Bifunctional Inhibitors of Mevalonate Kinase and Mevalonate 5-Diphosphate Decarboxylase

A bifunctional inhibitor of mevalonate kinase and mevalonate 5-diphosphate decarboxylase was synthesized. Both enzymes are in the cholesterol biosynthetic pathway and play an important role in regulating cholesterol biosynthesis. The molecule may become a useful lead compound for further development for treating cardiovascular disease and cancer. This study provides a novel example of a single inhibitor blocking two sequential steps simultaneously in the cholesterol biosynthetic pathway

Data_Sheet_3_Exploring the Extracellular Regulation of the Tumor Angiogenic Interaction Network Using a Systems Biology Model.zip

Tumor angiogenesis is regulated by pro- and anti-angiogenic factors. Anti-angiogenic agents target the interconnected network of angiogenic factors to inhibit neovascularization, which subsequently impedes tumor growth. Due to the complexity of this network, optimizing anti-angiogenic cancer treatments requires detailed knowledge at a systems level. In this study, we constructed a tumor tissue-based model to better understand how the angiogenic network is regulated by opposing mediators at the extracellular level. We consider the network comprised of two pro-angiogenic factors: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), and two anti-angiogenic factors: thrombospondin-1 (TSP1) and platelet factor 4 (PF4). The model’s prediction of angiogenic factors’ distribution in tumor tissue reveals the localization of different factors and indicates the angiogenic state of the tumor. We explored how the distributions are affected by the secretion of the pro- and anti-angiogenic factors, illustrating how the angiogenic network is regulated in the extracellular space. Interestingly, we identified a counterintuitive result that the secretion of the anti-angiogenic factor PF4 can enhance pro-angiogenic signaling by elevating the levels of the interstitial and surface-level pro-angiogenic species. This counterintuitive situation is pertinent to the clinical setting, such as the release of anti-angiogenic factors in platelet activation or the administration of exogenous PF4 for anti-angiogenic therapy. Our study provides mechanistic insights into this counterintuitive result and highlights the role of heparan sulfate proteoglycans in regulating the interactions between angiogenic factors. This work complements previous studies aimed at understanding the formation of angiogenic complexes in tumor tissue and helps in the development of anti-cancer strategies targeting angiogenesis.</p

Image_1_Exploring the Extracellular Regulation of the Tumor Angiogenic Interaction Network Using a Systems Biology Model.TIF

Tumor angiogenesis is regulated by pro- and anti-angiogenic factors. Anti-angiogenic agents target the interconnected network of angiogenic factors to inhibit neovascularization, which subsequently impedes tumor growth. Due to the complexity of this network, optimizing anti-angiogenic cancer treatments requires detailed knowledge at a systems level. In this study, we constructed a tumor tissue-based model to better understand how the angiogenic network is regulated by opposing mediators at the extracellular level. We consider the network comprised of two pro-angiogenic factors: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), and two anti-angiogenic factors: thrombospondin-1 (TSP1) and platelet factor 4 (PF4). The model’s prediction of angiogenic factors’ distribution in tumor tissue reveals the localization of different factors and indicates the angiogenic state of the tumor. We explored how the distributions are affected by the secretion of the pro- and anti-angiogenic factors, illustrating how the angiogenic network is regulated in the extracellular space. Interestingly, we identified a counterintuitive result that the secretion of the anti-angiogenic factor PF4 can enhance pro-angiogenic signaling by elevating the levels of the interstitial and surface-level pro-angiogenic species. This counterintuitive situation is pertinent to the clinical setting, such as the release of anti-angiogenic factors in platelet activation or the administration of exogenous PF4 for anti-angiogenic therapy. Our study provides mechanistic insights into this counterintuitive result and highlights the role of heparan sulfate proteoglycans in regulating the interactions between angiogenic factors. This work complements previous studies aimed at understanding the formation of angiogenic complexes in tumor tissue and helps in the development of anti-cancer strategies targeting angiogenesis.</p

Data_Sheet_2_Exploring the Extracellular Regulation of the Tumor Angiogenic Interaction Network Using a Systems Biology Model.docx

Tumor angiogenesis is regulated by pro- and anti-angiogenic factors. Anti-angiogenic agents target the interconnected network of angiogenic factors to inhibit neovascularization, which subsequently impedes tumor growth. Due to the complexity of this network, optimizing anti-angiogenic cancer treatments requires detailed knowledge at a systems level. In this study, we constructed a tumor tissue-based model to better understand how the angiogenic network is regulated by opposing mediators at the extracellular level. We consider the network comprised of two pro-angiogenic factors: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), and two anti-angiogenic factors: thrombospondin-1 (TSP1) and platelet factor 4 (PF4). The model’s prediction of angiogenic factors’ distribution in tumor tissue reveals the localization of different factors and indicates the angiogenic state of the tumor. We explored how the distributions are affected by the secretion of the pro- and anti-angiogenic factors, illustrating how the angiogenic network is regulated in the extracellular space. Interestingly, we identified a counterintuitive result that the secretion of the anti-angiogenic factor PF4 can enhance pro-angiogenic signaling by elevating the levels of the interstitial and surface-level pro-angiogenic species. This counterintuitive situation is pertinent to the clinical setting, such as the release of anti-angiogenic factors in platelet activation or the administration of exogenous PF4 for anti-angiogenic therapy. Our study provides mechanistic insights into this counterintuitive result and highlights the role of heparan sulfate proteoglycans in regulating the interactions between angiogenic factors. This work complements previous studies aimed at understanding the formation of angiogenic complexes in tumor tissue and helps in the development of anti-cancer strategies targeting angiogenesis.</p

