scholarly journals Acetylshikonin, a Novel AChE Inhibitor, Inhibits Apoptosis via Upregulation of Heme Oxygenase-1 Expression in SH-SY5Y Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Yan Wang ◽  
Wen-Liang Pan ◽  
Wei-Cheng Liang ◽  
Wai-Kit Law ◽  
Denis Tsz-Ming Ip ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Apoptotic Cell ◽  
Acetylcholinesterase Inhibitors ◽  
Docking Study ◽  
Ache Inhibitor ◽  
Heme Oxygenase 1 ◽  
Mitochondria Membrane Potential ◽  
Aloe Emodin ◽  
Angelicae Dahuricae Radix ◽  
First Time

Acetylcholinesterase inhibitors are prominent alternative in current clinical treatment for AD patients. Therefore, there is a continued need to search for novel AChEIs with good clinical efficacy and less side effects. By using our in-house natural product database and AutoDock Vina as a tool in docking study, we have identified twelve phytochemicals (emodin, aloe-emodin, chrysophanol, and rhein in Rhei Radix Et Rhizoma; xanthotoxin, phellopterin, alloisoimperatorin, and imperatorin in Angelicae dahuricae Radix; shikonin, acetylshikonin, isovalerylshikonin, andβ,β-dimethylacrylshikonin in Arnebiae Radix) as candidates of AChEIs that were not previously reported in the literature. In addition to AChEI activity, a series of cell-based experiments were conducted for the investigation of their neuroprotective activities. We found that acetylshikonin and its derivatives prevented apoptotic cell death induced by hydrogen peroxide in human and rat neuronal SH-SY5Y and PC12 cells at 10 μM. We showed that acetylshikonin exhibited the most potent antiapoptosis activity through the inhibition of the generation of reactive oxygen species as well as protection of the loss of mitochondria membrane potential. Furthermore, we identified for the first time that the upregulation of heme oxygenase 1 by acetylshikonin is a key step mediating its antiapoptotic activity from oxidative stress in SH-SY5Y cells.

Spirocyclohexadienones as an Uncommon Scaffold for Acetylcholinesterase Inhibitory Activity

2019 ◽  
Vol 15 (4) ◽  
pp. 373-382 ◽  
Author(s):  
Ralph C. Gomes ◽  
Renata P. Sakata ◽  
Wanda P. Almeida ◽  
Fernando Coelho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Population Aging ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
Docking Study ◽  
Biological Properties ◽  
Ache Inhibitor ◽  
Molecular Docking Study

Background: The most important cause of dementia affecting elderly people is the Alzheimer’s disease (AD). Patients affected by this progressive and neurodegenerative disease have severe memory and cognitive function impairments. Some medicines used for treating this disease in the early stages are based on inhibition of acetylcholinesterase. Population aging should contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the development of new therapeutic entities for the treatment of this disease. Methods: The objective of this work is to identify new substances that have spatial structural similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's disease, and to evaluate the capacity of inhibition of these new substances against the enzyme acetylcholinesterase. Results: Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones with different substitutions patterns in three steps and overall yield of up to 59%. These compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 µM. Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 µM), a mixedtype AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic (CAS) and the peripheral site (PAS). Conclusion: We described the first study aimed at investigating the biological properties of spirocyclohexadienones as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase inhibitors.

Induction of heme-oxygenase 1 requires the p38MAPK and PI3K pathways and suppresses apoptotic cell death following hypericin-mediated photodynamic therapy

APOPTOSIS ◽  
2007 ◽  
Vol 12 (4) ◽  
pp. 731-741 ◽  
Author(s):  
Silvia Kocanova ◽  
Esther Buytaert ◽  
Jean-Yves Matroule ◽  
Jacques Piette ◽  
Jakub Golab ◽  
...  
Keyword(s):  
Cell Death ◽  
Photodynamic Therapy ◽  
Heme Oxygenase ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Heme Oxygenase 1

Motexafin Gadolinium and Other Metallotexaphyrins Upregulate Heme Oxygenase-1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4468-4468
Author(s):  
Mint Sirisawad ◽  
Jun Chen ◽  
Jason Ramos ◽  
Richard A. Miller ◽  
Louie Naumovski
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Chemical Structure ◽  
Heme Oxygenase 1 ◽  
Oxygen Species ◽  
Redox Stress ◽  
Motexafin Gadolinium ◽  
Protein Thiols ◽  
Tin Protoporphyrin ◽  
First Time

