scholarly journals Effect of Alpha-Lactalbumin and Lactoferrin Oleic Acid Complexes on Chromatin Structural Organization

2019 ◽  
Author(s):  
Dmitry V Lebedev ◽  
Yana A Zabrodskaya ◽  
Vitaly Pipich ◽  
Alexander I Kuklin ◽  
Edward Ramsay ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Small Angle Neutron Scattering ◽  
Structural Organization ◽  
Protein Complexes ◽  
Isolated Nuclei ◽  
Nanoscale Particles ◽  
Chromatin Structural ◽  
Anti Tumor Activity ◽  
Monodisperse System ◽  
Alpha Lactalbumin

AbstractThis work focuses on the study of multimeric alpha-lactalbumin oleic acid and lactoferrin oleic acid complexes. The purpose of the research is to study possible mechanisms involved in their pro-apoptotic activities, as seen in some tumor cell cultures. Complexes featuring oleic acid (OA) with human alpha-lactalbumin (hAl) or with bovine alpha-lactalbumin (bAl), and human lactoferrin (hLf) were investigated using small-angle neutron scattering (SANS). It was shown that while alpha-lactalbumin protein complexes were formed on the surface of polydisperse OA micelles, the lactoferrin complexes comprised a monodisperse system of nanoscale particles. Both hAl and hLf complexes appeared to interact with the chromatin of isolated nuclei affecting chromatin structural organization. The possible roles of these processes in the specific anti-tumor activity of these complexes are discussed.

scholarly journals Effect of alpha-lactalbumin and lactoferrin oleic acid complexes on chromatin structural organization

2019 ◽  
Vol 520 (1) ◽  
pp. 136-139 ◽  
Author(s):  
Dmitry V. Lebedev ◽  
Yana A. Zabrodskaya ◽  
Vitaly Pipich ◽  
Alexander I. Kuklin ◽  
Edward Ramsay ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Structural Organization ◽  
Chromatin Structural ◽  
Alpha Lactalbumin

Augmenting the cytotoxicity of oleic acid-protein complexes: Potential of target-specific antibodies

Biochimie ◽  
2017 ◽  
Vol 137 ◽  
pp. 139-146 ◽  
Author(s):  
Mehboob Hoque ◽  
Jyoti Gupta ◽  
M. Saleemuddin
Keyword(s):  
Oleic Acid ◽  
Protein Complexes ◽  
Specific Antibodies ◽  
Acid Protein

scholarly journals Cytotoxic Lactalbumin-Oleic Acid Complexes in the Human Milk Diet of Preterm Infants

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4336
Author(s):  
Katherine E. Chetta ◽  
Joseph L. Alcorn ◽  
John E. Baatz ◽  
Carol L. Wagner
Keyword(s):  
Oleic Acid ◽  
Human Milk ◽  
Preterm Infants ◽  
Frozen Storage ◽  
Lipid Complex ◽  
Acid Complex ◽  
Very Preterm Infants ◽  
Very Preterm ◽  
Milk Casein ◽  
Alpha Lactalbumin

Frozen storage is necessary to preserve expressed human milk for critically ill and very preterm infants. Milk pasteurization is essential for donor milk given to this special population. Due to these storage and processing conditions, subtle changes occur in milk nutrients. These changes may have clinical implications. Potentially, bioactive complexes of unknown significance could be found in human milk given to preterm infants. One such complex, a cytotoxic α-lactalbumin-oleic acid complex named “HAMLET,” (Human Alpha-Lactalbumin Made Lethal to Tumor cells) is a folding variant of alpha-lactalbumin that is bound to oleic acid. This complex, isolated from human milk casein, has specific toxicity to both carcinogenic cell lines and immature non-transformed cells. Both HAMLET and free oleic acid trigger similar apoptotic mechanisms in tissue and stimulate inflammation via the NF-κB and MAPK p38 signaling pathways. This protein-lipid complex could potentially trigger various inflammatory pathways with unknown consequences, especially in immature intestinal tissues. The very preterm population is dependent on human milk as a medicinal and broadly bioactive nutriment. Therefore, HAMLET’s possible presence and bioactive role in milk should be addressed in neonatal research. Through a pediatric lens, HAMLET’s discovery, formation and bioactive benefits will be reviewed.

