scholarly journals Rheum tanguticum Alleviates Cognitive Impairment in APP/PS1 Mice by Regulating Drug-Responsive Bacteria and Their Corresponding Microbial Metabolites

2021 ◽  
Vol 12 ◽  
Author(s):  
Demin Gao ◽  
Huizhen Zhao ◽  
Zhihui Yin ◽  
Chen Han ◽  
Ying Wang ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Neuronal Damage ◽  
Intestinal Bacteria ◽  
Dependent Manner ◽  
Microbial Metabolites ◽  
Therapeutic Mechanisms ◽  
Polymerase Chain ◽  
Important Nodes ◽  
Rheum Tanguticum

Drugs targeting intestinal bacteria have shown great efficacy for alleviating symptoms of Alzheimer’s disease (AD), and microbial metabolites are important messengers. Our previous work indicated that Rheum tanguticum effectively improved cognitive function and reshaped the gut microbial homeostasis in AD rats. However, its therapeutic mechanisms remain unclear. Herein, this study aimed to elaborate the mechanisms of rhubarb for the treatment of AD by identifying effective metabolites associated with rhubarb-responsive bacteria. The results found that rhubarb reduced hippocampal inflammation and neuronal damage in APP/PS1 transgenic (Tg) mice. 16S rRNA sequencing and metabolomic analysis revealed that gut microbiota and their metabolism in Tg mice were disturbed in an age-dependent manner. Rhubarb-responsive bacteria were further identified by real-time polymerase chain reaction (RT-PCR) sequencing. Four different metabolites reversed by rhubarb were found in the position of the important nodes on rhubarb-responsive bacteria and their corresponding metabolites combined with pathological indicators co-network. Furthermore, in vitro experiments demonstrated o-tyrosine not only inhibited the viabilities of primary neurons as well as BV-2 cells, but also increased the levels of intracellular reactive oxygen species and nitric oxide. In the end, the results suggest that rhubarb ameliorates cognitive impairment in Tg mice through decreasing the abundance of o-tyrosine in the gut owing to the regulation of rhubarb-responsive bacteria. Our study provides a promising strategy for elaborating therapeutic mechanisms of bacteria-targeted drugs for AD.

Artemisinin improves neurocognitive deficits associated with sepsis by activating the AMPK axis in the microglia.

2020 ◽  
Author(s):  
Shao-Peng Lin ◽  
Jue-Xian Wei ◽  
Shan Ye ◽  
Jiasong Hu ◽  
Jingyi Bu ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Inflammatory Cytokines ◽  
Nuclear Translocation ◽  
Neuronal Damage ◽  
Protective Mechanism ◽  
Protective Effects ◽  
Neurocognitive Deficits ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Abstract Background and purpose: Artemisinin has been in use as an anti-malarial drug for almost half a century in the world. There is growing evidence that artemisinin also possesses potent anti-inflammatory and immunoregulatory properties. However, the efficacy of artemisinin treatment in neurocognitive deficits associated with sepsis remains unknown. Here, we evaluate the possible protective effects and explore the underlying mechanism of artemisinin on cognitive impairment resulting from sepsis.Methods: Male C57BL/6 mice were pretreated with either vehicle or artemisinin, and then injected with LPS to establish an animal model of sepsis. The cognitive function was then assessed using the Morris water maze. Neuronal damage and neuroinflammation in the hippocampus were evaluated by immunohistochemical and ELISA analysis. Additionally, the protective mechanism of artemisinin was determined in vitro.Results: The results showed that artemisinin preconditioning attenuated LPS-induced cognitive impairment, neural damage, and microglial activation in the mouse brain. The in vitro experiment revealed that artemisinin could reduce the production of pro-inflammatory cytokines and suppress the microglial migration in the BV2 microglia cells. Meanwhile, western blot demonstrated that artemisinin suppressed nuclear translocation of nuclear factor kappa-B and the expression of pro-inflammatory cytokines (i.e. tumor necrosis factor alpha, interleukin-6) by activating adenosine monophosphate-activated protein kinaseα1 (AMPKα1) pathway. Furthermore, knock-down of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin.Conclusion: Artemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect was probably mediated by the activation of AMPKα1 signalling pathway in microglia.

scholarly journals Resveratrol Mitigates Hippocampal Tau Acetylation and Cognitive Deficit by Activation SIRT1 in Aged Rats following Anesthesia and Surgery

