scholarly journals HDAC inhibition protects degenerating cone photoreceptors in vivo

2016 ◽  
Author(s):  
Dragana Trifunović ◽  
Blanca Arango-Gonzalez ◽  
Antonella Comitato ◽  
Melanie Barth ◽  
Ayse Sahaboglu ◽  
...  
Keyword(s):  
Cell Death ◽  
Trichostatin A ◽  
Treatment Options ◽  
Hdac Inhibition ◽  
Neuroprotective Effects ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
New Treatment ◽  
Future Therapy

AbstractRetinal diseases caused by cone photoreceptor cell death are devastating as the patients are experiencing loss of accurate and color vision. Understanding the mechanisms of cone cell death and the identification of key players therein could provide new treatment options. We studied the neuroprotective effects of a histone deacetylase inhibitor, Trichostatin A (TSA), in a mouse model of inherited, primary cone degeneration (cpfl1). We show that HDAC inhibition protects cones in vitro, in retinal explant cultures. More importantly, in vivo a single TSA injection increased cone survival for up to 10 days post-injection. In addition, the abnormal, incomplete cone migration pattern in the cpfl1 retina was significantly improved by HDAC inhibition. These findings suggest a crucial role for HDAC activity in primary cone degeneration and highlight a new avenue for future therapy developments for cone dystrophies and diseases associated with impaired cone migration.

scholarly journals Humanin is an endogenous activator of chaperone-mediated autophagy

2017 ◽  
Vol 217 (2) ◽  
pp. 635-647 ◽  
Author(s):  
Zhenwei Gong ◽  
Inmaculada Tasset ◽  
Antonio Diaz ◽  
Jaime Anguiano ◽  
Emir Tas ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Death ◽  
Heat Shock Protein 90 ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Selective Degradation ◽  
Cytosolic Side ◽  
Chaperone Mediated Autophagy

Chaperone-mediated autophagy (CMA) serves as quality control during stress conditions through selective degradation of cytosolic proteins in lysosomes. Humanin (HN) is a mitochondria-associated peptide that offers cytoprotective, cardioprotective, and neuroprotective effects in vivo and in vitro. In this study, we demonstrate that HN directly activates CMA by increasing substrate binding and translocation into lysosomes. The potent HN analogue HNG protects from stressor-induced cell death in fibroblasts, cardiomyoblasts, neuronal cells, and primary cardiomyocytes. The protective effects are lost in CMA-deficient cells, suggesting that they are mediated through the activation of CMA. We identified that a fraction of endogenous HN is present at the cytosolic side of the lysosomal membrane, where it interacts with heat shock protein 90 (HSP90) and stabilizes binding of this chaperone to CMA substrates as they bind to the membrane. Inhibition of HSP90 blocks the effect of HNG on substrate translocation and abolishes the cytoprotective effects. Our study provides a novel mechanism by which HN exerts its cardioprotective and neuroprotective effects.

Mesenchymal stem cell-derived extracellular vesicles in the failing heart: past, present, and future

2021 ◽  
Author(s):  
Catherine Karbasiafshar ◽  
Frank W. Sellke ◽  
M. Ruhul Abid
Keyword(s):  
Stem Cell ◽  
Extracellular Vesicles ◽  
Treatment Options ◽  
Current Treatment ◽  
Lifestyle Changes ◽  
Challenges And Opportunities ◽  
Artery Disease ◽  
New Treatment

Cardiovascular disease (CVD) is the leading cause of death globally. Current treatment options include lifestyle changes, medication, and surgical intervention. However, many patients are unsuitable candidates for surgeries due to comorbidities, diffuse coronary artery disease or advanced stages of heart failure. The search for new treatment options has recently transitioned from cell-based therapies to stem-cell derived extracellular vesicles (EVs). A number of challenges remain in the EV field, including the effect of comorbidities, characterization, and delivery, However, recent revolutionary developments and insight into the potential of 'personalizing' EV contents by bioengineering methods to alter specific signaling pathways in the ischemic myocardium hold promise. Here, we discuss the past limitations of cell-based therapies, and recent EV studies involving in vivo, in vitro, and omics, and future challenges and opportunities in EV-based treatments in CVD.

scholarly journals Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

2020 ◽  
Vol 2020 ◽  
pp. 1-27 ◽  
Author(s):  
Samuele Maramai ◽  
Mohamed Benchekroun ◽  
Moustafa T. Gabr ◽  
Samir Yahiaoui
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Event ◽  
Neuroprotective Effects ◽  
New Agents ◽  
Major Health ◽  
New Treatment ◽  
Neuronal Functions

Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer’s disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.

scholarly journals In VitroandIn VivoEfficacies of Mefloquine-Based Treatment against Alveolar Echinococcosis

2010 ◽  
Vol 55 (2) ◽  
pp. 713-721 ◽  
Author(s):  
Tatiana Küster ◽  
Britta Stadelmann ◽  
Corina Hermann ◽  
Sabrina Scholl ◽  
Jennifer Keiser ◽  
...  
Keyword(s):  
Alveolar Echinococcosis ◽  
Severe Disease ◽  
Treatment Options ◽  
Drug Candidate ◽  
Combined Application ◽  
New Treatment ◽  
Complete Detachment ◽  
Laminated Layer

ABSTRACTAlveolar echinococcosis (AE) is caused by the metacestode stage of the fox tapewormEchinococcus multilocularisand causes severe disease in the human liver, and occasionally in other organs, that is fatal when treatment is unsuccessful. The present chemotherapy against AE is based on mebendazole and albendazole. Albendazole treatment has been found to be ineffective in some instances, is parasitostatic rather than parasiticidal, and usually involves the lifelong uptake of large doses of drugs. Thus, new treatment options are urgently needed. In this study we investigated thein vitroandin vivoefficacy of mefloquine againstE. multilocularismetacestodes. Treatment using mefloquine (20 μM) againstin vitrocultures of metacestodes resulted in rapid and complete detachment of large parts of the germinal layer from the inner surface of the laminated layer within a few hours. Thein vitroactivity of mefloquine was dependent on the dosage.In vitroculture of metacestodes in the presence of 24 μM mefloquine for a period of 10 days was parasiticidal, as determined by murine bioassays, while treatment with 12 μM was not. Oral application of mefloquine (25 mg/kg of body weight administered twice a week for a period of 8 weeks) inE. multilocularis-infected mice was ineffective in achieving any reduction of parasite weight, whereas treatment with albendazole (200 mg/kg/day) was highly effective. However, when the same mefloquine dosage was applied intraperitoneally, the reduction in parasite weight was similar to the reduction seen with oral albendazole application. Combined application of both drugs did not increase the treatment efficacy. In conclusion, mefloquine represents an interesting drug candidate for the treatment of AE, and these results should be followed up in appropriatein vivostudies.

Rapamycin blocks hepatoblastoma growth in vitro and in vivo implicating new treatment options in high-risk patients

2012 ◽  
Vol 48 (15) ◽  
pp. 2442-2450 ◽  
Author(s):  
Ferdinand Wagner ◽  
Bente Henningsen ◽  
Christine Lederer ◽  
Melanie Eichenmüller ◽  
Jan Gödeke ◽  
...  
Keyword(s):  
High Risk ◽  
Treatment Options ◽  
High Risk Patients ◽  
Risk Patients ◽  
New Treatment

scholarly journals Shenzhi Jiannao formula ameliorates vascular dementia in vivo and in vitro by inhibition glutamate neurotoxicity via promoting clathrin-mediated endocytosis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Danfeng Tian ◽  
Yangyang Guo ◽  
Dandan Zhang ◽  
Qiang Gao ◽  
Ganlu Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Vascular Dementia ◽  
Pc12 Cells ◽  
Neuroprotective Effect ◽  
Glutamate Excitotoxicity ◽  
Mrna Levels ◽  
Neuroprotective Effects ◽  
Promising Alternative