Abstract Heme oxygenase-1 (HO-1) is an inducible enzyme that is upregulated by heme and acts to degrade heme into bilirubin, carbon monoxide and iron. HO-1 is known to be upregulated in response to oxidative stress and has anti-apoptotic properties. Motexafin gadolinium (MGd, Xcytrin®) is a tumor-selective redox mediator that produces oxidative stress in cancer cells by reacting with various reducing metabolites and protein thiols to generate reactive oxygen species. Also, MGd is an expanded porphyrin that has a chemical structure which resembles heme. Since redox stress and heme upregulate HO-1 expression, we hypothesized that MGd would produce similar effects. We treated 8 hematopoietic tumor-derived cell lines with MGd and found that 2 of them (Ramos and HF-1) upregulated HO-1 protein. In Ramos lymphoma cells, we found that MGd induced HO-1 up to 8 fold by 24 hrs and that longer incubations did not result in appreciably greater amounts of protein. HO-1 levels returned to baseline in Ramos cells 48 hrs after cells were cultured in fresh media in the absence of MGd. HO-1 levels were elevated at baseline in HF-1 cells (compared to Ramos) and increased about 2 fold with MGd treatment. Other metallotexaphyrins, europium texaphyrin and dysprosium texaphyrin, also induced HO-1 expression. To determine if HO-1 expression was important for cell survival, we co-treated cells with MGd and tin protoporphyrin (SnPP), an inhibitor of HO-1 enzymatic activity. We found that both HF-1 and Ramos cells were sensitized to MGd-induced cell death by SnPP. These results demonstrate for the first time that metallotexaphyrins can upregulate HO-1 expression. The induction of HO-1 could be related to oxidative stress and/or metallotexaphyrins acting as heme mimetics.

scholarly journals Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3860
Author(s):  
Giuseppe Romeo ◽  
Valeria Ciaffaglione ◽  
Emanuele Amata ◽  
Maria Dichiara ◽  
Loredana Calabrese ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Anticancer Agents ◽  
Sigma Receptor ◽  
Heme Oxygenase 1 ◽  
Sigma Receptors ◽  
Proof Of Concept ◽  
Hybrid Compounds ◽  
Receptor Modulation ◽  
Small Series ◽  
First Time

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (Rs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and R ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/Rs) 14 containing the chemical features needed for HO-1 inhibition and R modulation. Herein, we report for the first time that targeting simultaneously HO-1 and R proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/Rs hybrids to develop novel potential anticancer agents.

Ischemia-Induced Up-Regulation of Heme Oxygenase-1 Protects From Apoptotic Cell Death and Tissue Necrosis

2008 ◽  
Vol 150 (2) ◽  
pp. 293-303 ◽  
Author(s):  
Yves Harder ◽  
Michaela Amon ◽  
René Schramm ◽  
Martin Rücker ◽  
Claudia Scheuer ◽  
...  
Keyword(s):  
Cell Death ◽  
Heme Oxygenase ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Heme Oxygenase 1 ◽  
Tissue Necrosis

scholarly journals Heme oxygenase-1-mediated autophagy protects against pulmonary endothelial cell death and development of emphysema in cadmium-treated mice

2015 ◽  
Vol 309 (3) ◽  
pp. L280-L292 ◽  
Author(s):  
Ranu Surolia ◽  
Suman Karki ◽  
Hyunki Kim ◽  
Zhihong Yu ◽  
Tejaswini Kulkarni ◽  
...  
Keyword(s):  
Cell Death ◽  
Lung Function ◽  
Cigarette Smoke ◽  
Heme Oxygenase ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Intratracheal Instillation ◽  
Cigarette Smoke Exposure ◽  
Heme Oxygenase 1 ◽  
Micro Computed Tomography

Pulmonary exposure to cadmium, a major component of cigarette smoke, has a dramatic impact on lung function and the development of emphysema. Cigarette smoke exposure induces heme oxygenase-1 (HO-1), a cytoprotective enzyme. In this study, we employed a truncated mouse model of emphysema by intratracheal instillation of cadmium (CdCl2) solution (0.025% per 1 mg/kg body wt) in HO-1+/+, HO-1−/−, and overexpressing humanized HO-1 bacterial artificial chromosome (hHO-1BAC) mice. We evaluated the role of HO-1 in cadmium-induced emphysema in mice by analyzing histopathology, micro-computed tomography scans, and lung function tests. CdCl2-exposed HO-1−/− mice exhibited more severe emphysema compared with HO-1+/+ or hHO-1BAC mice. Loss of pulmonary endothelial cells (PECs) from the alveolar capillary membrane is recognized to be a target in emphysema. PECs from HO-1+/+, HO-1−/−, and hHO-1BAC were employed to define the underlying molecular mechanism for the protection from emphysema by HO-1. Electron microscopy, expression of autophagic markers (microtubule-associated protein 1B-light chain 3 II, autophagy protein 5, and Beclin1) and apoptotic marker (cleaved caspase 3) suggested induction of autophagy and apoptosis in PECs after CdCl2 treatment. CdCl2-treated HO-1−/− PECs exhibited downregulation of autophagic markers and significantly increased cleaved caspase 3 expression and activity (∼4-fold higher). Moreover, hHO-1BAC PECs demonstrated upregulated autophagy and absence of cleaved caspase 3 expression or activity. Pretreatment of HO-1+/+ PECs with rapamycin induced autophagy and resulted in reduced cell death upon cadmium treatment. Induction of autophagy following CdCl2 treatment was found to be protective from apoptotic cell death. HO-1 induced protective autophagy in PECs and mitigated cadmium-induced emphysema.

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