pig lungs while inhibiting Caspase 3 protein expression. Furthermore, GLY significantly enhanced lung antioxidant capacity by increasing superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity while simultaneously reducing malondialdehyde (MDA) levels. Lung histological observation and score further validated the protective effect of GLY on BoAHV-1-induced lung injury. Furthermore, we observed that the expression of phosphorylated NF-κB p65 (p-NF-κB p65) and NLRP3 proteins in the lung tissue of BoAHV-1-infected guinea pigs decreased after GLY treatment while the expression of Nrf2 and HO-1 proteins increased. These results indicated that GLY inhibited the NF-κB/NLRP3 Signaling pathway and activated the Nrf2/HO-1 Signaling pathway during BoAHV-1 infection. Ultimately, our findings demonstrated that GLY alleviates BoAHV-1-induced inflammation response, oxidative stress, and cell apoptosis by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway to protect guinea pigs from lung injury caused by BoAHV-1. Ultimately, our findings demonstrated that GLY alleviates BoAHV-1-induced inflammation response, oxidative stress, and cell apoptosis by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway to protect guinea pigs from lung injury caused by BoAHV-1. Importantly, this study provides a compelling argument for the GLY in combating respiratory disease in cattle caused by BoAHV-1.
Amyloid-beta (Aβ) peptide induces neurotoxicity through oxidative stress and inflammatory response. Brain deposition of a large amount of amyloid-beta (Aβ), in particular Aβ42, promotes the development of Alzheimer’s disease (AD). Maackiain is extracted from traditional Chinese medicine peony root and possesses antioxidative, antiosteoporosis, antitumor, and immunoregulatory effects. Whether Maackiain can reduce neurotoxicity caused by Aβ accumulation remains elusive. Herein, we found that Maackiain downregulated Aβ42-induced cell injury and apoptosis in PC12 cells. Moreover, Maackiain prevented Aβ42 stimulation-induced generation of oxidative stress and reduced Aβ42-caused impairment of mitochondrial membrane potential in PC12 cells. Maackiain increased the superoxide dismutase activity and decreased malondialdehyde content that was induced by Aβ42. Mechanistic studies showed that Maackiain increased intranuclear Nrf2 expression. Consistently, Nrf2 silencing by RNA interference weakened the protective role of Maackiain against Aβ exposure. In addition, calphostin C, a specific antagonist of protein kinase C, attenuated the promoting effects of Maackiain on Nrf2 nuclear translocation. Moreover, calphostin C attenuated the antioxidant and anti-inflammatory capabilities of Maackiain in PC12 cells. Collectively, Maackiain promoted Nrf2 activation through the PKC signaling pathway, thus preventing PC12 cells from Aβ-induced oxidative stress and cell injury, suggesting that Maackiain is a potential drug for AD treatment.
CRMG (Cultured Roots of Mountain Ginseng) have the advantages in scale-up production, safety, and pharmacological efficacies. Though several methods are available for the conversion of major to minor ginsenosides, which has more pharmacological activities, a single step process with high temperature and pressure as a puffing method took place in this study to gain and produce more pharmacologically active compounds. Puffed CRMG exhibited an acceleration of major ginsenosides to minor ginsenosides conversions, and released more phenolic and flavonoid compounds. HPLC analysis was used to detect a steep decrease in the contents of major ginsenosides (Re, Rf, Rg1, Rg2, Rb1, Rb2, Rb3, Rc and Rd) with increasing pressure; on the contrary, the minor ginsenosides (20 (S, R)-Rg3, Rg5, Rk1, Rh1, Rh2, Rg6, F4 and Rk3) contents increased. Minor ginsenosides, such as Rg6, F4 and Rk3, were firstly reported to be produced from puffed CRMG. After the puffing process, phenolics, flavonoids, and minor ginsenoside contents were increased, and also, the antioxidant properties, such as DPPH inhibition and reducing the power of puffed CRMG, were significantly enhanced. Puffed CRMG at 490.3 kPa and 588.4 kPa had a low toxicity on HaCaT (immortalized human epidermal keratinocyte) cells at 200 μg/mL, and could significantly reduce ROS by an average of 60%, compared to the group treated with H2O2. Therefore, single step puffing of CRMG has the potential to be utilized for functional food and cosmeceuticals.
Cognitive impairment (CI) refers to the dysfunction of memory, language, visual space, execution, calculation, understanding, and judgment in one or more aspects. With global aging, CI will become prevalent worldwide. At present, there is no effective cure for CI. However, Nobel laureate Tu Youyou's research on artemisinin has inspired Chinese researchers to focus on traditional Chinese herbs (TCHs) for the treatment of CI. Traditional Chinese Medicine (TCM) has led to a theory for an independent CI system. The pathogenesis of such impairment involves deficiency, phlegm, and stagnation and involves a range of organs, including the brain, kidneys, heart, liver, and spleen. Our current understanding of the etiology and pathogenesis of this condition has led to the realization that TCHs can improve cognitive dysfunction. Clinical research has shown that TCHs can improve the neuropsychological scale score of patients, the TCM symptom score, and the patient's quality of life. Research has also suggested that TCHs can retard A
β
deposits and tauopathy, regulate the metabolism of cholinergic neurotransmitters, and so on. However, due to their complexity, little is known of the safety and efficacy of TCHs in patients with CI. It is likely that we will be able to identify the precise mechanisms associated with the action of TCHs in such patients due to the integration of multiple technologies. This paper summarizes the pharmacokinetics, curative effect, and mechanisms of action of traditional Chinese herbs in order to provide a scientific basis for the improvement of cognitive dysfunction by TCHs.
