Formaldehyde induces ferritinophagy to damage hippocampal neuronal cells

2021 ◽  
pp. 074823372110485
Author(s):  
Yu Hu ◽  
Lei Wu ◽  
San-Qiao Yang ◽  
Hai-Jun Wei ◽  
Chun-Yan Wang ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Autophagic Flux ◽  
Potential Mechanism ◽  
Sprague Dawley ◽  
Ht22 Cells ◽  
New Thought ◽  
Nuclear Receptor Coactivator ◽  
Ferritin Heavy Chain ◽  
Toxic Damage ◽  
Insight Into

Formaldehyde (FA) causes neurotoxicity and contributes to the occurrence of neurodegenerative diseases. However, the mechanism of FA-induced neurotoxicity has not been fully elucidated. Ferritinophagy, an autophagy process of ferritin mediated by the nuclear receptor coactivator 4 (NCOA4), is a potential mechanism of neurotoxicity. In this study, we explored whether ferritinophagy is associated with the neurotoxicity of FA. Our results showed that FA (50, 100, 200 μM; 24 h) exposure upregulated ferritinophagy in the mouse hippocampal neuronal HT22 cells, which was evidenced by the upregulated autophagic flux, the increased colocalizations of NCOA4 with ferritin heavy chain (FTH1) and NCOA4 with microtubule-associated protein 1 light chain-3B (LC3B), the augmented expression of NCOA4, and the reduced content of FTH1. We also found that FA (0.1, 1, and 10 μmol, i.c.v., 7d) administration boosted ferritinophagy in the hippocampus of Sprague-Dawley (SD) rats, which was demonstrated by the accumulated autophagosomes, the increased expressions of LC3II/I and NCOA4, and the decreased contents of p62 and FTH1 in the hippocampus. Further, we confirmed that inhibition of ferritinophagy by silencing the expression of NCOA4 decreased FA-induced toxic damage in HT22 cells. These results indicated that FA induces neurotoxicity by promoting ferritinophagy. Our findings suggest a potential mechanism insight into the FA-induced neurotoxicity, which in turn provides a new thought for the treatment of FA-related neurodegenerative diseases.

scholarly journals Transglutaminases Are Active in Perivascular Adipose Tissue

2021 ◽  
Vol 22 (5) ◽  
pp. 2649
Author(s):  
Alexis N. Orr ◽  
Janice M. Thompson ◽  
Janae M. Lyttle ◽  
Stephanie W. Watts
Keyword(s):  
Adipose Tissue ◽  
Vascular Remodeling ◽  
Coagulation Factor ◽  
Sprague Dawley ◽  
Rt Pcr ◽  
Ideal Model ◽  
Perivascular Adipose Tissue ◽  
Tissue Sections ◽  
Insight Into ◽  
Immunohistochemical Analyses

Transglutaminases (TGs) are crosslinking enzymes best known for their vascular remodeling in hypertension. They require calcium to form an isopeptide bond, connecting a glutamine to a protein bound lysine residue or a free amine donor such as norepinephrine (NE) or serotonin (5-HT). We discovered that perivascular adipose tissue (PVAT) contains significant amounts of these amines, making PVAT an ideal model to test interactions of amines and TGs. We hypothesized that transglutaminases are active in PVAT. Real time RT-PCR determined that Sprague Dawley rat aortic, superior mesenteric artery (SMA), and mesenteric resistance vessel (MR) PVATs express TG2 and blood coagulation Factor-XIII (FXIII) mRNA. Consistent with this, immunohistochemical analyses support that these PVATs all express TG2 and FXIII protein. The activity of TG2 and FXIII was investigated in tissue sections using substrate peptides that label active TGs when in a catalyzing calcium solution. Both TG2 and FXIII were active in rat aortic PVAT, SMAPVAT, and MRPVAT. Western blot analysis determined that the known TG inhibitor cystamine reduced incorporation of experimentally added amine donor 5-(biotinamido)pentylamine (BAP) into MRPVAT. Finally, experimentally added NE competitively inhibited incorporation of BAP into MRPVAT adipocytes. Further studies to determine the identity of amidated proteins will give insight into how these enzymes contribute to functions of PVAT and, ultimately, blood pressure.