The Role of Linker Histones in Chromatin Structural Organization. 2. Interaction with DNA and Nuclear Proteins

BIOPHYSICS ◽  
2020 ◽  
Vol 65 (2) ◽  
pp. 202-212
Author(s):  
E. V. Chikhirzhina ◽  
T. Yu. Starkova ◽  
A. M. Polyanichko
Keyword(s):  
Structural Organization ◽  
Nuclear Proteins ◽  
Linker Histones ◽  
Chromatin Structural

Phase I trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid and hematologic cancers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3006-3006 ◽  
Author(s):  
Kent C. Shih ◽  
Johanna C. Bendell ◽  
Anne Reinert ◽  
Suzanne Jones ◽  
Robin Katie Kelley ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Mammalian Target Of Rapamycin ◽  
Treatment Resistance ◽  
Competitive Inhibitor ◽  
Maximum Tolerated Dose ◽  
Clinical Endpoints ◽  
Grade 3 ◽  
Pathway Inhibition ◽  
Dose Levels ◽  
Anti Tumor Activity

3006^ Background: The mammalian target of rapamycin (mTOR) signaling pathway is frequently activated in cancer. The mTOR kinase exists in two multi-protein complexes, TORC1 and TORC2, which drive key cellular metabolic and proliferative functions.  TORC1-selective inhibitors can induce feedback upregulation of TORC2 and treatment resistance.  CC-223 is an oral, potent, selective, ATP-competitive inhibitor of both TORC1 and TORC2, selected to address this escape mechanism. Methods: Subjects with advanced solid and hematologic cancers were enrolled using an accelerated (1+5) dose escalation design.  CC-223 was administered orally once daily (QD) in 28 day cycles until disease progression.  Safety, pharmacokinetic, pharmacodynamic and clinical endpoints were evaluated. Results:   28 subjects were treated across 5 dose levels:  7.5 (n=1), 15 (n=2), 30 (n=9), 45 (n=7) and 60 mg (n=8).  The most common (> 20%) related adverse events (all grades) were fatigue (64%), nausea (50%), hyperglycemia and diarrhea (43% each), mucositis (39%), anorexia and vomiting (32% each) and rash (29%).  Dose-limiting toxicity (all grade 3) occurred in 4 subjects:  hyperglycemia (30 mg), rash (45 mg), fatigue (60mg), and mucositis (60 mg).  The maximum tolerated dose (MTD) was 45 mg QD. Dose proportional exposure was observed with a terminal half life of 4 to 8 hrs (mean steady state Cmax 485 ng/mL, AUC0-24 2371 ngxhr/mL at 45 mg).  Inhibition of TORC1 (pS6, p4EBP1) and TORC2 (pAKT) biomarkers in blood cells was characterized to be exposure-dependent and described by an Emax model.   Near maximal inhibition of both TORC1 and TORC2 biomarkers was achieved at the peak concentrations of 30 or 45mg QD.  Target inhibition was predicted to last 8 to 20 hours at 45mg QD. Tumor responses included: 1 partial response lasting 9 months (ER+ breast) and 7 subjects with stable disease (SD) lasting 8+ weeks (range 8 to 23.3). Conclusions:   CC-223 was well tolerated with toxicities comparable to other drugs in this class.  Evidence of TORC1/TORC2 pathway inhibition was observed as well as preliminary signals of anti-tumor activity, including one durable PR.  Expansion cohorts in selected hematologic and solid tumors will evaluate CC-223 at the MTD of 45 mg QD.

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