Longevity in medicine can be defined as a long life without mental or physical deficits. This can be prevented by Alzheimer’s disease (AD). Current conventional AD treatments only alleviate the symptoms without reversing AD progression. Recent studies demonstrated that Panax ginseng extract improves AD symptoms in AD patients and the two main components of ginseng might contribute to AD amelioration. Ginsenosides show various AD-related neuroprotective effects. Gintonin is a newly identified ginseng constituent that contains lysophosphatidic acids (LPAs), and attenuates AD-related brain neuropathies. Ginsenosides decrease amyloid β-protein (Aβ) formation by inhibiting β- and γ-secretase activity or by activating the non-amyloidogenic pathway, inhibit acetylcholinesterase activity and Aβ-induced neurotoxicity, and decrease Aβ-induced production of reactive oxygen species and neuroinflammatory reactions. Oral administration of ginsenosides increases the expression levels of enzymes involved in acetylcholine synthesis in the brain and alleviates Aβ-induced cholinergic deficits in AD models. Similarly, gintonin inhibits Aβ-induced neurotoxicity and activates the non-amyloidogenic pathway to reduce Aβ formation and increase acetylcholine and choline acetyltransferase expression in the brain through LPA receptors. Oral administration of gintonin attenuates brain amyloid plaque deposits, boosting hippocampal cholinergic systems, neurogenesis and thereby ameliorating learning and memory impairments. It also improves cognitive functions in AD patient. Ginsenosides and gintonin attenuate AD-related neuropathology through multiple routes. This review focuses researches demonstrating that ginseng constituents could be a candidate as an adjuvant for AD treatment. However, clinical investigations including efficacy and tolerability analyses may be necessary for the clinical acceptance of ginseng components in combination with conventional AD drugs.
The BCL-2 family of proteins controls cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP) leading to the irreversible release of intermembrane space proteins, subsequent caspase activation and apoptosis. The affinities and relative abundance of the BCL-2 family proteins dictate the predominate interactions between anti-apoptotic and pro-apoptotic BCL-2 family proteins that regulate MOMP. We highlight the core mechanisms of BCL-2 family regulation of MOMP with an emphasis on how the interactions between the BCL-2 family proteins govern cell fate. We address the critical importance of both the concentration and affinities of BCL-2 family proteins and show how differences in either can greatly change the outcome. Further, we explain the importance of using full-length BCL-2 family proteins (versus truncated versions or peptides) to parse out the core mechanisms of MOMP regulation by the BCL-2 family. Finally, we discuss how post-translational modifications and differing intracellular localizations alter the mechanisms of apoptosis regulation by BCL-2 family proteins. Successful therapeutic intervention of MOMP regulation in human disease requires an understanding of the factors that mediate the major binding interactions between BCL-2 family proteins in cells.
Ginsenoside Rk1 (G-Rk1) is a unique component created by processing the ginseng plant (mainly Sung Ginseng (SG)) at high temperatures. The aim of our study was to systematically review the pharmacological effects of G-Rk1. We utilized and manually searched eight databases to select in vivo and in vitro original studies that provided information about biological, pharmaceutical effects of G-Rk1 and were published up to July 2017 with no restriction on language or study design. Out of the 156 papers identified, we retrieved 28 eligible papers in the first skimming phase of research. Several articles largely described the G-Rk1 anti-cancer activity investigating “cell viability”, “cell proliferation inhibition”, “apoptotic activity”, and “effects of G-Rk1 on G1 phase and autophagy in tumor cells” either alone or in combination with G-Rg5. Others proved that it has antiplatelet aggregation activities, anti-inflammatory effects, anti-insulin resistance, nephroprotective effect, antimicrobial effect, cognitive function enhancement, lipid accumulation reduction and prevents osteoporosis. In conclusion, G-Rk1 has a significant anti-tumor effect on liver cancer, melanoma, lung cancer, cervical cancer, colon cancer, pancreatic cancer, gastric cancer, and breast adenocarcinoma against in vitro cell lines. In vivo experiments are further warranted to confirm these effects.
Significance
Dysfunction of the innate immune system is involved in the pathogenesis of Alzheimer’s disease (AD); however, the pathophysiological mechanisms underlying these dysfunctions are unclear. Here we report that stimulation of IL-33/ST2 signaling rescues memory deficits and reduces the accumulation of β-amyloid in APP/PS1 mice that exhibit select pathologies associated with AD. Although impaired IL-33/ST2 signaling is associated with early progression of AD, IL-33 injection rescues contextual memory deficits and reduces the accumulation of β-amyloid in APP/PS1 mice. IL-33 skews the microglia toward an alternative activation state with enhanced Aβ phagocytic capacity and elevated antiinflammatory gene expression, which results in a decreased proinflammatory response in the brain. Thus, this study suggests that IL-33 can be developed as a new therapeutic intervention for AD.
Previously, it has been shown that strawberry (SB) or blueberry (BB) supplementations, when fed to rats from 19 to 21 months of age, reverse age-related decrements in motor and cognitive performance. We have postulated that these effects may be the result of a number of positive benefits of the berry polyphenols, including decreased stress signalling, increased neurogenesis, and increased signals involved in learning and memory. Thus, the present study was carried out to examine these mechanisms in aged animals by administering a control, 2 % SB- or 2 % BB-supplemented diet to aged Fischer 344 rats for 8 weeks to ascertain their effectiveness in reversing age-related deficits in behavioural and neuronal function. The results showed that rats consuming the berry diets exhibited enhanced motor performance and improved cognition, specifically working memory. In addition, the rats supplemented with BB and SB diets showed increased hippocampal neurogenesis and expression of insulin-like growth factor 1, although the improvements in working memory performance could not solely be explained by these increases. The diverse polyphenolics in these berry fruits may have additional mechanisms of action that could account for their relative differences in efficacy.