Lactobacillus plantarum DR7 improved brain health in aging rats via the serotonin, inflammatory and apoptosis pathways

2020 ◽  
Vol 11 (8) ◽  
pp. 753-766
Author(s):  
A.I. Zaydi ◽  
L.-C. Lew ◽  
Y.-Y. Hor ◽  
M.H. Jaafar ◽  
L.-O. Chuah ◽  
...  
Keyword(s):  
Lactobacillus Plantarum ◽  
Cognitive Functions ◽  
High Fat Diet ◽  
Normal Diet ◽  
Sprague Dawley ◽  
Brain Health ◽  
High Fat ◽  
Dietary Strategy ◽  
Apoptosis Pathways ◽  
Insight Into

Aging processes affect the brain in many ways, ranging from cellular to functional levels which lead to cognitive decline and increased oxidative stress. The aim of this study was to investigate the potentials of Lactobacillus plantarum DR7 on brain health including cognitive and memory functions during aging and the impacts of high fat diet during a 12-week period. Male Sprague-Dawley rats were separated into six groups: (1) young animals on normal diet (ND, (2) young animals on a high fat diet (HFD), (3) aged animals on ND, (4) aged animals on HFD, (5) aged animals on HFD and L. plantarum DR7 (109 cfu/day) and (6) aged animals receiving HFD and lovastatin. To induce ageing, all rats in group 3 to 6 were injected sub-cutaneously at 600 mg/kg/day of D-galactose daily. The administration of DR7 has reduced anxiety accompanied by enhanced memory during behavioural assessments in aged-HFD rats (P<0.05). Hippocampal concentration of all three pro-inflammatory cytokines were increased during aging but reduced upon administration of both statin and DR7. Expressions of hippocampal neurotransmitters and apoptosis genes showed reduced expressions of indoleamine dioxygenase and P53 accompanied by increased expression of TPH1 in aged- HFD rats administered with DR7, indicating potential effects of DR7 along the pathways of serotonin and oxidative senescence. This study provided an insight into potentials of L. plantarum DR7 as a prospective dietary strategy to improve cognitive functions during aging. This study provided an insight into potentials of L. plantarum DR7 as a prospective dietary strategy to improve cognitive functions during aging.

scholarly journals Simvastatin Improves the Jaw Bone Microstructural Defect Induced by High Cholesterol Diet in Rats by Regulating Autophagic Flux

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Jianhua Zhou ◽  
Xiaoli Gao ◽  
Shengyun Huang ◽  
Li Ma ◽  
Yanjun Cui ◽  
...  
Keyword(s):  
High Cholesterol Diet ◽  
Autophagic Flux ◽  
Cholesterol Diet ◽  
Sprague Dawley ◽  
High Cholesterol ◽  
Trabecular Thickness ◽  
Simvastatin Treatment ◽  
Jaw Bone ◽  
Microstructural Defect ◽  
Sprague Dawley Rats

Objective. The objective of this study is to evaluate the effect of simvastatin on the jaw bone microstructural defect and autophagy in rats with high cholesterol diet (HCD). Methods. Male Sprague-Dawley rats were fed a standard rodent chow (NC group) or a high cholesterol diet for 32 weeks and the HCD-fed rats were treated with vehicle (HC group) or simvastatin (5 mg/kg orally daily for 8 weeks, HC + SIM group, and n=10/group). The static histomorphometric changes in the jaw bone tissues in individual rats were evaluated. The relative levels of OPG, RANKL, NF-κB, LC3, and p62 in the jaw bone tissues were determined by quantitative RT-PCR and/or immunohistochemistry. Results. Compared with the NC group, the HC groups had lower trabecular bone volume, trabecular thickness and trabecular number, and increased ratios of RANKL/OPG in the jaw bone, accompanied by enhanced NF-κB activation and autophagy. Simvastatin treatment inhabited these changes, including the decreased levels of serum proinflammatory cytokines and increased autophagy. Conclusion. Simvastatin treatment could inhibit the hyperlipidemia-induced jaw bone microstructural defect in rats by increasing autophagic flux.

Microvascular Dysfunction in Obesity: A Potential Mechanism in the Pathogenesis of Obesity-Associated Insulin Resistance and Hypertension

Physiology ◽  
2007 ◽  
Vol 22 (4) ◽  
pp. 252-260 ◽  
Author(s):  
Amy M. Jonk ◽  
Alfons J. H. M. Houben ◽  
Renate T. de Jongh ◽  
Erik H. Serné ◽  
Nicoloaas C. Schaper ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Risk Factor ◽  
Microvascular Dysfunction ◽  
Important Risk Factor ◽  
Potential Mechanism ◽  
The Metabolic Syndrome ◽  
New Treatments ◽  
Insight Into

Obesity is an important risk factor for insulin resistance and hypertension and plays a central role in the metabolic syndrome. Insight into the pathophysiology of this syndrome may lead to new treatments. This paper has reviewed the evidence for an important role for the microcirculation as a possible link between obesity, insulin resistance and hypertension.

scholarly journals CaMKII Potentiates Store-Operated Ca2+ Entry Through Enhancing STIM1 Aggregation and Interaction with Orai1