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Jing Yan ◽  
Ailin Luo ◽  
Rao Sun ◽  
Xiaole Tang ◽  
Yilin Zhao ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Elderly Population ◽  
Cognitive Deficit ◽  
Neurological Complication ◽  
Postoperative Cognitive Dysfunction ◽  
The Elderly ◽  
Dependent Manner ◽  
Promising Avenue ◽  
Tau Acetylation

Postoperative cognitive dysfunction (POCD) is a sever postsurgical neurological complication in the elderly population. As the global acceleration of population ageing, POCD is proved to be a great challenge to the present labor market and healthcare system. In the present study, our findings showed that tau acetylation mediated by SIRT1 deficiency resulted in tau hyperphosphorylation in the hippocampus of the aged POCD model and consequently contributed to cognitive impairment. Interestingly, pretreatment with resveratrol almost restored the expression of SIRT1, reduced the levels of acetylated tau and hyperphosphorylated tau in the hippocampus, and improved the cognitive performance in the behavioral tests. What is more, we observed that microglia-derived neuroinflammation resulting from SIRT1 inhibition in microglia probably aggravated the tau acetylation in cultured neurons in vitro. Our findings supported the notion that activation SIRT1 provided dually beneficial effect in the aged POCD model. Taken together, our findings provided the initial evidence that tau acetylation was associated with cognitive impairment in the aged POCD model and paved a promising avenue to prevent POCD by inhibiting tau acetylation in a SIRT1-dependent manner.

Neuroprotective effect of Chunghyuldan from amyloid beta oligomer induced neuroinflammation in vitro and in vivo

2014 ◽  
Vol 92 (6) ◽  
pp. 429-437 ◽  
Author(s):  
Hyo Geun Kim ◽  
Ji-Young Kim ◽  
Wei-Wan Whang ◽  
Myung Sook Oh
Keyword(s):  
Cognitive Impairment ◽  
Amyloid Beta ◽  
Antioxidant Activities ◽  
Neuronal Damage ◽  
Biological Effects ◽  
Neuroprotective Effect ◽  
In Vivo Models ◽  
Aβ Oligomer

Microglia-mediated inflammation is a major pathological mechanism contributing to Alzheimer’s disease (AD), and has been proposed as a potential therapeutic target. Chunghyuldan (CHD; Qingxue-dan in Chinese and Daio-Orengedokuto in Japanese) possesses wide-ranging biological effects, including anti-hyperlipidemic, anti-stroke, anti-inflammatory, and antioxidant activities that could affect neurological functions. In this study, we examined the effects of CHD in in-vitro and in-vivo models of AD induced by the oligomeric form of amyloid-beta (Aβ oligomer), which acts directly on microglia-mediated neuroinflammation to result in neuronal damage and cognitive impairment. CHD at 0.1–100 μg·mL−1 significantly protected PC12 cells and rat primary hippocampal cells from Aβ oligomer1–42 toxicity. In addition, CHD at 1–10 μg·mL−1 inhibited Aβ oligomer1–42 induced production of nitric oxide, tumor necrosis factor-α, and interleukin-1β in microglial cells. In an in-vivo AD model, administration of CHD (50 mg·(kg body mass)−1, for 5 days, per oral) inhibited the activation of astrocytes and microglia in the dentate gyrus and neuronal damage in the CA1 of the ipsilateral hippocampus. Moreover, CHD ameliorated cognitive impairment induced by Aβ oligomer1–42 toxicity. These results demonstrate the neuroprotective effects of CHD through inhibition of microglia-mediated neuroinflammation in in-vitro and in-vivo AD-like models induced by Aβ oligomer1–42 toxicity.

scholarly journals An 18-Mer Peptide Fragment of Prosaposin Ameliorates Place Navigation Disability, Cortical Infarction, and Retrograde Thalamic Degeneration in Rats with Focal Cerebral Ischemia

1999 ◽  
Vol 19 (3) ◽  
pp. 298-306 ◽  
Author(s):  
Keiji Igase ◽  
Junya Tanaka ◽  
Yoshiaki Kumon ◽  
Bo Zhang ◽  
Yasutaka Sadamoto ◽  
...  
Keyword(s):  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Left Middle Cerebral Artery ◽  
Dependent Manner ◽  
Thalamic Degeneration ◽  
Cortical Infarction ◽  
Saposin C ◽  
Left Lateral Ventricle