It is now clear that insulin signaling has important roles in regulation of neuronal functions in the brain. Dysregulation of brain insulin signaling has been linked to neurodegenerative disease, particularly Alzheimer's disease (AD). In this regard, there is evidence that improvement of neuronal insulin signaling has neuroprotective activity against amyloid β (Aβ)-induced neurotoxicity for patients with AD. Linagliptin is an inhibitor of dipeptidylpeptidase-4 (DPP-4), which improves impaired insulin secretion and insulin downstream signaling in the in peripheral tissues. However, whether the protective effects of linagliptin involved in Aβ-mediated neurotoxicity have not yet been investigated.
In the present study, we evaluated the mechanisms by which linagliptin protects against Aβ-induced impaired insulin signaling and cytotoxicity in cultured SK-N-MC human neuronal cells.
Our results showed that Aβ impairs insulin signaling and causes cell death. However, linagliptin significantly protected against Aβ-induced cytotoxicity, and prevented the activation of glycogen synthase kinase 3β (GSK3β) and tau hyperphosphorylation by restoring insulin downstream signaling. Furthermore, linagliptin alleviated Aβ-induced mitochondrial dysfunction and intracellular ROS generation, which may be due to the activation of 5' AMP-activated protein kinase (AMPK)-Sirt1 signaling. This upregulation of Sirt1 expression was also observed in diabetic patients with AD coadministration of linagliptin.
Taken together, our findings suggest linagliptin can restore the impaired insulin signaling caused by Aβ in neuronal cells, suggesting DPP-4 inhibitors may have therapeutic potential for reducing Aβ-induced impairment of insulin signaling and neurotoxicity in AD pathogenesis.
© 2015 John Wiley & Sons Ltd.
Alzheimer's disease (AD) is the most common form of dementia characterized by progressive loss of memory and other cognitive functions among older people. Senile plaques and neurofibrillary tangles are the most hallmarks lesions in the brain of AD in addition to neurons loss. Accumulating evidence has shown that oxidative stress-induced damage may play an important role in the initiation and progression of AD pathogenesis. Redox impairment occurs when there is an imbalance between the production and quenching of free radicals from oxygen species. These reactive oxygen species augment the formation and aggregation of amyloid-β and tau protein hyperphosphorylation and vice versa. Currently, there is no available treatments can modify the disease. However, wide varieties of antioxidants show promise to delay or prevent the symptoms of AD and may help in treating the disease. In this review, the role of oxidative stress in AD pathogenesis and the common used antioxidant therapies for AD will summarize.
AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis and a central player in glucose and lipid metabolism, is potentially implicated in the pathogenesis of Alzheimer's disease (AD). AMPK activity decreases in AD brain, indicating decreased mitochondrial biogenesis and function. Emerging evidence demonstrates that AMPK activation is a potential target for improving perturbed brain energy metabolism that is involved in the pathogenesis of AD. The roles of AMPK in the pathogenesis of AD include β-amyloid protein (Aβ) generation and tau phosphorylation. In particular, AMPK may regulate Aβ generation through modulating neuronal cholesterol and sphingomyelin levels and through regulating APP distribution in the lipid rafts. AMPK is activated by phosphorylation of Thr-172 by LKB1 complex in response to increase in the AMP/ATP ratio and by calmodulin-dependent protein kinase kinase-beta in response to elevated Ca(2+) levels, which contributes to regulating Aβ generation. AMPK is a physiological tau kinase and can increase the phosphorylation of tau at Ser-262. AMPK can also directly phosphorylate tau at Thr-231 and Ser-396/404. Furthermore, AMPK activation decreases mTOR signaling activity to facilitate autophagy and promotes lysosomal degradation of Aβ. However, AMPK activation has non-neuroprotective property and may lead to detrimental outcomes, including Aβ generation and tau phosphorylation. Therefore, it is still unclear whether AMPK could serve a potential therapeutic target for AD, and hence, further studies will be needed to clarify the role of AMPK in AD.
The AMP-activated protein kinase (AMPK) system is a key player in regulating energy balance at both the cellular and whole-body levels, placing it at centre stage in studies of obesity, diabetes and the metabolic syndrome. It is switched on in response to metabolic stresses such as muscle contraction or hypoxia, and modulated by hormones and cytokines affecting whole-body energy balance such as leptin, adiponectin, resistin, ghrelin and cannabinoids. Once activated, it switches on catabolic pathways that generate adenosine triphosphate (ATP), while switching off ATP-consuming anabolic processes. AMPK exists as heterotrimeric complexes comprising a catalytic alpha-subunit and regulatory beta- and gamma-subunits. Binding of AMP to the gamma-subunit, which is antagonized by high ATP, causes activation of the kinase by promoting phosphorylation at threonine (Thr-172) on the alpha-subunit by the upstream kinase LKB1, allowing the system to act as a sensor of cellular energy status. In certain cells, AMPK is activated in response to elevation of cytosolic Ca2+ via phosphorylation of Thr-172 by calmodulin-dependent kinase kinase-beta (CaMKKbeta). Activation of AMPK, either in response to exercise or to pharmacological agents, has considerable potential to reverse the metabolic abnormalities associated with type 2 diabetes and the metabolic syndrome. Two existing classes of antidiabetic drugs, that is, biguanides (for example, metformin) and the thiazolidinediones (for example, rosiglitazone), both act (at least in part) by activation of AMPK. Novel drugs activating AMPK may also have potential for the treatment of obesity.
