scholarly journals The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases

2021 ◽  
Vol 22 (2) ◽  
pp. 934
Author(s):  
Woon-Man Kung ◽  
Muh-Shi Lin
Keyword(s):  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Management Strategies ◽  
Nuclear Factor Κb ◽  
Peroxisome Proliferator ◽  
Proinflammatory Response ◽  
Pharmacological Management ◽  
Peroxisome Proliferator Activated Receptor ◽  
Iron Sulfur ◽  
Promising Target

Proinflammatory response and mitochondrial dysfunction are related to the pathogenesis of neurodegenerative diseases (NDs). Nuclear factor κB (NFκB) activation has been shown to exaggerate proinflammation and mitochondrial dysfunction, which underlies NDs. CDGSH iron-sulfur domain 2 (CISD2) has been shown to be associated with peroxisome proliferator-activated receptor-β (PPAR-β) to compete for NFκB and antagonize the two aforementioned NFκB-provoked pathogeneses. Therefore, CISD2-based strategies hold promise in the treatment of NDs. CISD2 protein belongs to the human NEET protein family and is encoded by the CISD2 gene (located at 4q24 in humans). In CISD2, the [2Fe-2S] cluster, through coordinates of 3-cysteine-1-histidine on the CDGSH domain, acts as a homeostasis regulator under environmental stress through the transfer of electrons or iron-sulfur clusters. Here, we have summarized the features of CISD2 in genetics and clinics, briefly outlined the role of CISD2 as a key physiological regulator, and presented modalities to increase CISD2 activity, including biomedical engineering or pharmacological management. Strategies to increase CISD2 activity can be beneficial for the prevention of inflammation and mitochondrial dysfunction, and thus, they can be applied in the management of NDs.

scholarly journals Beneficial Impacts of Alpha-Eleostearic Acid from Wild Bitter Melon and Curcumin on Promotion of CDGSH Iron-Sulfur Domain 2: Therapeutic Roles in CNS Injuries and Diseases

2021 ◽  
Vol 22 (7) ◽  
pp. 3289
Author(s):  
Woon-Man Kung ◽  
Muh-Shi Lin
Keyword(s):  
Mitochondrial Function ◽  
Eleostearic Acid ◽  
Curcuma Longa ◽  
Natural Antioxidants ◽  
Nuclear Factor Κb ◽  
Bioactive Molecules ◽  
Peroxisome Proliferator ◽  
Bitter Melon ◽  
Peroxisome Proliferator Activated Receptor ◽  
Iron Sulfur

Neuroinflammation and abnormal mitochondrial function are related to the cause of aging, neurodegeneration, and neurotrauma. The activation of nuclear factor κB (NF-κB), exaggerating these two pathologies, underlies the pathogenesis for the aforementioned injuries and diseases in the central nervous system (CNS). CDGSH iron-sulfur domain 2 (CISD2) belongs to the human NEET protein family with the [2Fe-2S] cluster. CISD2 has been verified as an NFκB antagonist through the association with peroxisome proliferator-activated receptor-β (PPAR-β). This protective protein can be attenuated under circumstances of CNS injuries and diseases, thereby causing NFκB activation and exaggerating NFκB-provoked neuroinflammation and abnormal mitochondrial function. Consequently, CISD2-elevating plans of action provide pathways in the management of various disease categories. Various bioactive molecules derived from plants exert protective anti-oxidative and anti-inflammatory effects and serve as natural antioxidants, such as conjugated fatty acids and phenolic compounds. Herein, we have summarized pharmacological characters of the two phytochemicals, namely, alpha-eleostearic acid (α-ESA), an isomer of conjugated linolenic acids derived from wild bitter melon (Momordica charantia L. var. abbreviata Ser.), and curcumin, a polyphenol derived from rhizomes of Curcuma longa L. In this review, the unique function of the CISD2-elevating effect of α-ESA and curcumin are particularly emphasized, and these natural compounds are expected to serve as a potential therapeutic target for CNS injuries and diseases.

scholarly journals A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 7
Author(s):  
Dong-Hoon Hyun ◽  
Jaewang Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Redox Homeostasis ◽  
Protein Aggregates ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cellular Signalling

Neurodegenerative diseases are accompanied by oxidative stress and mitochondrial dysfunction, leading to a progressive loss of neuronal cells, formation of protein aggregates, and a decrease in cognitive or motor functions. Mitochondrial dysfunction occurs at the early stage of neurodegenerative diseases. Protein aggregates containing oxidatively damaged biomolecules and other misfolded proteins and neuroinflammation have been identified in animal models and patients with neurodegenerative diseases. A variety of neurodegenerative diseases commonly exhibits decreased activity of antioxidant enzymes, lower amounts of antioxidants, and altered cellular signalling. Although several molecules have been approved clinically, there is no known cure for neurodegenerative diseases, though some drugs are focused on improving mitochondrial function. Mitochondrial dysfunction is caused by oxidative damage and impaired cellular signalling, including that of peroxisome proliferator-activated receptor gamma coactivator 1α. Mitochondrial function can also be modulated by mitochondrial biogenesis and the mitochondrial fusion/fission cycle. Mitochondrial biogenesis is regulated mainly by sirtuin 1, NAD+, AMP-activated protein kinase, mammalian target of rapamycin, and peroxisome proliferator-activated receptor γ. Altered mitochondrial dynamics, such as increased fission proteins and decreased fusion products, are shown in neurodegenerative diseases. Due to the restrictions of a target-based approach, a phenotype-based approach has been performed to find novel proteins or pathways. Alternatively, plasma membrane redox enzymes improve mitochondrial function without the further production of reactive oxygen species. In addition, inducers of antioxidant response elements can be useful to induce a series of detoxifying enzymes. Thus, redox homeostasis and metabolic regulation can be important therapeutic targets for delaying the progression of neurodegenerative diseases.

