scholarly journals Chemical activation of prolyl hydroxylase-2 by BBAP-1 down regulates hypoxia inducible factor-1α and fatty acid synthase for mammary gland chemoprevention

RSC Advances ◽  
2018 ◽  
Vol 8 (23) ◽  
pp. 12848-12860 ◽  
Author(s):  
Manjari Singh ◽  
Uma Devi ◽  
Subhadeep Roy ◽  
Pushpraj S. Gupta ◽  
Gaurav Kaithwas
Keyword(s):  
Mammary Gland ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Chemical Activation ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Phenyl Acetate ◽  
Hypoxia Inducible Factor 1Α

(4-[7-(Acetyloxy)-2-ethyl-2H-chromen-3-yl] phenyl acetate) (BBAP-1) was identified as a potential prolyl hydroxylase-2 activator and tested for this activity using the 2-oxoglutarate dependentin vitroassay.

scholarly journals Repurposing combination therapy of Voacamine with Vincristine for down regulation of HIF-1α/FASN co-axis and PHD2 activation in ER+ mammary neoplasia

2020 ◽  
Author(s):  
Lakhveer Singh ◽  
Manjari Singh ◽  
Dinesh Kumar ◽  
Mohd. Nazam Ansari ◽  
Abdulaziz S. Saeedan ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Fatty Acid ◽  
Combination Therapy ◽  
Fatty Acid Synthase ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Over Expression ◽  
Hypoxia Inducible Factor 1Α ◽  
Gland Carcinoma

Abstract Background The current study was attempted to inquest the role of combination therapy of Voacamine and Vincristine for the prevention of mammary gland carcinoma through prolyl hydroxylase-2 activation. The prolyl hydroxylase‐2 activation leads the downregulation of hypoxia‐inducible factor‐1α and fatty acid synthase. Over expression of hypoxia inducible factor-1α and fatty acid synthase is previously reported in solid tumor of mammary gland. Methods After screening a battery of natural compounds which were similar to vincristine, vocamine was selected as a possible prolyl hydroxylase-2 activator and justify its activity using 7, 12-Dimethylbenz[a]anthracene induced rat model. The combination therapy was evaluated for cardiac toxicity using hemodynamic profile. The angiogenic markers were evaluated using carmine staining. Monotherapy and combination therapy were also evaluated for liver and kidney toxicity through haematoxylin and eosin staining. The combination therapy also delineated the markers of oxidative stress favorably. Afterwards, the disruption of fatty acids was evaluated using gas chromatography. Results The immunoblotting analysis validated that combination therapy has a potential to switch on the prolyl hydroxylase-2 activity and thus initiate proteolytic degradation of hypoxia‐inducible factor‐1α and its consequence effects. The combination therapy also stimulated programmed cell death (apoptosis) in rapidly dividing cancer cells. Conclusion The present study explores the role of voacamine in activation of prolyl hydroxylase-2 which can decrease over expression of hypoxia‐inducible factor‐1α and fatty acid synthase in cells of mammary gland carcinoma.

scholarly journals Repurposing Combination Therapy of Voacamine with Vincristine for Down Regulation of HIF-1α/FASN Co-Axis and PHD2 Activation in ER+ Mammary Neoplasia

2020 ◽  
Author(s):  
Lakhveer Singh ◽  
Manjari Singh ◽  
Mohd. Nazam Ansari ◽  
Abdulaziz S. Saeedan ◽  
Gaurav Kaithwas
Keyword(s):  
Mammary Gland ◽  
Fatty Acid ◽  
Combination Therapy ◽  
Fatty Acid Synthase ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Over Expression ◽  
Hypoxia Inducible Factor 1Α ◽  
Gland Carcinoma

Abstract Background: The current study was attempted to inquest the role of combination therapy of Voacamine and Vincristine for the prevention of mammary gland carcinoma through prolyl hydroxylase‐2 activation. The prolyl hydroxylase‐2 activation leads the downregulation of hypoxia‐inducible factor‐1α and fatty acid synthase. Over expression of hypoxia inducible factor-1α and fatty acid synthase is previously reported in solid tumor of mammary gland. Methods: After screening a battery of natural compounds which were similar to vincristine, vocamine was selected as a possible prolyl hydroxylase‐2 activator and justify its activity using 7, 12-Dimethylbenz[a]anthracene induced rat model. The combination therapy was evaluated for cardiac toxicity using hemodynamic profile. The angiogenic markers were evaluated using carmine staining. Monotherapy and combination therapy were also evaluated for liver and kidney toxicity through haematoxylin and eosin staining. The combination therapy also delineated the markers of oxidative stress favorably. Afterwards, the disruption of fatty acids was evaluated using gas chromatography. Results: The immunoblotting analysis validated that combination therapy has a potential to switch on the prolyl hydroxylase‐2 activity and thus initiate proteolytic degradation of hypoxia‐inducible factor‐1α and its consequence effects. The combination therapy also stimulated programmed cell death (apoptosis) in rapidly dividing cancer cells.Conclusion: The present study explores the role of voacamine in activation of prolyl hydroxylase‐2 which can decrease over expression of hypoxia‐inducible factor‐1α and fatty acid synthase in cells of mammary gland carcinoma.