Abstract Background Synaptic damage and glutamate excitotoxicity have been implicated in the pathogenesis of vascular dementia (VD). Clathrin, RAB5B and N-methyl-d-aspartic acid receptor 1 (NMDAR1) proteins play a vital role in endocytosis of synaptic vesicles in neurons and glutamate over accumulation. Previous researches have been confirmed that Shenzhi Jiannao (SZJN) formula has an anti-apoptotic and neuroprotective effect in VD, but the underlying mechanisms are still unclear. In this study, we aimed to explore the effect of SZJN formula on cognitive impairment and glutamate excitotoxicity via clathrin-mediated endocytosis (CME) in vivo and in vitro. Methods SZJN formula consists of Panax ginseng C.A.Mey., Anemarrhena asphodeloides Bunge, and Paeonia anomala subsp. veitchii (Lynch) D.Y.Hong & K.Y.Pan. All herbs were prepared into granules. Both common carotid arteries were permanent occluded (2‐vessel occlusion, 2VO) in male Sprague Dawley (SD) rats to model VD. One day after operation, the rats began daily treatment with SZJN formula for 2 weeks. The neuroprotective effects of SZJN formula was subsequently assessed by the novel object recognition test, Morris water maze, hematoxylin–eosin (HE) staining and Nissl staining. Glutamate cytotoxicity was assessed by detecting cell viability and cell death of PC12 cells. Immunohistochemistry, immunofluorescence, Western blot, and quantitative real‐time PCR were used to detect the expression levels of clathrin, RAB5B, and NMDAR1. Results Administration of SZJN formula effectively improved short-term memory and spatial memory. SZJN formula treatment significantly reduced hippocampal neuronal loss, and recovered the arrangement and morphology of neurons and Nissl bodies. Moreover, SZJN formula promoted the proliferation of PC12 cells and inhibited glutamate-induced cell death. The down-regulation of clathrin and RAB5B, as well as the upregulation of NMDAR1 in the brain induced by 2VO or glutamate was also notably reversed by SZJN formula at both the protein and mRNA levels, which may contribute to SZJN formula induced improved neurological function. Conclusions Taken together, our findings provide evidence that the neuroprotective effects of SZJN formula in experimental VD maybe mediated through promoting the expression of clathrin-mediated endocytosis and reducing NMDARs‐associated glutamate excitotoxicity. SZJN formula serves as a promising alternative therapy and may be a useful herbal medicine for preventing progression of VD. Graphic abstract

scholarly journals Neuroprotective effects of some epigenetic modifying drugs’ on Chlamydia pneumoniae-induced neuroinflammation: A novel model

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260633
Author(s):  
Elif Kaya-Tilki ◽  
Miriş Dikmen
Keyword(s):  
Chlamydia Pneumoniae ◽  
Trichostatin A ◽  
Treatment Options ◽  
Regulatory System ◽  
Intracellular Pathogen ◽  
Neuroprotective Effects ◽  
Neuroprotective Actions ◽  
New Treatment ◽  
Analysis System ◽  
Novel Model

Chlamydia pneumoniae (Cpn) is a gram-negative intracellular pathogen that causes a variety of pulmonary diseases, and there is growing evidence that it may play a role in Alzheimer’s disease (AD) pathogenesis. Cpn can interact functionally with host histones, altering the host’s epigenetic regulatory system by introducing bacterial products into the host tissue and inducing a persistent inflammatory response. Because Cpn is difficult to propagate, isolate, and detect, a modified LPS-like neuroinflammation model was established using lyophilized cell free supernatant (CFS) obtained from infected cell cultures, and the effects of CFS were compared to LPS. The neuroprotective effects of Trichostatin A (TSA), givinostat, and RG108, which are effective on epigenetic mechanisms, and the antibiotic rifampin, were studied in this newly introduced model and in the presence of amyloid beta (Aβ) 1–42. The neuroprotective effects of the drugs, as well as the effects of CFS and LPS, were evaluated in Aβ-induced neurotoxicity using a real-time cell analysis system, total ROS, and apoptotic impact. TSA, RG108, givinostat, and rifampin all demonstrated neuroprotective effects in both this novel model and Aβ-induced neurotoxicity. The findings are expected to provide early evidence on neuroprotective actions against Cpn-induced neuroinflammation and Aβ-induced neurotoxicity, which could represent a new treatment option for AD, for which there are currently few treatment options.

scholarly journals CR6-Interacting Factor 1 Interacts with Orphan Nuclear Receptor Nur77 and Inhibits Its Transactivation

2005 ◽  
Vol 19 (1) ◽  
pp. 12-24 ◽  
Author(s):  
Ki Cheol Park ◽  
Kwang-Hoon Song ◽  
Hyo Kyun Chung ◽  
Ho Kim ◽  
Dong Wook Kim ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nuclear Receptor ◽  
Promoter Activity ◽  
Trichostatin A ◽  
In Vivo Studies ◽  
Orphan Nuclear Receptor ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
Responsive Element

