scholarly journals STAT3 inhibitor mitigates cerebral amyloid angiopathy and parenchymal amyloid plaques while improving cognitive functions and brain networks

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jogender Mehla ◽  
Itender Singh ◽  
Deepti Diwan ◽  
James W. Nelson ◽  
Molly Lawrence ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Human Brain ◽  
Cognitive Functions ◽  
Specific Inhibitor ◽  
Amyloid Angiopathy ◽  
In Vitro Experiments ◽  
Aβ Peptides ◽  
Cerebral Amyloid

AbstractPrevious reports indicate a potential role for signal transducer and activator of transcription 3 (STAT3) in amyloid-β (Aβ) processing and neuritic plaque pathogenesis. In the present study, the impact of STAT3 inhibition on cognition, cerebrovascular function, amyloid pathology, oxidative stress, and neuroinflammation was studied using in vitro and in vivo models of Alzheimer’s disease (AD)-related pathology. For in vitro experiments, human brain vascular smooth muscle cells (HBVSMC) and human brain microvascular endothelial cells (HBMEC) were used, and these cultured cells were exposed to Aβ peptides followed by measurement of activated forms of STAT3 expression and reactive oxygen species (ROS) generation. Further, 6 months old 5XFAD/APOE4 (5XE4) mice and age-matched negative littermates were used for in vivo experiments. These mice were treated with STAT3 specific inhibitor, LLL-12 for 2 months followed by neurobehavioral and histopathological assessment. In vitro experiments showed exposure of cerebrovascular cells to Aβ peptides upregulated activated forms of STAT3 and produced STAT3-mediated vascular oxidative stress. 5XE4 mice treated with the STAT3-specific inhibitor (LLL-12) improved cognitive functions and functional connectivity and augmented cerebral blood flow. These functional improvements were associated with a reduction in neuritic plaques, cerebral amyloid angiopathy (CAA), oxidative stress, and neuroinflammation. Reduction in amyloid precursor protein (APP) processing and attenuation of oxidative modification of lipoprotein receptor related protein-1 (LRP-1) were identified as potential underlying mechanisms. These results demonstrate the broad impact of STAT3 on cognitive functions, parenchymal and vascular amyloid pathology and highlight the therapeutic potential of STAT3 specific inhibition for treatment of AD and CAA.

scholarly journals (Pro)renin receptor involves in myocardial fibrosis and oxidative stress in diabetic cardiomyopathy via the PRR–YAP pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shiran Yu ◽  
Xuefei Dong ◽  
Min Yang ◽  
Qingtao Yu ◽  
Jie Xiong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Fibrosis ◽  
Cardiac Fibroblasts ◽  
Animal Experiments ◽  
Specific Inhibitor ◽  
Neonatal Rat ◽  
Rnai Silencing ◽  
The Impact

Abstract(Pro)renin receptor (PRR) and Yes-associated protein (YAP) play an important role in cardiovascular diseases. However, the role of PRR–YAP pathway in the pathogenesis of DCM is also not clear. We hypothesized that PRR–YAP pathway may promote pathological injuries in DCM by triggering redox. Wistar rats and neonatal rat cardiac fibroblasts were respectively used in vivo and in vitro studies. In order to observe the effects of PRR mediated YAP pathway on the pathogenesis of DCM, animal experiments were divided into 3 parts, including the evaluation the effects of PRR overexpression, PRR RNAi silencing and YAP RNAi silencing. Recombinant-adenoviruses-carried-PRR-gene (Ad-PRR), Ad-PRR-shRNA and lentivirus-carried-YAP-shRNA were constructed and the effects of PRR mediated YAP on the pathogenesis of DCM were evaluated. YAP specific inhibitor Verteporfin was also administrated in cardiac fibroblasts to explore the impact of PRR–YAP pathway on oxidative stress and myocardial fibrosis. The results displayed that PRR overexpression could enhance YAP expression but PRR RNAi silencing down-regulated its expression. Moreover, PRR overexpression could exacerbate oxidative stress and myocardial fibrosis in DCM, and these pathological changes could be rescued by YAP blockade. We concluded that PRR–YAP pathway plays a key role in the pathogenesis of DCM.

scholarly journals Berberine Ameliorates Doxorubicin-Induced Cardiotoxicity via a SIRT1/p66Shc-Mediated Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Yan-Zhao Wu ◽  
Lan Zhang ◽  
Zi-Xiao Wu ◽  
Tong-tong Shan ◽  
Chen Xiong
Keyword(s):  
Oxidative Stress ◽  
Specific Inhibitor ◽  
Adaptor Protein ◽  
Cardiomyocyte Apoptosis ◽  
Sirtuin 1 ◽  
H9c2 Cell ◽  
H9c2 Cells ◽  
Sirt1 Expression

