scholarly journals Methylglyoxal modification of TrkB promotes synaptic plasticity and enhances resilience to chronic stress

2018 ◽  
Author(s):  
Ziyin Wu ◽  
Yingxue Fu ◽  
Yinfeng Yang ◽  
Chao Huang ◽  
Chunli Zheng ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Synaptic Plasticity ◽  
Chronic Stress ◽  
Low Dose ◽  
Anxiety And Depression ◽  
Antidepressant Effects ◽  
Subsequent Activation

AbstractThe endogenous metabolite methylglyoxal (MGO) has recently emerged as a potential mediator of psychiatric disorders, such as anxiety and depression, but its precise mechanism of action remains poorly understood. Here, we find that MGO concentrations are decreased in the prefrontal cortex and hippocampus in rats subjected to chronic stress, and low-dose MGO treatment remarkedly enhances resilience to stress and alleviates depression-like symptoms. This effect is achieved by MGO’s promotion on the synaptic plasticity in prefrontal cortex and hippocampus. Both in vitro and in vivo experiments show that MGO provokes the dimerization and autophosphorylation of TrkB and the subsequent activation of downstream Akt/CREB signaling, which leads to a rapid and sustained expression of brain-derived neurotrophic factor (BDNF). We further demonstrate that MGO directly binds to the extracellular domain of TrkB, but not its intracellular domain. In addition, we also identify a natural product luteolin and its derivative lutD as potent inhibitors of Glyoxalase 1 and validate their antidepressant effects in chronic stress rat models. The antidepressant role of endogenous MGO provides a new basis for the understanding and therapeutic intervention design for stress-associated mental disorders.

scholarly journals Chronic Microcystin-LR Exposure Induces Hepatocarcinogenesis via Increased Gankyrin in Vitro and in Vivo

2018 ◽  
Vol 49 (4) ◽  
pp. 1420-1430 ◽  
Author(s):  
Lixiong He ◽  
Yujing Huang ◽  
Qiaonan Guo ◽  
Hui Zeng ◽  
Chuanfen Zheng ◽  
...  
Keyword(s):  
Low Dose ◽  
Soft Agar ◽  
Tumor Formation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
L02 Cells ◽  
Insight Into

Background/Aims: Our recent study indicated that the serum microcystin-LR (MC-LR) level is positively linked to the risk of human hepatocellular carcinoma (HCC). Gankyrin is over-expressed in cancers and mediates oncogenesis; however, whether MC-LR induces tumor formation and the role of gankyrin in this process is unclear. Methods: We induced malignant transformation of L02 liver cells via 35 passages with exposure to 1, 10, or 100 nM MC-LR. Wound healing, plate and soft agar colony counts, and nude mice tumor formation were used to evaluate the tumorigenic phenotype of MC-LR-treated cells. Silencing gankyrin was used to confirm its function. We established a 35-week MC-LR exposure rat model by twice weekly intraperitoneal injection with 10 μg/kg body weight. In addition, 96 HCC patients were tested for tumor tissue gankyrin expression and serum MC-LR levels. Results: Chronic low-dose MC-LR exposure increased proliferation, mobility, clone and tumor formation abilities of L02 cells as a result of gankyrin activation, while silencing gankyrin inhibited the carcinogenic phenotype of MC-LR-treated cells. MC-LR also induced neoplastic liver lesions in Sprague-Dawley rats due to up-regulated gankyrin. Furthermore, a trend of increased gankyrin was observed in humans exposed to MC-LR. Conclusion: These results suggest that MC-LR induces hepatocarcinogenesis in vitro and in vivo by increasing gankyrin levels, providing new insight into MC-LR carcinogenicity studies.

scholarly journals The Role of Phosphoinositide 3-Kinase/Akt Signaling in Low-Dose Mercury-Induced Mouse Pancreatic  -Cell Dysfunction In Vitro and In Vivo

Diabetes ◽  
2006 ◽  
Vol 55 (6) ◽  
pp. 1614-1624 ◽  
Author(s):  
Y. W. Chen ◽  
C. F. Huang ◽  
K. S. Tsai ◽  
R. S. Yang ◽  
C. C. Yen ◽  
...  
Keyword(s):  
Low Dose ◽  
Akt Signaling ◽  
Pancreatic Cell ◽  
Cell Dysfunction ◽  
Phosphoinositide 3 Kinase

scholarly journals Fluoxetine regulates eEF2 activity (phosphorylation) via HDAC1 inhibitory mechanism in an LPS-induced mouse model of depression

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Weifen Li ◽  
Tahir Ali ◽  
Chengyou Zheng ◽  
Zizhen Liu ◽  
Kaiwu He ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Antidepressant Effects ◽  
Immobility Time ◽  
In Vivo Analysis ◽  
Vitro Analysis ◽  
Nlrp3 Expression ◽  
In Vitro Analysis