Abstract CR6-interacting factor 1 (CRIF1) was recently identified as a nuclear protein that interacts with the Gadd45 (growth arrest and DNA damage inducible 45) family of proteins and participates in the regulation of the G1/S phase of the cell cycle. However, the nuclear action of CRIF1 is largely unknown. In this study, we demonstrate that CRIF1 acts as a novel coregulator of transactivation of the orphan nuclear receptor Nur77. Both in vitro and in vivo studies show that CRIF1 interacts with Nur77 via the Nur77 AB domain and that it dramatically inhibits the AB domain-mediated transactivation of Nur77. Transient transfection assays demonstrate that CRIF1 inhibits steroid receptor coactivator-2-mediated Nur77 transactivation, and silencing of endogenous CRIF1 by small interfering RNA relieves this repression. CRIF1 possesses intrinsic repressor activities that are not affected by the histone deacetylase inhibitor Trichostatin A. In addition, overexpression of CRIF1 inhibits TSH/protein kinase A-induced Nur-responsive element promoter activity. CRIF1 inhibited Nur77-dependent induction of E2F1 promoter activity, mRNA expression, and Nur77-mediated G1/S progression in cell cycle. These results suggest that CRIF1 acts as a repressor of the orphan nuclear receptor Nur77 by inhibiting AB domain-mediated transcriptional activity.

scholarly journals Neuroprotective Activities of Boophone haemanthoides (Amaryllidaceae) Extract and Its Chemical Constituents

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5376
Author(s):  
Abobaker S. Ibrakaw ◽  
Sylvester I. Omoruyi ◽  
Okobi E. Ekpo ◽  
Ahmed A. Hussein
Keyword(s):  
Bioactive Compounds ◽  
Chemical Constituents ◽  
Treatment Options ◽  
Neuroblastoma Cells ◽  
Neuroprotective Effects ◽  
Vitro Model ◽  
New Treatment ◽  
Induced Apoptosis ◽  
Alkaloidal Constituents

Parkinson’s disease (PD) is a neurodegenerative condition that progresses as age increases, and some of its major symptoms include tremor and postural and movement-related difficulties. To date, the treatment of PD remains a challenge because available drugs only treat the symptoms of the disease or possess serious side effects. In light of this, new treatment options are needed; hence, this study investigates the neuroprotective effects of an organic Boophone haemanthoides extract (BHE) and its bioactive compounds using an in vitro model of PD involving the toxin 1-methyl-4-phenylpyridinium (MPP+) and SH-SY5Y neuroblastoma cells. A total of seven compounds were isolated from BHE, viz distichamine (1), 1α,3α-diacetylnerbowdine (2), hippadine (3), stigmast-4-ene-3,6-dione (4), cholest-4-en-3-one (5), tyrosol (6), and 3-hydroxy-1-(4′-hydroxyphenyl)-1-propanone (7). Six compounds (1, 2, 4, 5, 6 and 7) were investigated, and five showed neuroprotection alongside the BHE. This study gives insight into the bioactivity of the non-alkaloidal constituents of Amaryllidaceae, since the isolated compounds and the BHE showed improved cell viability, increased ATP generation in the cells as well as inhibition of MPP+-induced apoptosis. Together, these findings support the claim that the Amaryllidaceae plant family could be a potential reserve of bioactive compounds for the discovery of neuroprotective agents.

scholarly journals Minocycline Up-regulates Bcl-2 and Protects against Cell Death in Mitochondria

2004 ◽  
Vol 279 (19) ◽  
pp. 19948-19954 ◽  
Author(s):  
Jinzhao Wang ◽  
Qingqing Wei ◽  
Cong-Yi Wang ◽  
William D. Hill ◽  
David C. Hess ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Antisense Oligonucleotides ◽  
Membrane Damage ◽  
Neuroprotective Effects ◽  
Antiapoptotic Protein ◽  
Molecular Determinant ◽  
Kidney Epithelial Cells

Robust neuroprotective effects have been shown for minocycline. Whether it also protects nonneuronal cells or tissues is unknown. More importantly, the mechanisms of minocylcine protection appear multifaceted and remain to be clarified. Here we show that minocycline can protect kidney epithelial cellsin vitroand protect the kidneys from ischemic injuryin vivo. We further show that Bcl-2 is a key molecular determinant of minocycline protection. Minocycline protected kidney epithelial cells against apoptosis induced by hypoxia, azide, cisplatin, and staurosporine. The protection occurred at mitochondria, involving the suppression of Bax accumulation, outer membrane damage, and cytochromecrelease. Minocycline induced Bcl-2, which accumulated in mitochondria and interacted with death-promoting molecules including Bax, Bak, and Bid. Down-regulation of Bcl-2 by specific antisense oligonucleotides abolished the cytoprotective effects of minocycline. Thus, minocycline can protect neuronal as well as nonneuronal cells and tissues. One mechanism for minocycline protection involves the induction of Bcl-2, an antiapoptotic protein.

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