Apoptosis is orchestrated by a family of cysteine proteases known as the caspases. Fourteen mammalian caspases have been identified, three of which (caspase-3, -6, and -7) are thought to coordinate the execution phase of apoptosis by cleaving multiple structural and repair proteins. However, the relative contributions that the "executioner" caspases make to the demolition of the cell remains speculative. Here we have used cell-free extracts immuno-depleted of either caspase-3, -6, or -7 to examine the caspase requirements for apoptosis-associated proteolysis of 14 caspase substrates as well as nuclear condensation, chromatin margination, and DNA fragmentation. We show that caspase-3 is the primary executioner caspase in this system, necessary for cytochrome c/dATP-inducible cleavage of fodrin, gelsolin, U1 small nuclear ribonucleoprotein, DNA fragmentation factor 45 (DFF45)/inhibitor of caspase-activated DNase (ICAD), receptor-interacting protein (RIP), X-linked inhibitor of apoptosis protein (X-IAP), signal transducer and activator of transcription-1 (STAT1), topoisomerase I, vimentin, Rb, and lamin B but not for cleavage of poly(ADP-ribose) polymerase (PARP) or lamin A. In addition, caspase-3 was also essential for apoptosis-associated chromatin margination, DNA fragmentation, and nuclear collapse in this system. Surprisingly, although caspase-6 and -7 are considered to be important downstream effector caspases, depletion of either caspase had minimal impact on any of the parameters investigated, calling into question their precise role during the execution phase of apoptosis.
The AMP-activated protein kinase (AMPK) is a metabolic-stress-sensing protein kinase that regulates metabolism in response to energy demand and supply by directly phosphorylating rate-limiting enzymes in metabolic pathways as well as controlling gene expression.
Plaques are a defining neuropathological hallmark of Alzheimer's disease (AD) and the major constituent of plaques, the beta-amyloid peptide (Abeta), is considered to play an important role in the pathophysiology of AD. But the biological origin of Abeta plaques and the mechanism whereby Abeta is involved in pathogenesis have been unknown. Abeta plaques were thought to form from the gradual accumulation and aggregation of secreted Abeta in the extracellular space. More recently, the accumulation of Abeta has been demonstrated to occur within neurons with AD pathogenesis. Moreover, intraneuronal Abeta accumulation has been reported to be critical in the synaptic dysfunction, cognitive dysfunction and the formation of plaques in AD. Here we provide a historical overview on the origin of plaques and a discussion on potential biological and therapeutic implications of intraneuronal Abeta accumulation for AD.
The Morris water maze (MWM) is a test of spatial learning for rodents that relies on distal cues to navigate from start locations around the perimeter of an open swimming arena to locate a submerged escape platform. Spatial learning is assessed across repeated trials and reference memory is determined by preference for the platform area when the platform is absent. Reversal and shift trials enhance the detection of spatial impairments. Trial-dependent, latent and discrimination learning can be assessed using modifications of the basic protocol. Search-to-platform area determines the degree of reliance on spatial versus non-spatial strategies. Cued trials determine whether performance factors that are unrelated to place learning are present. Escape from water is relatively immune from activity or body mass differences, making it ideal for many experimental models. The MWM has proven to be a robust and reliable test that is strongly correlated with hippocampal synaptic plasticity and NMDA receptor function. We present protocols for performing variants of the MWM test, from which results can be obtained from individual animals in as few as 6 days.
Alzheimer’s disease (AD) is a common neurodegenerative disorder in the elderly characterized by memory loss and cognitive dysfunction. The pathogenesis of AD is complex. One-targeted anti-AD drugs usually fail to delay AD progression. Traditional Chinese medicine records have documented the use of the roots of Panax ginseng (ginseng roots) and its prescriptions to treat dementia. Ginsenoside Rg1, the main ginsenoside component of ginseng roots, exhibits a certain therapeutic effect in the abovementioned diseases, suggesting its potential in the management of AD. Therefore, we combed the pathogenesis of AD and currently used anti-AD drugs, and reviewed the availability, pharmacokinetics, and pharmaceutic studies of ginsenoside Rg1. This review summarizes the therapeutic effects and mechanisms of ginsenoside Rg1 and its deglycosylated derivatives in AD in vivo and in vitro. The main mechanisms include improvement in Aβ and Tau pathologies, regulation of synaptic function and intestinal microflora, and reduction of inflammation, oxidative stress, and apoptosis. The underlying mechanisms mainly involve the regulation of PKC, MAPK, PI3K/Akt, CDK5, GSK-3β, BDNF/TrkB, PKA/CREB, FGF2/Akt, p21WAF1/CIP1, NF-κB, NLRP1, TLR3, and TLR4 signaling pathways. As the effects and underlying mechanisms of ginsenoside Rg1 on AD have not been systematically reviewed, we have provided a comprehensive review and shed light on the future directions in the utilization of ginsenoside Rg1 and ginseng roots as well as the development of anti-AD drugs.
