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Determination of hyaluronan molecular mass distribution in human breast milk.

ABSTRACT: Hyaluronan (HA) in human milk mediates host responses to microbial infection via TLR4- and CD44-dependent signaling. Signaling by HA is generally size specific. Because pure HA with average molecular mass (M) of 35 kDa can elicit a protective response in intestinal epithelial cells, it has been proposed that human milk HA may have a bioactive low-M component. Here we report the size distribution of HA in human milk samples from 20 unique donors. A new method for HA analysis, employing ion exchange (IEX) chromatography to fractionate HA by size and specific quantification of each size fraction by competitive enzyme-linked sorbent assay (ELSA), was developed. When separated into four fractions, milk HA with M?20 kDa, M?20 to 60 kDa, and M?60 to 110 kDa comprised averages of 1.5, 1.4, and 2.0% of the total HA, respectively. The remaining 95% was HA with M?110 kDa. Electrophoretic analysis of the higher M HA from 13 samples showed nearly identical M distributions, with an average M of approximately 440 kDa. This higher M HA component in human milk is proposed to bind to CD44 and to enhance human beta defensin 2 (HBD2) induction by the low-M HA components.

SUBMITTER: Yuan H

PROVIDER: S-EPMC4357551 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Determination of hyaluronan molecular mass distribution in human breast milk.

Yuan Han H Amin Ripal R Ye Xin X de la Motte Carol A CA Cowman Mary K MK

Analytical biochemistry 20150109

Hyaluronan (HA) in human milk mediates host responses to microbial infection via TLR4- and CD44-dependent signaling. Signaling by HA is generally size specific. Because pure HA with average molecular mass (M) of 35 kDa can elicit a protective response in intestinal epithelial cells, it has been proposed that human milk HA may have a bioactive low-M component. Here we report the size distribution of HA in human milk samples from 20 unique donors. A new method for HA analysis, employing ion exchan ...[more]

PMID: 25579786

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Project description:Rationale: Optimal intratumor distribution of an anticancer drug is fundamental to reach an active concentration in neoplastic cells, ensuring the therapeutic effect. Determination of drug concentration in tumor homogenates by LC-MS/MS gives important information about this issue but the spatial information gets lost. Targeted mass spectrometry imaging (MSI) has great potential to visualize drug distribution in the different areas of tumor sections, with good spatial resolution and superior specificity. MSI is rapidly evolving as a quantitative technique to measure the absolute drug concentration in each single pixel. Methods: Different inorganic nanoparticles were tested as matrices to visualize the PARP inhibitors (PARPi) niraparib and olaparib. Normalization by deuterated internal standard and a custom preprocessing pipeline were applied to achieve a reliable single pixel quantification of the two drugs in human ovarian tumors from treated mice. Results: A quantitative method to visualize niraparib and olaparib in tumor tissue of treated mice was set up and validated regarding precision, accuracy, linearity, repeatability and limit of detection. The different tumor penetration of the two drugs was visualized by MSI and confirmed by LC-MS/MS, indicating the homogeneous distribution and higher tumor exposure reached by niraparib compared to olaparib. On the other hand, niraparib distribution was heterogeneous in an ovarian tumor model overexpressing the multidrug resistance protein P-gp, a possible cause of resistance to PARPi. Conclusions: The current work highlights for the first time quantitative distribution of PAPRi in tumor tissue. The different tumor distribution of niraparib and olaparib could have important clinical implications. These data confirm the validity of MSI for spatial quantitative measurement of drug distribution providing fundamental information for pharmacokinetic studies, drug discovery and the study of resistance mechanisms.

Dataset Information

Determination of hyaluronan molecular mass distribution in human breast milk.

Publications

Determination of hyaluronan molecular mass distribution in human breast milk.

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