Doxorubicin- (DOX-) induced cardiotoxicity is associated with oxidative stress and cardiomyocyte apoptosis. The adaptor protein p66Shc regulates the cellular redox status and determines cell susceptibility to apoptosis. This study is aimed at investigating the involvement of sirtuin 1- (SIRT1-) mediated p66Shc inhibition in DOX-induced redox signalling and exploring the possible protective mechanisms of berberine (Ber) against DOX-triggered cardiac injury in rats and a cultured H9c2 cell line. Our results showed that the Ber pretreatment markedly increased CAT, SOD, and GSH-PX activities, decreased the levels of MDA, and improved the electrocardiogram and histopathological changes in the myocardium in DOX-treated rats (in vivo). Furthermore, Ber significantly ameliorated the DOX-induced oxidative insult and mitochondrial damage by adjusting the levels of intracellular ROS, ΔΨm, and [Ca2+]m in H9c2 cells (in vitro). Importantly, the Ber pretreatment increased SIRT1 expression following DOX exposure but downregulated p66Shc. Consistent with the results demonstrating the SIRT1-mediated inhibition of p66Shc expression, the Ber pretreatment inhibited DOX-triggered cardiomyocyte apoptosis and mitochondrial dysfunction. After exposing H9c2 cells to DOX, the increased SIRT1 expression induced by Ber was abrogated by a SIRT1-specific inhibitor (EX527) or the use of siRNA against SIRT1. Accordingly, SIRT1 inhibition significantly abrogated the suppression of p66Shc expression and protection of Ber against DOX-induced oxidative stress and apoptosis. These results suggest that Ber protects the heart from DOX injury through SIRT1-mediated p66Shc suppression, offering a novel mechanism responsible for the protection of Ber against DOX-induced cardiomyopathy.

scholarly journals Hispidulin Attenuates Cardiac Hypertrophy by Improving Mitochondrial Dysfunction

2020 ◽  
Vol 7 ◽  
Author(s):  
Yan Wang ◽  
Zengshuo Xie ◽  
Nan Jiang ◽  
Zexuan Wu ◽  
Ruicong Xue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Mitochondrial Function ◽  
Specific Inhibitor ◽  
Cardiomyocyte Hypertrophy ◽  
Mitochondrial Morphology ◽  
Protective Effects

Cardiac hypertrophy is a pathophysiological response to harmful stimuli. The continued presence of cardiac hypertrophy will ultimately develop into heart failure. The mitochondrion is the primary organelle of energy production, and its dysfunction plays a crucial role in the progressive development of heart failure from cardiac hypertrophy. Hispidulin, a natural flavonoid, has been substantiated to improve energy metabolism and inhibit oxidative stress. However, how hispidulin regulates cardiac hypertrophy and its underlying mechanism remains unknown. We found that hispidulin significantly inhibited pressure overload-induced cardiac hypertrophy and improved cardiac function in vivo and blocked phenylephrine (PE)-induced cardiomyocyte hypertrophy in vitro. We further proved that hispidulin remarkably improved mitochondrial function, manifested by increased electron transport chain (ETC) subunits expression, elevated ATP production, increased oxygen consumption rates (OCR), normalized mitochondrial morphology, and reduced oxidative stress. Furthermore, we discovered that Sirt1, a well-recognized regulator of mitochondrial function, might be a target of hispidulin, as evidenced by its upregulation after hispidulin treatment. Cotreatment with EX527 (a Sirt1-specific inhibitor) and hispidulin nearly completely abolished the antihypertrophic and protective effects of hispidulin on mitochondrial function, providing further evidence that Sirt1 could be the pivotal downstream effector of hispidulin in regulating cardiac hypertrophy.

P1-460: Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice

2008 ◽  
Vol 4 ◽  
pp. T354-T355
Author(s):  
Monica Garcia-Alloza ◽  
Claudia Prada ◽  
Elissa M. Robbins ◽  
Rebecca A. Betensky ◽  
Steven M. Greenberg ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transgenic Mice ◽  
Matrix Metalloproteinase ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

scholarly journals Glycine, the smallest amino acid, confers neuroprotection against d-galactose-induced neurodegeneration and memory impairment by regulating c-Jun N-terminal kinase in the mouse brain

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Rahat Ullah ◽  
Myeung Hoon Jo ◽  
Muhammad Riaz ◽  
Sayed Ibrar Alam ◽  
Kamran Saeed ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amino Acid ◽  
Protein Expression ◽  
Mouse Brain ◽  
Memory Impairment ◽  
Specific Inhibitor ◽  
Synaptic Dysfunction ◽  
Ht22 Cells