Ginsenoside Rk1, a saponin component produced by heat-processed ginseng, possesses anti-inflammatory and antitumor activities. The aim of our study was to explore the effects of Rk1 on Lipopolysaccharide (LPS)-induced depression-like behavior in mice and to observe its effects on oxidative stress, the inflammatory response and brain-derived neurotrophic factor (BDNF) - tropomyosin-related kinase B (TrkB) signaling. After mice were pretreated with Rk1 (5, 10, and 20 mg/kg), the immobility time in both the forced swimming test (FST) and the tail suspension test (TST) was reduced, suggesting that Rk1 effectively improved depression-like symptoms. Rk1 (10 and 20 mg/kg) and Fluoxetine (Flu, 20 mg/kg) increased the activity of the antioxidant enzyme SOD in the brain and protected against lipid peroxidation. Different concentrations of Rk1 (10 and 20 mg/kg) and Flu significantly decreased the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1 in serum, while Rk1 (5, 10, and 20 mg/kg) and Flu reduced the concentrations of IL-6 in a dose-dependent manner. Western blot analysis showed that the administration of Rk1 (20 mg/kg) and Flu significantly downregulated the level of Sirt1 and that Rk1 (5, 10, and 20 mg/kg) and Flu inhibited the p-NF-κb/NF-κb and p-IκB-α/IκB-α ratios, which indicated that the neuroprotective effect of Rk1 may be related to the suppression of inflammation. In addition 5, 10 and 20 mg/kg Rk1 significantly attenuated the LPS-induced decreases in BDNF and TrkB. These results indicated that Rk1 acts as an antidepressant through its antioxidant activity, the inhibition of neuroinflammation, and the positive regulation of the BDNF-TrkB pathway. This study may help develop active ginsenoside-based compounds for neurodegenerative diseases.
Ginseng, the roots and rhizomes of Panax ginseng C. A Meyer, is not only used as herbal medicine but also used as functional food to support body functions. Ginsenoside Rg3 (GRg3) is a major bioactive component in ginseng. In this study, the beneficial effects of GRg3 on Alzheimer’s disease (AD) rats were evaluated via the behavioral experiment and anti-oxidant capacity. Moreover, metabolomic analysis based on UPLC-QTOF-MS/MS and apoptosis analysis were used to obtain the change between AD and GRg3-administrated rats to assess the underlying mechanisms on improving mitochondrial dysfunction. Results showed that GRg3 could prevent cognitive impairment of AD rats by improving the mitochondrial dysfunction. The potential mechanisms were related to regulate abnormality of energy metabolism, electron transport chain, amino acid metabolism, purine metabolism, and anti-apoptosis. These findings support the exploitation of GRg3 as an effective complementary and functional food to prevent and delay AD.
Ginseng Radix et Rhizome, which originated from Panax ginseng C. A. Meyer, has been used as traditional medicine in Asian for >2000 years. It is famous for its healthcare and therapeutic effects. Phytochemistry studies revealed that the major components of P. ginseng are: ginsenosides, polysaccharides, small peptides and essential oil. Modern research has proved that polysaccharide is one of the most important active ingredients in P. ginseng, which also takes up the largest slice of the chemical components. However, the past research was heavily oriented towards the small molecular ginsenosides. Thus, the main purpose of the present review is to summarize the preparation process, structure and biological functions of P. ginseng polysaccharides for further science research and application in medicine.
Background
Alzheimer's disease (AD) is a neurodegenerative disorder that affects over 45 million people worldwide. Patients with severe AD require help with daily activities and show severe memory impairment. Currently, donepezil is one of two drugs approved by FDA and Health Canada for the treatment of severe AD (MMSE score <10). It is prescribed as 5 or 10 mg/d and an FDA‐approved 23‐mg/d dose.
Method
This review will discuss risks and benefits of donepezil at these doses in severe AD. Articles were identified using PubMed using the MeSH terms “donepezil” AND “Alzheimer Disease” AND “severe.” Three double‐blind, placebo‐controlled, randomized studies, one post hoc analysis, and one subgroup analysis were selected.
Results
Donepezil was found to benefit patients in cognition and global functioning. The most consistent improvement was in severe impairment battery (SIB) scores. However, more patients treated with high dosage of donepezil discontinued their treatment due to various adverse events (AEs).
Conclusion
Clinicians must weigh benefits against adverse events when determining the course of therapy, as recommendations for cholinesterase inhibitors in advanced AD remain unclear and vary with different guidelines.
Among viability assays that depend on the conversion of substrate to chromogenic product by live cells, the MTT assay is still among one of the most versatile and popular assays. The MTT assay involves the conversion of the water-soluble yellow dye MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] to an insoluble purple formazan by the action of mitochondrial reductase. Formazan is then solubilized and the concentration determined by optical density at 570 nm. The result is a sensitive assay with excellent linearity up to ∼106 cells per well. As with the alamarBlue assay, small changes in metabolic activity can generate large changes in MTT, allowing one to detect cell stress upon exposure to a toxic agent in the absence of direct cell death. The assay has been standardized for adherent or nonadherent cells grown in multiple wells. The protocol uses a standard 96-well plate. This can be scaled up, however, to suit a different plate format. Plate 500-10,000 cells per well in a 96-well plate. The assay has good linearity up to 106 cells.
