scholarly journals Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7660
Author(s):  
Arpita Dey ◽  
Ran Chen ◽  
Feng Li ◽  
Subhamita Maitra ◽  
Jean-Francois Hernandez ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Neuroblastoma Cells ◽  
Amyloid Peptide ◽  
Hek293 Cells ◽  
Human Neuroblastoma ◽  
Full Characterization ◽  
Amyloidogenic Processing ◽  
Starting Point ◽  
Abnormal Accumulation ◽  
Labdane Diterpene

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, one of the main characteristics of which is the abnormal accumulation of amyloid peptide (Aβ) in the brain. Whereas β-secretase supports Aβ formation along the amyloidogenic processing of the β-amyloid precursor protein (βAPP), α-secretase counterbalances this pathway by both preventing Aβ production and triggering the release of the neuroprotective sAPPα metabolite. Therefore, stimulating α-secretase and/or inhibiting β-secretase can be considered a promising anti-AD therapeutic track. In this context, we tested andrographolide, a labdane diterpene derived from the plant Andrographis paniculata, as well as 24 synthesized derivatives, for their ability to induce sAPPα production in cultured SH-SY5Y human neuroblastoma cells. Following several rounds of screening, we identified three hits that were subjected to full characterization. Interestingly, andrographolide (8,17-olefinic) and its close derivative 14α-(5′,7′-dichloro-8′-quinolyloxy)-3,19-acetonylidene (compound 9) behave as moderate α-secretase activators, while 14α-(2′-methyl-5′,7′-dichloro-8′-quinolyloxy)-8,9-olefinic compounds 31 (3,19-acetonylidene) and 37 (3,19-diol), whose two structures are quite similar although distant from that of andrographolide and 9, stand as β-secretase inhibitors. Importantly, these results were confirmed in human HEK293 cells and these compounds do not trigger toxicity in either cell line. Altogether, these findings may represent an encouraging starting point for the future development of andrographolide-based compounds aimed at both activating α-secretase and inhibiting β-secretase that could prove useful in our quest for the therapeutic treatment of AD.

scholarly journals Neuroinductive properties of mGDNF depend on the producer, E. Coli or human cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258289
Author(s):  
Dzhirgala V. Shamadykova ◽  
Dmitry Y. Panteleev ◽  
Nadezhda N. Kust ◽  
Ekaterina A. Savchenko ◽  
Ekaterina Y. Rybalkina ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ganglion Cells ◽  
Neuroblastoma Cells ◽  
Human Cells ◽  
Hek293 Cells ◽  
Human Neuroblastoma ◽  
Mammalian Expression

The glial cell line‐derived neurotrophic factor (GDNF) is involved in the survival of dopaminergic neurons. Besides, GDNF can also induce axonal growth and creation of new functional synapses. GDNF potential is promising for translation to treat diseases associated with neuronal death: neurodegenerative disorders, ischemic stroke, and cerebral or spinal cord damages. Unproductive clinical trials of GDNF for Parkinson’s disease treatment have induced to study this failure. A reason could be due to irrelevant producer cells that cannot perform the required post-translational modifications. The biological activity of recombinant mGDNF produced by E. coli have been compared with mGDNF produced by human cells HEK293. mGDNF variants were tested with PC12 cells, rat embryonic spinal ganglion cells, and SH-SY5Y human neuroblastoma cells in vitro as well as with a mouse model of the Parkinson’s disease in vivo. Both in vitro and in vivo the best neuro-inductive ability belongs to mGDNF produced by HEK293 cells. Keywords: GDNF, neural differentiation, bacterial and mammalian expression systems, cell cultures, model of Parkinson’s disease.

scholarly journals HSP70 protects human neuroblastoma cells from apoptosis and oxidative stress induced by amyloid peptide isoAsp7-Aβ(1–42)

2015 ◽  
Vol 6 (11) ◽  
pp. e1977-e1977 ◽  
Author(s):  
M M Yurinskaya ◽  
V A Mitkevich ◽  
S A Kozin ◽  
M B Evgen'ev ◽  
A A Makarov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neuroblastoma Cells ◽  
Amyloid Peptide ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
And Oxidative Stress

scholarly journals Sinapic Acid Protects SH-SY5Y Human Neuroblastoma Cells against 6-Hydroxydopamine-Induced Neurotoxicity