scholarly journals Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia

2021 ◽  
Vol 9 ◽  
Author(s):  
Lakhveer Singh ◽  
Subhadeep Roy ◽  
Anurag Kumar ◽  
Shubham Rastogi ◽  
Dinesh Kumar ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Tumor Microenvironment ◽  
Fatty Acid Synthesis ◽  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Hypoxia Inducible Factor ◽  
Acid Synthesis ◽  
Prolyl Hydroxylase ◽  
Proliferating Cells ◽  
Hypoxia Inducible Factor 1Α

Graphical AbstractMechanism of VOA and VIN to inhibit fatty acid synthesis in DMBA-induced mammary gland carcinoma of albino Wistar rats. Hypoxia-activated HIF-1α enhances lactate acidosis in the tumor microenvironment, and dysregulated pH in the tumor microenvironment activates SREBP-1c and FASN expression to speed up the fatty acid synthesis required for plasma membrane synthesis in rapidly proliferating cells. VOA- and VIN-activated PHD-2 enhanced the proteolytic degradation of HIF, thus inhibiting fatty acid synthesis. HIF-1α, hypoxia-inducible factor-1α; SREBP-1c, sterol regulatory element-binding protein-1c; FASN, fatty acid synthesis; PHD-2, prolyl hydroxylase-2.

Prolyl hydroxylase mediated inhibition of fatty acid synthase to combat tumor growth in mammary gland carcinoma

Breast Cancer ◽  
2016 ◽  
Vol 23 (6) ◽  
pp. 820-829 ◽  
Author(s):  
Manjari Singh ◽  
Uma Devi ◽  
Subhadeep Roy ◽  
Pushpraj S. Gupta ◽  
Shubhini A. Saraf ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Fatty Acid ◽  
Tumor Growth ◽  
Fatty Acid Synthase ◽  
Prolyl Hydroxylase ◽  
Mammary Gland Carcinoma ◽  
Gland Carcinoma

scholarly journals Hypoxia-inducible Factor-1α Induces ErbB4 Signaling in the Differentiating Mammary Gland

2014 ◽  
Vol 289 (32) ◽  
pp. 22459-22469 ◽  
Author(s):  
Ilkka Paatero ◽  
Tiffany N. Seagroves ◽  
Katri Vaparanta ◽  
Wen Han ◽  
Frank E. Jones ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1Α

scholarly journals Structural comparison of Acinetobacter baumannii β-ketoacyl-acyl carrier protein reductases in fatty acid and aryl polyene biosynthesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Woo Cheol Lee ◽  
Sungjae Choi ◽  
Ahjin Jang ◽  
Kkabi Son ◽  
Yangmee Kim
Keyword(s):  
Fatty Acid ◽  
Acinetobacter Baumannii ◽  
Gene Cluster ◽  
Fatty Acid Synthase ◽  
Acyl Carrier Protein ◽  
Gene Clusters ◽  
Carrier Protein ◽  
Aryl Group ◽  
Visible Absorption

AbstractSome Gram-negative bacteria harbor lipids with aryl polyene (APE) moieties. Biosynthesis gene clusters (BGCs) for APE biosynthesis exhibit striking similarities with fatty acid synthase (FAS) genes. Despite their broad distribution among pathogenic and symbiotic bacteria, the detailed roles of the metabolic products of APE gene clusters are unclear. Here, we determined the crystal structures of the β-ketoacyl-acyl carrier protein (ACP) reductase ApeQ produced by an APE gene cluster from clinically isolated virulent Acinetobacter baumannii in two states (bound and unbound to NADPH). An in vitro visible absorption spectrum assay of the APE polyene moiety revealed that the β-ketoacyl-ACP reductase FabG from the A. baumannii FAS gene cluster cannot be substituted for ApeQ in APE biosynthesis. Comparison with the FabG structure exhibited distinct surface electrostatic potential profiles for ApeQ, suggesting a positively charged arginine patch as the cognate ACP-binding site. Binding modeling for the aryl group predicted that Leu185 (Phe183 in FabG) in ApeQ is responsible for 4-benzoyl moiety recognition. Isothermal titration and arginine patch mutagenesis experiments corroborated these results. These structure–function insights of a unique reductase in the APE BGC in comparison with FAS provide new directions for elucidating host–pathogen interaction mechanisms and novel antibiotics discovery.