It was previously reported that prosaposin possesses neurotrophic activity that is ascribed to an 18-mer peptide comprising the hydrophilic sequence of the rat saposin C domain. To evaluate the effect of the 18-mer peptide on ischemic neuronal damage, the peptide was infused in the left lateral ventricle immediately after occlusion of the left middle cerebral artery (MCA) in stroke-prone spontaneously hypertensive (SP-SH) rats. The treatment ameliorated the ischemia-induced space navigation disability and cortical infarction and prevented secondary thalamic degeneration in a dose-dependent manner. In culture experiments, treatment with the 18-mer peptide attenuated free radical-induced neuronal injury at low concentrations (0.002 to 2 pg/mL), and the peptide at higher concentrations (0.2 to 20 ng/mL) protected neurons against hypoxic insult. Furthermore, a saposin C fragment comprising the 18-mer peptide bound to synaptosomal fractions of the cerebral cortex, and this binding decreased at the 1st day after MCA occlusion and recovered to the preischemic level at the 7th day after ischemia. These findings suggest that the 18-mer peptide ameliorates neuronal damage in vivo and in vitro through binding to the functional receptor, although the cDNA encoding prosaposin receptor has not been determined yet.

scholarly journals Streptococcus gallolyticus Increases Expression and Activity of Aryl Hydrocarbon Receptor-Dependent CYP1 Biotransformation Capacity in Colorectal Epithelial Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Rahwa Taddese ◽  
Rian Roelofs ◽  
Derk Draper ◽  
Xinqun Wu ◽  
Shaoguang Wu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Specific Inhibitor ◽  
Intestinal Bacteria ◽  
Opportunistic Pathogen ◽  
Dependent Manner ◽  
Aryl Hydrocarbon ◽  
Streptococcus Gallolyticus

ObjectiveThe opportunistic pathogen Streptococcus gallolyticus is one of the few intestinal bacteria that has been consistently linked to colorectal cancer (CRC). This study aimed to identify novel S. gallolyticus-induced pathways in colon epithelial cells that could further explain how S. gallolyticus contributes to CRC development.Design and ResultsTranscription profiling of in vitro cultured CRC cells that were exposed to S. gallolyticus revealed the specific induction of oxidoreductase pathways. Most prominently, CYP1A and ALDH1 genes that encode phase I biotransformation enzymes were responsible for the detoxification or bio-activation of toxic compounds. A common feature is that these enzymes are induced through the Aryl hydrocarbon receptor (AhR). Using the specific inhibitor CH223191, we showed that the induction of CYP1A was dependent on the AhR both in vitro using multiple CRC cell lines as in vivo using wild-type C57bl6 mice colonized with S. gallolyticus. Furthermore, we showed that CYP1 could also be induced by other intestinal bacteria and that a yet unidentified diffusible factor from the S. galloltyicus secretome (SGS) induces CYP1A enzyme activity in an AhR-dependent manner. Importantly, priming CRC cells with SGS increased the DNA damaging effect of the polycyclic aromatic hydrocarbon 3-methylcholanthrene.ConclusionThis study shows that gut bacteria have the potential to modulate the expression of biotransformation pathways in colonic epithelial cells in an AhR-dependent manner. This offers a novel theory on the contribution of intestinal bacteria to the etiology of CRC by modifying the capacity of intestinal epithelial or (pre-)cancerous cells to (de)toxify dietary components, which could alter intestinal susceptibility to DNA damaging events.

scholarly journals Transforming Growth Factor-β1 Prevents Glutamate Neurotoxicity in Rat Neocortical Cultures and Protects Mouse Neocortex from Ischemic Injury in vivo

1993 ◽  
Vol 13 (3) ◽  
pp. 521-525 ◽  
Author(s):  
Jochen H. M. Prehn ◽  
Cord Backhauß ◽  
Josef Krieglstein
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Neuronal Damage ◽  
Ischemic Injury ◽  
Left Middle Cerebral Artery ◽  
Dependent Manner ◽  
Vessel Occlusion ◽  
Trypan Blue Exclusion

Transforming growth factor-β1 (TGF-β1) has been shown to be an injury-related peptide growth factor within the mammalian central nervous system. We tested whether TGF-β1 has the capacity to protect rat neocortical neurons against excitotoxic damage in vitro and mouse neocortex against ischemic injury in vivo. After 14 days in vitro, cultured neurons from rat cerebral cortex were exposed to 1 m M l-glutamate in serum-free culture medium. The cultures received TGF-β1 immediately after the addition of glutamate. Eighteen hours later, the cell viability of the cultures was determined using trypan blue exclusion. TGF-β1 (1–10 ng/ml) significantly reduced the excitotoxic neuronal damage in a concentration-dependent manner. In vivo, male NMRI mice were subjected to a permanent occlusion of the left middle cerebral artery by microbipolar electrocoagulation. After 48 h, the animals received a transcardiac injection of carbon black. The area of ischemia (devoid of carbon) was restricted to the neocortex and its size was determined planimetrically by means of an image-analyzing system. The treatment with TGF-β1 (1 μg/kg i.c.v.) at 6, 4, or 2 h prior to vessel occlusion reduced the area of ischemia by 5.3, 10.0, and 9.6%, respectively. The effect of the treatment with TGF-β1 was statistically significant (p < 0.05 by two-way ANOVA). The present in vitro and in vivo data suggest that TGF-β1 has the capacity to diminish the deleterious consequences of an excitotoxic or ischemic insult.