Abstract Background Glycine is the smallest nonessential amino acid and has previously unrecognized neurotherapeutic effects. In this study, we examined the mechanism underlying the neuroprotective effect of glycine (Gly) against neuroapoptosis, neuroinflammation, synaptic dysfunction, and memory impairment resulting from d-galactose-induced elevation of reactive oxygen species (ROS) during the onset of neurodegeneration in the brains of C57BL/6N mice. Methods After in vivo administration of d-galactose (d-gal; 100 mg/kg/day; intraperitoneally (i/p); for 60 days) alone or in combination with glycine (1 g/kg/day in saline solution; subcutaneously; for 60 days), all of the mice were sacrificed for further biochemical (ROS/lipid peroxidation (LPO) assay, Western blotting, and immunohistochemistry) after behavioral analyses. An in vitro study, in which mouse hippocampal neuronal HT22 cells were treated with or without a JNK-specific inhibitor (SP600125), and molecular docking analysis were used to confirm the underlying molecular mechanism and explore the related signaling pathway prior to molecular and histological analyses. Results Our findings indicated that glycine (an amino acid) inhibited d-gal-induced oxidative stress and significantly upregulated the expression and immunoreactivity of antioxidant proteins (Nrf2 and HO-1) that had been suppressed in the mouse brain. Both the in vitro and in vivo results indicated that d-gal induced oxidative stress-mediated neurodegeneration primarily by upregulating phospho-c-Jun N-terminal kinase (p-JNK) levels. However, d-gal + Gly cotreatment reversed the neurotoxic effects of d-gal by downregulating p-JNK levels, which had been elevated by d-gal. We also found that Gly reversed d-gal-induced neuroapoptosis by significantly reducing the protein expression levels of proapoptotic markers (Bax, cytochrome c, cleaved caspase-3, and cleaved PARP-1) and increasing the protein expression level of the antiapoptotic protein Bcl-2. Both the molecular docking approach and the in vitro study (in which the neuronal HT22 cells were treated with or without a p-JNK-specific inhibitor (SP600125)) further verified our in vivo findings that Gly bound to the p-JNK protein and inhibited its function and the JNK-mediated apoptotic pathway in the mouse brain and HT22 cells. Moreover, the addition of Gly alleviated d-gal-mediated neuroinflammation by inhibiting gliosis via attenuation of astrocytosis (GFAP) and microgliosis (Iba-1) in addition to reducing the protein expression levels of various inflammatory cytokines (IL-1βeta and TNFα). Finally, the addition of Gly reversed d-gal-induced synaptic dysfunction by upregulating the expression of memory-related presynaptic protein markers (synaptophysin (SYP), syntaxin (Syn), and a postsynaptic density protein (PSD95)) and markedly improved behavioral measures of cognitive deficits in d-gal-treated mice. Conclusion Our findings demonstrate that Gly-mediated deactivation of the JNK signaling pathway underlies the neuroprotective effect of Gly, which reverses d-gal-induced oxidative stress, apoptotic neurodegeneration, neuroinflammation, synaptic dysfunction, and memory impairment. Therefore, we suggest that Gly (an amino acid) is a safe and promising neurotherapeutic candidate that might be used for age-related neurodegenerative diseases.

scholarly journals Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites

2021 ◽  
Author(s):  
Jacqueline M. Tokarew ◽  
Daniel N. El-Kodsi ◽  
Nathalie A. Lengacher ◽  
Travis K. Fehr ◽  
Angela P. Nguyen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Human Brain ◽  
Posttranslational Modifications ◽  
Redox Activity ◽  
Wild Type ◽  
Dopamine Metabolites ◽  
Adult Human ◽  
Melanin Formation

AbstractThe mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson’s-linked neurodegeneration.

scholarly journals Vitamin B12 Attenuates Acute Pancreatitis by Suppressing Oxidative Stress and Improving Mitochondria Dysfunction via CBS/SIRT1 Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Jiyan Yuan ◽  
Zeliang Wei ◽  
Guang Xin ◽  
Xubao Liu ◽  
Zongguang Zhou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Pancreatitis ◽  
Vitamin B12 ◽  
Specific Inhibitor ◽  
Inflammatory Disorder ◽  
Pancreatic Damage ◽  
Acinar Cell Necrosis ◽  
Substantial Morbidity

Acute pancreatitis is an inflammatory disorder of the pancreas associated with substantial morbidity and mortality, which is characterized by a rapid depletion of glutathione (GSH). Cysthionine-β-synthase (CBS) is a key coenzyme in GSH synthesis, and its deficiency is related to a variety of clinical diseases. However, whether CBS is involved in the pathogenesis of acute pancreatitis remains unclear. First, we found that CBS was downregulated in both in vivo and in vitro AP models. The pancreatic damage and acinar cell necrosis related to CBS deficiency were significantly improved by VB 12, which stimulated clearance of reactive oxygen species (ROS) by conserving GSH. Furthermore, EX-527 (a specific inhibitor of SIRT1) exposure counteracted the protective effect of VB 12 by promoting oxidative stress and aggravating mitochondrial damage without influencing CBS, indicating that vitamin B12 regulates SIRT1 to improve pancreatical damage by activating CBS. In conclusion, we found that VB 12 protected acute pancreatitis associated with oxidative stress via CBS/SIRT1 pathway.

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