scholarly journals Hypoxia-Inducible Factor Prolyl-Hydroxylase 2 Senses High-Salt Intake to Increase Hypoxia Inducible Factor 1α Levels in the Renal Medulla

Hypertension ◽  
2010 ◽  
Vol 55 (5) ◽  
pp. 1129-1136 ◽  
Author(s):  
Zhengchao Wang ◽  
Qing Zhu ◽  
Min Xia ◽  
Pin-Lan Li ◽  
Shante J. Hinton ◽  
...  
Keyword(s):  
Salt Intake ◽  
Hypoxia Inducible Factor ◽  
Renal Medulla ◽  
Prolyl Hydroxylase ◽  
High Salt ◽  
Hypoxia Inducible Factor 1Α ◽  
High Salt Intake

scholarly journals A Fatty Acid Synthase Gene in Cochliobolus carbonum Required for Production of HC-Toxin, Cyclo(d-Prolyl-l-Alanyl- d-Alanyl- l-2-Amino-9,10-Epoxi-8-Oxodecanoyl)

1997 ◽  
Vol 10 (2) ◽  
pp. 207-214 ◽  
Author(s):  
Joong-Hoon Ahn ◽  
Jonathan D. Walton
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Cyclic Peptide ◽  
Decanoic Acid ◽  
Toxin Production ◽  
Gene Encoding ◽  
Cochliobolus Carbonum ◽  
Primary Amino ◽  
Hc Toxin

The fungal maize pathogen Cochliobolus carbonum produces a phytotoxic and cytostatic cyclic peptide, HC-toxin, of structure cyclo(D-prolyl-L-alanyl-D-alanyl-L-Aeo), in which Aeo stands for 2-amino-9,10-epoxi-8-oxodecanoic acid. Here we report the isolation of a gene, TOXC, that is present only in HC-toxin-producing (Tox2+) fungal strains. TOXC is present in most Tox2+ strains in three functional copies, all of which are on the same chromosome as the gene encoding HC-toxin synthetase. When all copies of TOXC are mutated by targeted gene disruption, the fungus grows and sporulates normally in vitro but no longer makes HC-toxin and is not pathogenic, indicating that TOXC has a specific role in HC-toxin production and hence virulence. The TOXC mRNA is 6.5 kb and the predicted product has 2,080 amino acids and a molecular weight of 233,000. The primary amino acid sequence is highly similar (45 to 47% identity) to the β subunit of fatty acid synthase from several lower eukaryotes, and contains, in the same order as in other β subunits, domains predicted to encode acetyl transferase, enoyl reductase, dehydratase, and malonyl-palmityl transferase. The most plausible function of TOXC is to contribute to the synthesis of the decanoic acid backbone of Aeo.

scholarly journals Regulation of lipogenic capacity in lactating rats

1982 ◽  
Vol 208 (3) ◽  
pp. 611-618 ◽  
Author(s):  
M R Grigor ◽  
A Geursen ◽  
M J Sneyd ◽  
S M Warren
Keyword(s):  
Mammary Gland ◽  
Fatty Acid ◽  
Malic Enzyme ◽  
Fatty Acid Synthase ◽  
Specific Activity ◽  
Mammary Glands ◽  
Lipogenic Enzymes ◽  
Pregnancy And Lactation ◽  
Specific Activities

1. The rate of mammary-gland lipogenesis measured in vivo from 3H2O was suppressed after decreasing the milk demand by decreasing the number of pups from ten to two or three, as well as by giving diets containing lipid [Grigor & Warren (1980) Biochem. J. 188, 61-65]. 2. The specific activities of the lipogenic enzymes fatty acid synthase, glucose 6-phosphate dehydrogenase and ‘malic’ enzyme increased between 6- and 10-fold in the mammary gland and between 2- and 3-fold in the livers during the first 10 days of lactation. The increases in specific activity coupled with the doubling of liver mass which occurred during pregnancy and lactation resulted in considerable differences in total liver activities when compared with virgin animals. 3. Although consumption of a diet containing 20% peanut oil suppressed the activities of the three lipogenic enzymes in the livers, only the ‘malic’ enzyme was affected in the mammary glands. 4. In contrast, decreased milk demand did not affect the specific activities of any of the liver enzymes, whereas it resulted in suppression of all three lipogenic enzymes of the mammary glands. There was no effect on either the cytoplasmic malate dehydrogenase or the lactate dehydrogenase of the mammary gland. 5. In all the experiments performed, the activity of the fatty acid synthase correlated with the amount of material precipitated by the rabbit antibody raised against rat fatty acid synthase.

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