scholarly journals Sevoflurane-Induced miR-211-5p Promotes Neuronal Apoptosis by Inhibiting Efemp2

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110350
Author(s):  
Yousu Shen ◽  
Tao Zhou ◽  
Xiaobing Liu ◽  
Yanlong Liu ◽  
Yaqi Li ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Neuronal Apoptosis ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Inflammatory Factor ◽  
Dependent Manner ◽  
Apoptotic Pathway ◽  
The Impact

Sevoflurane exposure can result in serious neurological side effects including neuronal apoptosis and cognitive impairment. Although the microRNA miR-211-5p is profoundly upregulated following sevoflurane exposure in neonatal rodent models, the impact of miR-211-5p on neuronal apoptosis and cognitive impairment postsevoflurane exposure has not yet been elucidated. Here, we found that sevoflurane upregulated miR-211-5p and downregulated EGF-Containing Fibulin Extracellular Matrix Protein 2 (Efemp2, Fibulin-4) levels in vitro and in vivo. Sevoflurane's effect on miR-211-5p expression was based on enhancing primary miR-211 transcription. miR-211-5p targets Efemp2's mRNA 3′-untranslated region, reducing Efemp2 expression. RNA immunoprecipitation revealed significant enrichment of the miR-211-5p:Efemp2 mRNA dyad in the RNA-induced silencing complex. miR-211-5p mimics downregulated Efemp2, leading to phosphorylation of Smad2 and Smad3, upregulation of pro-apoptotic Bim, and mitochondrial release of allograft inflammatory factor 1 and cytochrome C. In contrast, miR-211-5p hairpin inhibitor (AntimiR-211-5p) negatively regulated this apoptotic pathway and reduced neuronal apoptosis in an Efemp2-dependent manner. Sevoflurane-exposed mice administered AntimiR-211-5p displayed reduced cortical apoptosis levels and near-term cognitive impairment. In conclusion, sevoflurane-induced miR-211-5p promotes neuronal apoptosis via Efemp2 inhibition. Summary statement: This study revealed the significance of sevoflurane-induced increases in miR-211-5p on the promotion of neuronal apoptosis via inhibition of Efemp2 and its downstream targets.

An in vitro Experimental Insight into the Osteoblast Responses to Vitamin D3 and Its Metabolites

Pharmacology ◽  
2018 ◽  
Vol 101 (5-6) ◽  
pp. 225-235 ◽  
Author(s):  
Dong Wang ◽  
Jiang Song ◽  
Huasong Ma
Keyword(s):  
Vitamin D3 ◽  
Osteoblast Differentiation ◽  
Cell Types ◽  
Cell Counting ◽  
Dependent Manner ◽  
Dihydroxyvitamin D3 ◽  
Osteogenic Markers ◽  
Polymerase Chain ◽  
Dose Dependent

Background: 25-hydroxyvitamin D3 (25[OH]VD3) has recently been found to be an active hormone. Its biological actions are also demonstrated in various cell types. However, the precise influences of vitamin D3 (VD3) and its metabolites (25[OH]VD3, 1α,25-dihydroxyvitamin D3 [1α,25-(OH)2VD3]) on the osteoblast differentiation remain largely unknown. In this work, we investigated the effects of VD3 and its metabolites in different concentrations on the early and later osteoblast differentiation and biomineralization. Methods: We first used quantitative real-time polymerase chain reaction (RT-qPCR) to evaluate the responsiveness of osteoblasts to VD3, 25(OH)VD3 or 1α,25-(OH)2VD3. We also evaluated the proliferation, differentiation and biomineralization of osteoblast at different time points via cell counting kit-8 assay and the analysis of osteogenic markers. Results: The experimental results confirmed that osteoblasts could be responsive to 25(OH)VD3 and 1α,25-(OH)2VD3 but could not directly metabolize VD3 and 25(OH)VD3. Only 200 nmol/L VD3 significantly promoted osteoblast proliferation, while 25(OH)VD3 and 1α,25-(OH)2VD3 did not show obvious actions. Moreover, the early osteogenic markers were increased by 25(OH)VD3 and 1α,25-(OH)2VD3 in a dose-dependent manner. More importantly, only 25(OH)VD3 had accelerated the gene and protein expressions of osteocalcin and the biomineralization level of osteoblasts. Conclusions: Our findings provide reliable evidence that 25(OH)VD3 at 100–200 nmol/L can induce the early and later osteoblast differentiation and biomineralization for clinical bone tissue engineering.