Abstract Background Selective serotonin reuptaker inhibitors, including fluoxetine, are widely studied and prescribed antidepressants, while their exact molecular and cellular mechanism are yet to be defined. We investigated the involvement of HDAC1 and eEF2 in the antidepressant mechanisms of fluoxetine using a lipopolysaccharide (LPS)-induced depression-like behavior model. Methods For in vivo analysis, mice were treated with LPS (2 mg/kg BW), fluoxetine (20 mg/kg BW), HDAC1 activator (Exifone: 54 mg/kg BW) and NH125 (1 mg/kg BW). Depressive-like behaviors were confirmed via behavior tests including OFT, FST, SPT, and TST. Cytokines were measured by ELISA while Iba-1 and GFAP expression were determined by immunofluorescence. Further, the desired gene expression was measured by immunoblotting. For in vitro analysis, BV2 cell lines were cultured; treated with LPS, exifone, and fluoxetine; collected; and analyzed. Results Mice treated with LPS displayed depression-like behaviors, pronounced neuroinflammation, increased HDAC1 expression, and reduced eEF2 activity, as accompanied by altered synaptogenic factors including BDNF, SNAP25, and PSD95. Fluoxetine treatment exhibited antidepressant effects and ameliorated the molecular changes induced by LPS. Exifone, a selective HDAC1 activator, reversed the antidepressant and anti-inflammatory effects of fluoxetine both in vivo and in vitro, supporting a causing role of HDAC1 in neuroinflammation allied depression. Further molecular mechanisms underlying HDAC1 were explored with NH125, an eEF2K inhibitor, whose treatment reduced immobility time, altered pro-inflammatory cytokines, and NLRP3 expression. Moreover, NH125 treatment enhanced eEF2 and GSK3β activities, BDNF, SNAP25, and PSD95 expression, but had no effects on HDAC1. Conclusions Our results showed that the antidepressant effects of fluoxetine may involve HDAC1-eEF2 related neuroinflammation and synaptogenesis.

scholarly journals APPsα rescues impaired Ca2+ homeostasis in APP- and APLP2-deficient hippocampal neurons

2021 ◽  
Vol 118 (26) ◽  
pp. e2011506118
Author(s):  
Susann Ludewig ◽  
Ulrike Herrmann ◽  
Kristin Michaelsen-Preusse ◽  
Kristin Metzdorf ◽  
Jennifer Just ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Hippocampal Neurons ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Physiological Role ◽  
In Vivo Studies ◽  
Associated Proteins

Alterations in Ca2+ homeostasis have been reported in several in vitro and in vivo studies using mice expressing the Alzheimer’s disease–associated transgenes, presenilin and the amyloid precursor protein (APP). While intense research focused on amyloid-β–mediated functions on neuronal Ca2+ handling, the physiological role of APP and its close homolog APLP2 is still not fully clarified. We now elucidate a mechanism to show how APP and its homolog APLP2 control neuronal Ca2+ handling and identify especially the ectodomain APPsα as an essential regulator of Ca2+ homeostasis. Importantly, we demonstrate that the loss of APP and APLP2, but not APLP2 alone, impairs Ca2+ handling, the refill of the endoplasmic reticulum Ca2+ stores, and synaptic plasticity due to altered function and expression of the SERCA-ATPase and expression of store-operated Ca2+ channel–associated proteins Stim1 and Stim2. Long-term AAV-mediated expression of APPsα, but not acute application of the recombinant protein, restored physiological Ca2+ homeostasis and synaptic plasticity in APP/APLP2 cDKO cultures. Overall, our analysis reveals an essential role of the APP family and especially of the ectodomain APPsα in Ca2+ homeostasis, thereby highlighting its therapeutic potential.

scholarly journals Aloe vera gel homogenate shows anti-inflammatory activity through lysosomal membrane stabilization and downregulation of TNF-α and Cox-2 gene expressions in inflammatory arthritic animals

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Subhashis Paul ◽  
Debabrata Modak ◽  
Sutanuka Chattaraj ◽  
Deblina Nandi ◽  
Aditi Sarkar ◽  
...  
Keyword(s):  
Low Dose ◽  
Protein Denaturation ◽  
Aloe Vera ◽  
High Dose ◽  
Gene Expressions ◽  
Tnf Α ◽  
Cox 2

Abstract Background Aloe vera leaf gel has proven efficacious roles in the amelioration of several human diseases and illness-conditions. Specific purified gel-derived bio-constituents as well as the naturally harvested unprocessed A. vera gel have shown promise in modifying systemic inflammation. However, the synergistic role of natural herbal remedies, a mainstay of traditional Indian Ayurveda, has not been evaluated rigorously in this plant. In this study, the prevention of membrane lysis and protein denaturation in the presence of A. vera gel homogenate up to the concentration of 1000 μg/ml of gel has been assessed in vitro. Also, regulation of expression of inflammation-mediator genes (TNF-α and Cox-2) has been investigated in vivo in Freund’s complete adjuvant (FCA)-induced inflammatory arthritic Wistar albino rats in a 28-day long study following the daily oral supplementation of Aloe vera gel homogenate doses up to 0.40 and 0.80 g/kg body weight (low-dose and high-dose groups respectively). Results Our results indicated that A. vera gel homogenate inhibits hypotonicity-induced (74.89 ± 1.26%) and heat-induced (20.86 ± 0.77%) RBC membrane lyses respectively at a concentration of 1000 μg/ml, compared to indomethacin standard (80.52 ± 0.65% and 43.98 ± 1.52% respectively at 200 μg/ml concentration). The similar concentration of gel also showed 39.35 ± 4.25% inhibition of protein denaturation compared to standard diclofenac sodium (46.74 ± 1.84% at 100 μg/ml concentration) in vitro. When assessed in vivo, TNF-α expression was found to be decreased by 35.88% and 38.52%, and Cox-2 expression was found to be decreased by 31.65% and 34.96%, in low-dose and high-dose groups respectively, when compared to the arthritic controls. Conclusions Our findings justify the role of unprocessed A. vera gel homogenate in preventing tissue damage and in the downregulation of TNF-α and Cox-2 gene expressions for the immune-modulation of inflammatory arthritis condition.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Anti-obesity role of Aster glehni extract: in vivo and in vitro effects

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
HM Lee ◽  
TG Ahn ◽  
CW Kim ◽  
HJ An
Keyword(s):  
In Vitro Effects
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