2018 ◽  
Vol 46 (3) ◽  
pp. 1042-1054 ◽  
Author(s):  
Shu Li ◽  
Jingyi Xue ◽  
Zhipeng Sun ◽  
Tiantian Liu ◽  
Lane Zhang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Confocal Microscopy ◽  
Specific Inhibitor ◽  
Potential Mechanism ◽  
Additional Insight ◽  
Dependent Protein Kinase ◽  
Store Depletion ◽  
Selective Channel ◽  
Dependent Protein ◽  
Insight Into

Background/Aims: Upon Ca2+ store depletion, stromal interaction molecule 1 (STIM1) oligomerizes, redistributes near plasmalemma to interact with Ca2+ selective channel-forming subunit (Orai1) and initiates store-operated Ca2+ entry (SOCE). Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a regulator of SOCE, but how CaMKII regulates SOCE remains obscure. Methods: Using Fura2, confocal microscopy, co-immunoprecipitation, specific blocker and overexpression/knockdown approaches, we evaluated STIM1 aggregation and its interaction with Orai1, and SOCE upon Ca2+ store depletion in thapsigargin (TG) treated HEK293 and HeLa cells. Results: Overexpression of CaMKIIδ enhanced TG-induced STIM1 co-localization and interaction with Orai1 as well as SOCE. In contrast, CaMKIIδ knockdown and a specific inhibitor of CaMKII suppressed them. In addition, overexpression or knockdown of CaMKIIδ in TG treated cells exhibited increased or reduced STIM1 clustering and plasmalemma redistribution, respectively. Conclusion: CaMKII up-regulates SOCE by increasing STIM1 aggregation and interaction with Orai1. This study provides an additional insight into SOCE regulation and a potential mechanism for CaMKII involvement in some pathological situations through crosstalk with SOCE.

scholarly journals Amitriptyline interferes with autophagy-mediated clearance of protein aggregates via inhibiting autophagosome maturation in neuronal cells

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Yoonjung Kwon ◽  
Yeojin Bang ◽  
Soung-Hee Moon ◽  
Aeri Kim ◽  
Hyun Jin Choi
Keyword(s):  
Neurodegenerative Diseases ◽  
Depressive Disorders ◽  
Neuronal Cells ◽  
Protein Aggregates ◽  
Underlying Mechanism ◽  
Tricyclic Antidepressant ◽  
Autophagic Flux ◽  
Autophagosome Maturation

Abstract Amitriptyline is a tricyclic antidepressant commonly prescribed for major depressive disorders, as well as depressive symptoms associated with various neurological disorders. A possible correlation between the use of tricyclic antidepressants and the occurrence of Parkinson’s disease has been reported, but its underlying mechanism remains unknown. The accumulation of misfolded protein aggregates has been suggested to cause cellular toxicity and has been implicated in the common pathogenesis of neurodegenerative diseases. Here, we examined the effect of amitriptyline on protein clearance and its relevant mechanisms in neuronal cells. Amitriptyline exacerbated the accumulation of abnormal aggregates in both in vitro neuronal cells and in vivo mice brain by interfering with the (1) formation of aggresome-like aggregates and (2) autophagy-mediated clearance of aggregates. Amitriptyline upregulated LC3B-II, but LC3B-II levels did not increase further in the presence of NH4Cl, which suggests that amitriptyline inhibited autophagic flux rather than autophagy induction. Amitriptyline interfered with the fusion of autophagosome and lysosome through the activation of PI3K/Akt/mTOR pathway and Beclin 1 acetylation, and regulated lysosome positioning by increasing the interaction between proteins Arl8, SKIP, and kinesin. To the best of our knowledge, we are the first to demonstrate that amitriptyline interferes with autophagic flux by regulating the autophagosome maturation during autophagy in neuronal cells. The present study could provide neurobiological clue for the possible correlation between the amitriptyline use and the risk of developing neurodegenerative diseases.

scholarly journals Peroxiredoxin 5 Inhibits Glutamate-Induced Neuronal Cell Death through the Regulation of Calcineurin-Dependent Mitochondrial Dynamics in HT22 Cells

2019 ◽  
Vol 39 (20) ◽  
Author(s):  
Mi Hye Kim ◽  
Hong Jun Lee ◽  
Sang-Rae Lee ◽  
Hyun-Shik Lee ◽  
Jae-Won Huh ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Glutamate Toxicity ◽  
Ht22 Cells ◽  
Peroxidase Enzyme ◽  
The Central Nervous System