There have been many reports about the anti-aging effect of traditional Chinese medicine (TCM), but the material basis and mechanism of action have not been clearly elucidated. AMP-activated protein kinase (AMPK) is the receptor of energy metabolism and its life extending effect has been confirmed in different experiments. Over expression or activation with metform in of AAK-2/AMPK has been shown to extend life expectancy in nematodes and Drosophila. The possible downstream pathways of AMPK against aging include TOR/S6k pathway, FOXOs pathway and CRTC pathway. One of the core concepts of traditional Chinese medicine is disease prevention, for which one of manifestations is to improve the body with the same source of medicine and food to achieve longevity. It is possible to activate AMPK to achieve the goal of health preservation and prolonging the life by some of the "medicine-food harmony" treatments. Our survey finds that in "medicine-food harmony" compound TCM, "invigorating the kidney deficiency and promoting blood circulation" class dominates and Salviae Miltiorrhizae Radix Rhizoma, Astragali Radix, Coptidis Rhizoma, Poria, Atractylodes Macrocephalae Rhizoma, Radix et Rhizoma Rhei, and Ginseng Radix et Rhizoma are used in high frequency. Network pharmacology analysis using ingenuity pathway analysis (IPA) software revealed that TCM-derived drugs interacting with AMPK target proteins included berberine, emodin, curcumin, resveratrol, alcohol, cordyceps, arctiin, suggesting in a certain extent the feasibility of "medicine -food homology" drugs to extend the lifespan through the AMPK pathway. Our study combines a comprehensive database query and an IPA network pharmacology analysis to identify Chinese medicine monomer and components that may activate AMPK pathway to delay aging and to discuss the potential of these medicine by improving energy metabolism to delay the aging process, based on the concept of traditional Chinese medicine "medicine-food homology".
Ginseng, an herbaceous plant, belonging to the family Araliaceae is a traditional medicinal herb. Also, it is emerging as a functional food and potent adjunct medicine. Saponin ginsenosides (protopanaxadiol and protopanaxatriol) are the signature phytochemicals of this plant. With the surfacing of scientific validations, ginseng is gaining unprecedented attention from consumers as well as researchers. As a number of drug-herb interaction-caused health issues have emerged, the medicinal relevance of this plant has been critically assessed here. In this regard, the recent publications on health benefits of ginseng have been extracted from NCBI and ScienceDirect database. The claimed antioxidant, anti-inflammation, anti-fatigue, antidiabetic, antitumor, immunomodulation, anti-obesity, cardioprotective, antimicrobial, neuroprotective and aphrodisiac properties have been analyzed. This review presents a fair assessment and insights on complementary and alternative medicine (CAM) potential of this herb.
The production of nitric oxide (NO) is one of the primary mediators of ischemic damage, glutamate neurotoxicity and neurodegeneration and therefore inhibition of NO−induced neurotoxicity may be considered a therapeutic target for reducing neuronal cell death (neuroprotection). In this study, artemisinin, a well-known anti-malaria drug was found to suppress sodium nitroprusside (SNP, a nitric oxide donor)-induced cell death in the PC12 cells and brain primary cortical neuronal cultures. Pretreatment of PC12 cells with artemisinin significantly suppressed SNP-induced cell death by decreasing the extent of oxidation, preventing the decline of mitochondrial membrane potential, restoring abnormal changes in nuclear morphology and reducing LDH release and inhibiting caspase 3/7 activities. Western blotting analysis revealed that artemisinin was able to activate extracellular regulated protein kinases (ERK) pathway. Furthermore, the ERK inhibitor PD98059 blocked the neuroprotective effect of artemisinin whereas the PI3K inhibitor LY294002 had no effect. Cumulatively these findings support the notion that artemisinin confers neuroprotection from SNP-induce neuronal cell death insult, a phenomenon coincidentally related to activation of ERK phosphorylation. This sodium nitroprusside-induced oxidative insult in PC12 cell culture model may be useful to investigate molecular mechanisms of NO-induced neurotoxicity and drug-induced neuroprotection, and to generate novel therapeutic concepts for ischemic disease treatment.
Nrf2 is an antioxidant transcription factor. AMPK functions as a central regulator of cell survival in response to stressful stimuli. Nrf2 should be coordinated with the cell survival pathway controlled by AMPK, but so far the mechanistic connections remain undefined. This study investigated the role of AMPK in Nrf2 trafficking and its activity regulation. A sub-network integrating neighbor molecules suggested direct interaction between AMPK and Nrf2. In cells, AMPK activation caused nuclear accumulation of Nrf2. In the
in vitro
kinase and peptide competition assays, AMPK phosphorylated Nrf2 at Ser558 residue (Ser550 in mouse) located in the canonical nuclear export signal. Nrf2 with S550A mutation failed to be accumulated in the nucleus after AMPK activation. Leptomycin B, a nuclear export inhibitor, did not enhance nuclear accumulation of WT-Nrf2 activated by AMPK or phospho-Ser550 mimetic Nrf2 mutant, corroborating that AMPK facilitated nuclear accumulation of Nrf2 probably by inhibiting nuclear export. Activated GSK3β diminished the basal nuclear level of Myc-S550A-Nrf2. Collectively, AMPK phosphorylates Nrf2 at Ser550 residue, which in conjunction with AMPK-mediated GSK3β inhibition promotes nuclear accumulation of Nrf2 for antioxidant response element (ARE)-driven gene transactivation.
The brain is very sensitive to changes in redox status; thus maintaining redox homeostasis in the brain is critical for the prevention of accumulating oxidative damage. Aging is the primary risk factor for developing neurodegenerative diseases. In addition to age, genetic and environmental risk factors have also been associated with disease development. The primary reactive insults associated with the aging process are a result of oxidative stress (OS) and nitrosative stress (NS). Markers of increased oxidative stress, protein and DNA modification, inflammation, and dysfunctional proteostasis have all been implicated in contributing to the progression of neurodegeneration. The ability of the cell to combat OS/NS and maintain a clearance mechanism for misfolded aggregating proteins determines whether or not it will survive. A critical pathway in this regard is the Nrf2 (nuclear factor erythroid 2-related factor 2)- antioxidant response element (ARE) pathway. Nrf2 activation has been shown to mitigate a number of pathologic mechanisms associated with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. This review will focus on the role of Nrf2 in these diseases and the potential for Nrf2 activation to mitigate disease progression.