scholarly journals Purification and Functional Characterization of the Chloroform/Methanol-Soluble Protein 3 (CM3) From Triticum aestivum in Drosophila melanogaster

2020 ◽  
Vol 7 ◽  
Author(s):  
Anna-Lena Thiel ◽  
Mohab Ragab ◽  
Anika E. Wagner ◽  
Senad Divanovic ◽  
Stefanie Derer ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Soluble Protein ◽  
Functional Characterization ◽  
Gastrointestinal Symptoms ◽  
Bacterial Overgrowth ◽  
Intestinal Bacteria ◽  
Dependent Manner ◽  
Modern Wheat ◽  
Chloroform Methanol

Non-celiac wheat sensitivity (NCWS) has been proposed to be an independent disease entity that is characterized by intestinal (e.g., abdominal pain, flatulence) and extra-intestinal symptoms (e.g., headache, fatigue), which are propagated following the ingestion of wheat products. Increased activity of amylase trypsin inhibitors (ATIs) in modern wheat is suggested to be major trigger of NCWS, while underlying mechanisms still remain elusive. Here, we aimed to generate and functionally characterize the most abundant ATI in modern wheat, chloroform/methanol-soluble protein 3 (CM3), in vitro and in Drosophila melanogaster. We demonstrate that CM3 displays α-glucosidase but not α-amylase or trypsin inhibitory activity in vitro. Moreover, fruit flies fed a sucrose-containing diet together with CM3 displayed significant overgrowth of intestinal bacteria in a sucrose-dependent manner while the consumption of α-amylase and α-glucosidase inhibitors was sufficient to limit bacterial quantities in the intestine. Notably, both CM3 and acarbose-treated flies showed a reduced lifespan. However, this effect was absent in amylase inhibitor (AI) treated flies. Together, given α-glucosidase is a crucial requirement for disaccharide digestion, we suggest that inhibition of α-glucosidase by CM3 enhances disaccharide load in the distal gastrointestinal tract, thereby promoting intestinal bacteria overgrowth. However, it remains speculative if this here described former unknown function of CM3 might contribute to the development of gastrointestinal symptoms observed in NCWS patients which are very similar to symptoms of patients with small intestinal bacterial overgrowth.

scholarly journals Comparison of Antiviral Activity of Gemcitabine with 2′-Fluoro-2′-Deoxycytidine and Combination Therapy with Remdesivir against SARS-CoV-2

2021 ◽  
Vol 22 (4) ◽  
pp. 1581
Author(s):  
Yejin Jang ◽  
Jin Soo Shin ◽  
Myoung Kyu Lee ◽  
Eunhye Jung ◽  
Timothy An ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Dependent Manner ◽  
Fluorescent Image ◽  
Lung Epithelial ◽  
Infected Cells ◽  
Polymerase Chain ◽  
Dose Dependent

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. The virus still spreads globally through human-to-human transmission. Nevertheless, there are no specific treatments clinically approved. This study aimed to compare antiviral activity of gemcitabine and its analogue 2′-fluoro-2′-deoxycytidine (2FdC) against SARS-CoV-2 as well as cytotoxicity in vitro. Fluorescent image-based antiviral assays revealed that gemcitabine was highly potent, with a 50% effective concentration (EC50) of 1.2 μM, more active than the well-known nucleoside monophosphate remdesivir (EC50 = 35.4 μM). In contrast, 2FdC was marginally active (EC50 = 175.2 μM). For all three compounds, the 50% cytotoxic concentration (CC50) values were over 300 μM toward Vero CCL-81 cells. Western blot and quantitative reverse-transcription polymerase chain reaction analyses verified that gemcitabine blocked viral protein expression in virus-infected cells, not only Vero CCL-81 cells but also Calu-3 human lung epithelial cells in a dose-dependent manner. It was found that gemcitabine has a synergistic effect when combined with remdesivir. This report suggests that the difluoro group of gemcitabine is critical for the antiviral activity and that its combination with other evaluated antiviral drugs, such as remdesivir, could be a desirable option to treat SARS-CoV-2 infection.

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