ABSTRACT Glutamate is an essential neurotransmitter in the central nervous system (CNS). However, high glutamate concentrations can lead to neurodegenerative diseases. A hallmark of glutamate toxicity is high levels of reactive oxygen species (ROS), which can trigger Ca2+ influx and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Peroxiredoxin 5 (Prx5) is a well-known cysteine-dependent peroxidase enzyme. However, the precise effects of Prx5 on glutamate toxicity are still unclear. In this study, we investigated the role of Prx5 in glutamate-induced neuronal cell death. We found that glutamate treatment induces endogenous Prx5 expression and Ca2+/calcineurin-dependent dephosphorylation of Drp1, resulting in mitochondrial fission and neuronal cell death. Our results indicate that Prx5 inhibits glutamate-induced mitochondrial fission through the regulation of Ca2+/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca2+/calcineurin-dependent mitochondrial dynamics are deeply associated with glutamate-induced neurotoxicity. Consequently, Prx5 may be used as a potential agent for developing therapies against glutamate-induced neurotoxicity and neurodegenerative diseases where it plays a key role.

scholarly journals The Role of Astragaloside IV against Cerebral Ischemia/Reperfusion Injury: Suppression of Apoptosis via Promotion of P62-LC3-Autophagy

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1838 ◽  
Author(s):  
Yi Zhang ◽  
Ying Zhang ◽  
Xiao-fei Jin ◽  
Xiao-hong Zhou ◽  
Xian-hui Dong ◽  
...  
Keyword(s):  
Cell Viability ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Sprague Dawley ◽  
Astragaloside Iv ◽  
Ht22 Cells ◽  
Sd Rats ◽  
Neurological Score

Background: Ischemia/reperfusion (I/R) caused by ischemic stroke treatments leads to brain injury, and autophagy plays a role in the pathology. Astragaloside IV is a potential neuroprotectant, but its underlying mechanism on cerebral I/R injury needs to be explored. The objective of this study is to investigate the neuroprotective mechanism of Astragaloside IV against cerebral I/R injury. Methods: Middle cerebral artery occlusion method (MCAO) and oxygen and glucose deprivation/reoxygenation (OGD/R) method were used to simulate cerebral I/R injury in Sprague-Dawley (SD) rats and HT22 cells, respectively. The neurological score, 2,3,5-Triphe-nyltetrazolium chloride (TTC) staining, and transmission electron microscope were used to detect cerebral damage in SD rats. Cell viability and cytotoxicity assay were tested in vitro. Fluorescent staining and flow cytometry were applied to detect the level of apoptosis. Western blotting was conducted to examine the expression of proteins associated with autophagy. Results: This study found that Astragaloside IV could decrease the neurological score, reduce the infarct volume in the brain, and alleviate cerebral I/R injury in MCAO rats. Astragaloside IV promoted cell viability and balanced Bcl-2 and Bax expression in vitro, reduced the rate of apoptosis, decreased the expression of P62, and increased the expression of LC3II/LC3I in HT22 cells after OGD/R. Conclusions: These data suggested that Astragaloside IV plays a neuroprotective role by down-regulating apoptosis by promoting the degree of autophagy.

Mechanisms of hypertension in transgenic rats expressing the mouse Ren-2 gene

1994 ◽  
Vol 266 (4) ◽  
pp. R1273-R1279 ◽  
Author(s):  
A. Moriguchi ◽  
K. B. Brosnihan ◽  
H. Kumagai ◽  
D. Ganten ◽  
C. M. Ferrario
Keyword(s):  
Mature Female ◽  
Response To Therapy ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Transgenic Rats ◽  
Contrast Administration ◽  
Systemic Injection ◽  
Endothelin 1 ◽  
Sd Rats ◽  
Insight Into

Transgenic (TG) rats carrying the mouse Ren-2 gene (Ren-2d)27 are a newly established monogenetic model in hypertension research. To gain an insight into the mechanisms of this form of hypertension we determined the effects of a 13-day therapy with losartan (10 mg/kg) or lisinopril (20 mg/kg) on the blood pressure (BP) and plasma levels of angiotensin (ANG) peptides of mature female TG hypertensive and Sprague-Dawley (SD) rats. The contribution of endothelium-derived nitric oxide (NO) to the maintenance of their hypertension and the response to therapy was evaluated by systemic injection of either NG-monomethyl-L-arginine (L-NMMA) or endothelin-1. Hypertension in TG rats was associated with decreased plasma ANG I, no differences in plasma ANG II, and plasma ANG-(1-7) near the detectable level. Lisinopril lowered BP more than losartan in both TG hypertensive and normotensive controls. In both strains, the chronic fall in BP produced by lisinopril was accompanied by significant increases in plasma ANG I and ANG-(1-7), while losartan augmented plasma ANG I and ANG II in both strains and plasma ANG-(1-7) in TG rats. Inhibition of NO synthase reversed the fall in BP produced by either lisinopril or losartan in SD controls. In contrast, administration of L-NMMA to TG rats given the same therapy did not. The transient endothelium-mediated relaxing phase of the depressor response to systemic injections of endothelin-1 was attenuated by losartan and lisinopril in TG rats. These studies indicate that hypertension in female TG rats is mediated by the RAS.(ABSTRACT TRUNCATED AT 250 WORDS)

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