Abstract 419: Human ApoB100/CETP Transgenic Mouse is a Useful Animal Model for Evaluation of HDL-C Elevation and Suppression of Atherosclerosis by Peroxisome Proliferator-Activated Receptor Delta Agonist

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Noriyuki Naya ◽  
Keita Fukao ◽  
Akemi Nakamura ◽  
Kohji Nomura ◽  
Seijiro Hara ◽  
...  
Keyword(s):  
Term Treatment ◽  
Serum Lipoprotein ◽  
Peroxisome Proliferator ◽  
Cross Sectional ◽  
Peroxisome Proliferator Activated Receptor ◽  
New Class ◽  
Promising Target ◽  
Long Term Treatment ◽  
Apoe Ko Mice ◽  
Lipoprotein Profiles

PPARδ is one of the transcription factors that regulate lipid metabolism. Recently, PPARδ agonists have been reported to induce the elevation of plasma HDL-C levels in obese mice, rhesus monkeys as well as humans, indicating their potentials as a new class of HDL-C raising agent. In addition, anti-atherosclerotic effects of PPARδ agonists were reported in LDLR-KO and ApoE-KO mice. In these mice, however, the lipoprotein profiles are greatly different from those in humans in terms of the deficiency in CETP and ApoB100, and thus the anti-inflammatory effects were regarded as a main anti-atherosclerotic mechanism of PPARδ agonists. It has been reported that human ApoB100/CETP transgenic (hApoB100/CETP-Tg) mice have similar lipoprotein profiles with humans. In this study, we used hApoB100/CETP-Tg mice placed under a western diet for evaluation of GW501516, one of the most potent and selective PPARδ agonists, in order to investigate the linkage between HDL-C elevation and anti-atherosclerotic potency. For evaluation of plasma HDL-C levels, the hApoB100/CETP-Tg mice were orally treated with GW501516 for 1 week and its potency was compared with fenofibrate, a PPARα agonist used in the clinic. For evaluation of the anti-atherosclerotic effect, the mice were orally treated with GW501516 for 18 weeks and atherosclerosis at the aortic valves was determined by cross-sectional lesion analysis. Serum lipoprotein parameters were periodically monitored and lipoprotein profiles were analyzed by FPLC method. Treatment with GW501516 resulted in significant elevation of plasma HDL-C levels with more potency compared to fenofibrate (24% and 15% elevation at 10mg/kg, respectively). Serum apoA-I was also increased by the similar ratio as HDL-C, and the particle size of HDL was not changed, suggesting that the numbers of HDL particle are increased by GW501516. Long term treatment of GW501516 (3 and 10 mg/kg) resulted in dose-dependent suppression of atherosclerosis (42 and 57% inhibition, respectively) with a strong correlation with HDL-C elevation (p<0.001). By using hApoB100/CETP-Tg mice, PPARδ was confirmed as a promising target of anti-atherosclerotic therapy as a new class of HDL-C raising agent.

scholarly journals Angiogenic Deficiency and Adipose Tissue Dysfunction Are Associated with Macrophage Malfunction in SIRT1−/− Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1706-1716 ◽  
Author(s):  
Fen Xu ◽  
David Burk ◽  
Zhanguo Gao ◽  
Jun Yin ◽  
Xia Zhang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Adipocyte Differentiation ◽  
Nuclear Factor Κb ◽  
The Body ◽  
Sirtuin 1 ◽  
Vascular Density ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor

The histone deacetylase sirtuin 1 (SIRT1) inhibits adipocyte differentiation and suppresses inflammation by targeting the transcription factors peroxisome proliferator-activated receptor γ and nuclear factor κB. Although this suggests that adiposity and inflammation should be enhanced when SIRT1 activity is inactivated in the body, this hypothesis has not been tested in SIRT1 null (SIRT1−/−) mice. In this study, we addressed this issue by investigating the adipose tissue in SIRT1−/− mice. Compared with their wild-type littermates, SIRT1 null mice exhibited a significant reduction in body weight. In adipose tissue, the average size of adipocytes was smaller, the content of extracellular matrix was lower, adiponectin and leptin were expressed at 60% of normal level, and adipocyte differentiation was reduced. All of these changes were observed with a 50% reduction in capillary density that was determined using a three-dimensional imaging technique. Except for vascular endothelial growth factor, the expression of several angiogenic factors (Pdgf, Hgf, endothelin, apelin, and Tgf-β) was reduced by about 50%. Macrophage infiltration and inflammatory cytokine expression were 70% less in the adipose tissue of null mice and macrophage differentiation was significantly inhibited in SIRT1−/− mouse embryonic fibroblasts in vitro. In wild-type mice, macrophage deletion led to a reduction in vascular density. These data suggest that SIRT1 controls adipose tissue function through regulation of angiogenesis, whose deficiency is associated with macrophage malfunction in SIRT1−/− mice. The study supports the concept that inflammation regulates angiogenesis in the adipose tissue.

Sign in / Sign up

Export Citation Format

Share Document