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 295
Author(s):  
Tsendsuren Tungalag ◽  
Dong Kwon Yang
Keyword(s):  
Stress Responses ◽  
Neurodegenerative Disorder ◽  
Apoptotic Cell ◽  
Antioxidant Properties ◽  
Sinapic Acid ◽  
Neuroblastoma Cells ◽  
Mitogen Activated Protein Kinase ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
6 Hydroxydopamine

Parkinson’s disease (PD) is characterized by progressive dopaminergic neuron loss or dysfunction and is the second most prevalent neurodegenerative disorder after Alzheimer’s disease. However, current therapeutic strategies for PD are limited to treating the outcomes of this disease rather than preventing it. Sinapic acid (SA) is a phenolic compound with potential antioxidant properties, which reportedly acts as a therapeutic agent against many diseases including cancer, as well as cardiac and liver diseases. However, little is known about the effects of SA against neurodegenerative disorders. Therefore, our study sought to evaluate the neuroprotective effects of non-cytotoxic concentrations of SA against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y human neuroblastoma cells, which we used as an in vitro PD model. SA increased cell viability and rescued the cells from 6-OHDA-induced apoptotic cell death. Additionally, oxidative stress responses were significantly blocked by SA, including reactive oxygen species (ROS) overproduction and decreased expression levels of antioxidant proteins. Notably, SA also attenuated mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Moreover, SA dramatically inhibited the activation of mitogen-activated protein kinase (MAPK) proteins. Taken together, our findings highlight the potential PD prevention effects of SA, as well as its underlying mechanisms, making this compound a promising prevention and treatment agent for PD.

scholarly journals Alpha-synuclein enhances lipid droplet accumulation in neurons in a Drosophila model of Parkinson’s disease

2020 ◽  
Author(s):  
Victor Girard ◽  
Florence Jollivet ◽  
Oskar Knittelfelder ◽  
Jean-Noel Arsac ◽  
Gilles Chatelain ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
De Novo ◽  
Neurodegenerative Disorder ◽  
Neuroblastoma Cells ◽  
Alpha Synuclein ◽  
Human Neuroblastoma ◽  
Drosophila Model ◽  
Human Neurons ◽  
Photoreceptor Neurons

AbstractParkinson’s disease is a neurodegenerative disorder characterized by accumulation of alpha-synuclein (αSyn) aggregates and by abnormalities in lipid storage. To investigate the potential pathophysiological consequences of interactions between αSyn and proteins that regulate the homeostasis of intracellular lipid droplets (LDs), we employed a transgenic Drosophila model of PD in which human αSyn is specifically expressed in photoreceptor neurons. We found that overexpression of the LD-coating proteins perilipin 1 and 2 (dPlin1/2) markedly increased LD accumulation in the neurons. Perilipins also co-localized with αSyn at the LD surface in both Drosophila photoreceptor neurons (dPlin2) and human neuroblastoma cells (PLIN3). Co-expression of αSyn and dPlin2 in photoreceptor neurons synergistically amplified LD content through a mechanism involving LD stabilization, independently of Brummer-mediated lipolysis or de novo synthesis of triacylglycerols. Accumulation of LDs also increased the resistance of αSyn to proteolytic digestion, a phenomenon associated with αSyn aggregation in human neurons. Our results suggest that binding of αSyn to PLIN-coated LDs stabilizes the LD structure and may contribute to the pathogenic misfolding and aggregation of αSyn in neurons.

p-Trifluoroacetophenone Oxime Ester Derivatives: Synthesis, Antimicrobial and Cytotoxic Evaluation and Molecular Modeling Studies

2020 ◽  
Vol 17 (2) ◽  
pp. 169-183 ◽  
Author(s):  
İrem Bozbey ◽  
Suat Sari ◽  
Emine Şalva ◽  
Didem Kart ◽  
Arzu Karakurt
Keyword(s):  
Molecular Modeling ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Cytotoxic Agents ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Modeling Studies ◽  
Broth Microdilution Method ◽  
Molecular Modeling Studies