Image_2_Exploring the Extracellular Regulation of the Tumor Angiogenic Interaction Network Using a Systems Biology Model.TIF

Tumor angiogenesis is regulated by pro- and anti-angiogenic factors. Anti-angiogenic agents target the interconnected network of angiogenic factors to inhibit neovascularization, which subsequently impedes tumor growth. Due to the complexity of this network, optimizing anti-angiogenic cancer treatments requires detailed knowledge at a systems level. In this study, we constructed a tumor tissue-based model to better understand how the angiogenic network is regulated by opposing mediators at the extracellular level. We consider the network comprised of two pro-angiogenic factors: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), and two anti-angiogenic factors: thrombospondin-1 (TSP1) and platelet factor 4 (PF4). The model’s prediction of angiogenic factors’ distribution in tumor tissue reveals the localization of different factors and indicates the angiogenic state of the tumor. We explored how the distributions are affected by the secretion of the pro- and anti-angiogenic factors, illustrating how the angiogenic network is regulated in the extracellular space. Interestingly, we identified a counterintuitive result that the secretion of the anti-angiogenic factor PF4 can enhance pro-angiogenic signaling by elevating the levels of the interstitial and surface-level pro-angiogenic species. This counterintuitive situation is pertinent to the clinical setting, such as the release of anti-angiogenic factors in platelet activation or the administration of exogenous PF4 for anti-angiogenic therapy. Our study provides mechanistic insights into this counterintuitive result and highlights the role of heparan sulfate proteoglycans in regulating the interactions between angiogenic factors. This work complements previous studies aimed at understanding the formation of angiogenic complexes in tumor tissue and helps in the development of anti-cancer strategies targeting angiogenesis.</p

Data_Sheet_1_Exploring the Extracellular Regulation of the Tumor Angiogenic Interaction Network Using a Systems Biology Model.xlsx

Tumor angiogenesis is regulated by pro- and anti-angiogenic factors. Anti-angiogenic agents target the interconnected network of angiogenic factors to inhibit neovascularization, which subsequently impedes tumor growth. Due to the complexity of this network, optimizing anti-angiogenic cancer treatments requires detailed knowledge at a systems level. In this study, we constructed a tumor tissue-based model to better understand how the angiogenic network is regulated by opposing mediators at the extracellular level. We consider the network comprised of two pro-angiogenic factors: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), and two anti-angiogenic factors: thrombospondin-1 (TSP1) and platelet factor 4 (PF4). The model’s prediction of angiogenic factors’ distribution in tumor tissue reveals the localization of different factors and indicates the angiogenic state of the tumor. We explored how the distributions are affected by the secretion of the pro- and anti-angiogenic factors, illustrating how the angiogenic network is regulated in the extracellular space. Interestingly, we identified a counterintuitive result that the secretion of the anti-angiogenic factor PF4 can enhance pro-angiogenic signaling by elevating the levels of the interstitial and surface-level pro-angiogenic species. This counterintuitive situation is pertinent to the clinical setting, such as the release of anti-angiogenic factors in platelet activation or the administration of exogenous PF4 for anti-angiogenic therapy. Our study provides mechanistic insights into this counterintuitive result and highlights the role of heparan sulfate proteoglycans in regulating the interactions between angiogenic factors. This work complements previous studies aimed at understanding the formation of angiogenic complexes in tumor tissue and helps in the development of anti-cancer strategies targeting angiogenesis.</p

Comparative Inhibition Studies of Enoyl-CoA Hydratase 1 and Enoyl-CoA Hydratase 2 in Long-Chain Fatty Acid Oxidation

Enoyl-CoA hydratase 1 and enoyl-CoA hydratase 2 in long-chain fatty acid oxidation were comparatively investigated through mechanistic studies for inactivation of the enzymes with methylenecyclopropylformyl-CoA and 3-octynoyl-CoA. Methylenecyclopropylformyl-CoA can inactivate both enzymes, while 3-octynoyl-CoA inactivates enoyl-CoA hydratase 2 only. The study increased our understanding of these two enzymes in fatty acid oxidation

Distribution of unique genes (DB = 1) in all studies.

<p>Distribution of unique genes (DB = 1) in all studies.</p

Hierarchical analysis of 15 HK-gene studies.

<p>The presence of a gene is assigned “1” and the absence of a gene is assigned “0”.</p

Control gene candidates with DB ≥ 13^*.

<p>* pseudo genes are removed.</p><p>Control gene candidates with DB ≥ 13^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123691#t003fn001" target="_blank">*</a>}.</p