Copyright © 2015 Elsevier B.V. All rights reserved.
Alzheimer's disease is a neurodegenerative disease associated with progressive memory and cognitive decline. Previous studies have identified the benefits of cognitive enrichment on reducing disease pathology. Additionally, epidemiological and clinical data suggest that repeated exercise, and cognitive and social enrichment, can improve and/or delay the cognitive deficiencies associated with aging and neurodegenerative diseases. In the present study, 3xTg-AD mice were exposed to a rigorous training routine beginning at 3 months of age, which consisted of repeated training in the Morris water maze spatial recognition task every 3 months, ending at 18 months of age. At the conclusion of the final Morris water maze training session, animals subsequently underwent testing in another hippocampus-dependent spatial task, the Barnes maze task, and on the more cortical-dependent novel object recognition memory task. Our data show that periodic cognitive enrichment throughout aging, via multiple learning episodes in the Morris water maze task, can improve the memory performance of aged 3xtg-AD mice in a separate spatial recognition task, and in a preference memory task, when compared to naïve aged matched 3xTg-AD mice. Furthermore, we observed that the cognitive enrichment properties of Morris water maze exposer, was detectable in repeatedly trained animals as early as 6 months of age. These findings suggest early repeated cognitive enrichment can mitigate the diverse cognitive deficits observed in Alzheimer's disease.
Copyright © 2015. Published by Elsevier Inc.
Mitochondrial biogenesis is involved in the regulation of mitochondrial content, morphology, and function. Impaired mitochondrial biogenesis has been observed in Alzheimer's disease. Amyloid-β (Aβ) has been shown to cause mitochondrial dysfunction in cultured neurons, but its role in mitochondrial biogenesis in neurons remains poorly defined. AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) are key energy-sensing molecules regulating mitochondrial biogenesis. In addition, peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis, is a target for SIRT1 deacetylase activity. In this study, we investigated the effects of Aβ25-35 on mitochondrial biogenesis in cultured hippocampal neurons and the underlying mechanisms. In primary hippocampal neurons, we found that 24-h incubation with Aβ25-35 suppressed both phosphorylations of AMPK and SIRT1 expression and increased PGC-1α acetylation expression. In addition, Aβ25-35 also resulted in a decrease in mitochondrial DNA copy number, as well as decreases in the expression of mitochondrial biogenesis factors (PGC-1α, NRF 1, NRF 2, and Tfam). Taken together, these data show that Aβ25-35 suppresses mitochondrial biogenesis in hippocampal neurons. Aβ25-35-induced impairment of mitochondrial biogenesis may be associated with the inhibition of the AMPK-SIRT1-PGC-1α pathway.
Oxidative stress and endoplasmic reticulum (ER) stress have been associated with Alzheimer's disease (AD) progression. In this study we analyzed whether oxidative stress involving changes in Nrf2 and ER stress may constitute early events in AD pathogenesis by using human peripheral blood cells and an AD transgenic mouse model at different disease stages. Increased oxidative stress and increased phosphorylated Nrf2 (p(Ser40)Nrf2) were observed in human peripheral blood mononuclear cells (PBMCs) isolated from individuals with mild cognitive impairment (MCI). Moreover, we observed impaired ER Ca(2+) homeostasis and increased ER stress markers in PBMCs from MCI individuals and mild AD patients. Evidence of early oxidative stress defense mechanisms in AD was substantiated by increased p(Ser40)Nrf2 in 3 month-old 3xTg-AD male mice PBMCs, and also with increased nuclear Nrf2 levels in brain cortex. However, SOD1 protein levels were decreased in human MCI PBMCs and in 3xTg-AD mice brain cortex; the latter further correlated with reduced SOD1 mRNA levels. Increased ER stress was also detected in the brain cortex of young female and old male 3xTg-AD mice. We demonstrate oxidative stress and early Nrf2 activation in AD human and mouse models, which fails to regulate some of its targets, leading to repressed expression of antioxidant defenses (e.g. SOD-1), and extending to ER stress. Results suggest markers of prodromal AD linked to oxidative stress associated with Nrf2 activation and ER stress that may be followed in human peripheral blood mononuclear cells.
Copyright © 2015. Published by Elsevier B.V.
In the course of this experiment on the anti-inflammatory effect of ginsenosides, protopanaxdiol ginsenosides have shown inhibition activities in inflammatory responses: NF-κB, COX-2, and iNOS were induced by TNF-α. The responses of this experiment were evaluated by NF-κB-luciferase assay and RT-PCR experiment of COX-2 and iNOS genes. The NF-κB expressions were inhibited by ginsenosides Rd, Rg5, Rz1, and Rk1 in a dose-dependent manner. The IC50 values were 3.47, 0.61, 0.63, and 0.75 μM, respectively. Particularly, ginsenosides Rg5, Rz1, and Rk1 as converted ginsenosides from primary protopanaxdiol ginsenosidess significantly inhibited COX-2 and iNOS gene expression. These inhibition levels were similar to sulfasalazine as reference material. Copyright © 2014 John Wiley & Sons, Ltd.