Background: Azole antifungals are among the first-line drugs clinically used for the treatment of systemic candidiasis, a deadly type of fungal infection that threatens mostly immunecompromised and hospitalized patients. Some azole derivatives were also reported to have antiproliferative effects on cancer cells. Objective: In this study, 1-(4-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)ethanone (3), its oxime (4), and a series of its novel oxime ester derivatives (5a-v) were synthesized and tested for their in vitro antimicrobial activities against certain ATCC standard strains of Candida sp. fungi and bacteria. The compounds were also tested for their cytotoxic effects against mouse fibroblast and human neuroblastoma cell lines. Molecular modeling studies were performed to provide insights into their possible mechanisms for antifungal and antibacterial actions. Methods: The compounds were synthesized by the reaction of various oximes with acyl chlorides. Antimicrobial activity of the compounds was determined according to the broth microdilution method. For the determination of cytotoxic effect, we used MTS assay. Molecular docking and QM/MM studies were performed to predict the binding mechanisms of the active compounds in the catalytic site of C. albicans CYP51 (CACYP51) and S. aureus flavohemoglobin (SAFH), the latter of which was created via homology modeling. Results: 5d, 5l, and 5t showed moderate antifungal activity against C. albicans, while 3, 5c, and 5r showed significant antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Most of the compounds showed approximately 40-50% inhibition against the human neuroblastoma cells at 100 µM. In this line, 3 was the most potent with an IC50 value of 82.18 μM followed by 5a, 5o, and 5t. 3 and 5a were highly selective to the neuroblastoma cells. Molecular modelling results supported the hypothesis that our compounds were inhibitors of CAYP51 and SAFH. Conclusion: This study supports that oxime ester derivatives may be used for the development of new antimicrobial and cytotoxic agents.

scholarly journals 4-Hydroxychalcone Induces Cell Death via Oxidative Stress in MYCN-Amplified Human Neuroblastoma Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Amnah M. Alshangiti ◽  
Eszter Tuboly ◽  
Shane V. Hegarty ◽  
Cathal M. McCarthy ◽  
Aideen M. Sullivan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Cytotoxic Effect ◽  
Neuroblastoma Cells ◽  
Reactive Oxygen ◽  
Prognostic Indicator ◽  
Oxygen Species ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma

Neuroblastoma is an embryonal malignancy that arises from cells of sympathoadrenal lineage during the development of the nervous system. It is the most common pediatric extracranial solid tumor and is responsible for 15% of childhood deaths from cancer. Fifty percent of cases are diagnosed as high-risk metastatic disease with a low overall 5-year survival rate. More than half of patients experience disease recurrence that can be refractory to treatment. Amplification of the MYCN gene is an important prognostic indicator that is associated with rapid disease progression and a poor prognosis, highlighting the need for new therapeutic approaches. In recent years, there has been an increasing focus on identifying anticancer properties of naturally occurring chalcones, which are secondary metabolites with variable phenolic structures. Here, we report that 4-hydroxychalcone is a potent cytotoxin for MYCN-amplified IMR-32 and SK-N-BE (2) neuroblastoma cells, when compared to non-MYCN-amplified SH-SY5Y neuroblastoma cells and to the non-neuroblastoma human embryonic kidney cell line, HEK293t. Moreover, 4-hydroxychalcone treatment significantly decreased cellular levels of the antioxidant glutathione and increased cellular reactive oxygen species. In addition, 4-hydroxychalcone treatment led to impairments in mitochondrial respiratory function, compared to controls. In support of this, the cytotoxic effect of 4-hydroxychalcone was prevented by co-treatment with either the antioxidant N-acetyl-L-cysteine, a pharmacological inhibitor of oxidative stress-induced cell death (IM-54) or the mitochondrial reactive oxygen species scavenger, Mito-TEMPO. When combined with the anticancer drugs cisplatin or doxorubicin, 4-hydroxychalcone led to greater reductions in cell viability than was induced by either anti-cancer agent alone. In summary, this study identifies a cytotoxic effect of 4-hydroxychalcone in MYCN-amplified human neuroblastoma cells, which rationalizes its further study in the development of new therapies for pediatric neuroblastoma.

Sign in / Sign up

Export Citation Format

Share Document