Primary neuronal cultures and neuronal cell lines derived from rodents are widely used to study basic physiological properties of neurons, and represent a useful tool to study the potential neurotoxicity of chemicals. While short-term culturing of neurons can be a very straightforward process, long-term cultures of relatively pure neuronal populations require more effort. This chapter describes methods and protocols to isolate and culture primary neurons obtained from the rodent cerebellum (cerebellar granule cells), the hippocampus, and the striatum. Furthermore, culturing of rat pheochromocytoma (PC-12) cells is also described, as these cells represent a useful and widely used cell line for in vitro neurotoxicological studies.
The microtubule-associated protein tau accumulates in Alzheimer's and other fatal dementias, which manifest when forebrain neurons die. Recent advances in understanding these disorders indicate that brain dysfunction precedes neurodegeneration, but the role of tau is unclear. Here, we show that early tau-related deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic abnormalities caused by the accumulation of hyperphosphorylated tau within intact dendritic spines, where it disrupts synaptic function by impairing glutamate receptor trafficking or synaptic anchoring. Mutagenesis of 14 disease-associated serine and threonine amino acid residues to create pseudohyperphosphorylated tau caused tau mislocalization while creation of phosphorylation-deficient tau blocked the mistargeting of tau to dendritic spines. Thus, tau phosphorylation plays a critical role in mediating tau mislocalization and subsequent synaptic impairment. These data establish that the locus of early synaptic malfunction caused by tau resides in dendritic spines.
Alzheimer's disease (AD) a progressive neurodegenerative disorder of later life, is characterized by brain deposition of amyloid beta-protein (Abeta) plaques, accumulation of intracellular neurofibrillatory tangles, synaptic loss and neuronal cell death. There is significant evidence that oxidative stress is a critical event in the pathogenesis of AD. In the present study Abeta formation was induced in NT2N neurons, one of the most appropriate cell line models in AD. Our results indicate that oxidative stress resulting from the treatment of H(2)O(2)/FeSO(4) and/or 4-hydroxy-2-noenal (HNE) can be inhibited in the presence of tBHQ, a known inducer of nuclear factor-erythroid 2 related factor 2 (Nrf2) in NT2N neurons and can therefore be used to elucidate the relationship between oxidative stress, Abeta formation and Nrf2. The role of Nrf2 was confirmed using retinoic acid as an inhibitor of Nrf2. It provides the first documentation that tBHQ not only protects the neurons against cell death but also decreases amyloid beta formation. Moreover, the results indicate that oxidative stress fosters Abeta formation in NT2N neurons, creating a vicious neurodegenerative loop.
The major hurdle in understanding Alzheimer's disease (AD) is a lack of knowledge about the etiology and pathogenesis of selective neuron death. In recent years, considerable data have accrued indicating that the brain in AD is under increased oxidative stress and this may have a role in the pathogenesis of neuron degeneration and death in this disorder. The direct evidence supporting increased oxidative stress in AD is: (1) increased brain Fe, Al, and Hg in AD, capable of stimulating free radical generation; (2) increased lipid peroxidation and decreased polyunsaturated fatty acids in the AD brain, and increased 4-hydroxynonenal, an aldehyde product of lipid peroxidation in AD ventricular fluid; (3) increased protein and DNA oxidation in the AD brain; (4) diminished energy metabolism and decreased cytochrome c oxidase in the brain in AD; (5) advanced glycation end products (AGE), malondialdehyde, carbonyls, peroxynitrite, heme oxygenase-1 and SOD-1 in neurofibrillary tangles and AGE, heme oxygenase-1, SOD-1 in senile plaques; and (6) studies showing that amyloid beta peptide is capable of generating free radicals. Supporting indirect evidence comes from a variety of in vitro studies showing that free radicals are capable of mediating neuron degeneration and death. Overall, these studies indicate that free radicals are possibly involved in the pathogenesis of neuron death in AD. Because tissue injury itself can induce reactive oxygen species (ROS) generation, it is not known whether this is a primary or secondary event. Even if free radical generation is secondary to other initiating causes, they are deleterious and part of a cascade of events that can lead to neuron death, suggesting that therapeutic efforts aimed at removal of ROS or prevention of their formation may be beneficial in AD.
The brain and nervous system are prone to oxidative stress, and are inadequately equipped with antioxidant defense systems to prevent 'ongoing' oxidative damage, let alone the extra oxidative damage imposed by the neurodegenerative diseases. Indeed, increased oxidative damage, mitochondrial dysfunction, accumulation of oxidized aggregated proteins, inflammation, and defects in protein clearance constitute complex intertwined pathologies that conspire to kill neurons. After a long lag period, therapeutic and other interventions based on a knowledge of redox biology are on the horizon for at least some of the neurodegenerative diseases.
Impairment in the regulation of energy homeostasis and imbalance between energy intake and energy expenditure lead to many metabolic disorders and diseases such as obesity and type 2 diabetes. AMP-activated protein kinase (AMPK) is considered as a "fuel-gauge" in the cell and plays a key role in the regulation of energy metabolism. Activated by an increase in the AMP/ATP ratio, AMPK switches on catabolic pathways such as fatty acid oxidation and switches off anabolic pathways such as lipogenesis or gluconeogenesis. Insulin-sensitizing adipokines (leptin and adiponectin) and anti-diabetic drugs (thiazolidinediones and biguanides) are acting in part through the activation of AMPK. More recent findings indicate that AMPK plays also a major role in the control of whole body energy homeostasis by integrating, at the hypothalamus level, nutrient and hormonal signals that regulate food intake and energy expenditure. AMPK provides therefore a potential target for the treatment of metabolic diseases such as obesity and type II diabetes.
Amyloid-beta, TAu protein or both?
- de Jesus de Paula