PMID- 33605181
OWN - NLM
STAT- MEDLINE
DCOM- 20211021
LR  - 20220107
IS  - 1521-0464 (Electronic)
IS  - 1071-7544 (Print)
IS  - 1071-7544 (Linking)
VI  - 28
IP  - 1
DP  - 2021 Dec
TI  - Skin-specific knockdown of hyaluronan in mice by an optimized topical 
      4-methylumbelliferone formulation.
PG  - 422-432
LID - 10.1080/10717544.2021.1886376 [doi]
AB  - Hyaluronan (HA) is abundant in the skin; while HA can be synthesized by the 
      synthases (HAS1-3), HAS2 is the leading contributor. Dysregulation and 
      accumulation of HA is implicated in the pathogenesis of diseases such as keloid 
      scarring, lymphedema and metastatic melanoma. To understand how HA synthesis 
      contributes to skin physiology, and pathologic and fibrotic disorders, we propose 
      the development of skin-specific HA inhibition model, which tests an optimal 
      delivery system of topical 4-methylumbelliferone (4-MU). A design-of-experiments 
      (DOE) approach was employed to develop an optimal 4-MU skin-delivery formulation 
      comprising propylene glycol, ethanol, and water, topically applied to dorsal skin 
      in male and female C57BL/6J wildtype mice to determine the effect on HAS gene 
      expression and HA inhibition. Serum and skin samples were analyzed for HA content 
      along with analysis of expression of HAS1-3, hyaluronidases (HYAL 1-2), and 
      KIAA1199. Using results from DOE and response surface methodology with genetic 
      algorithm optimization, we developed an optimal topical 4-MU formulation to 
      result in  approximately 70% reduction of HA in dorsal skin, with validation demonstrating  approximately 50% 
      reduction in HA in dorsal skin. 4-MU topical application resulted in significant 
      decrease in skin HAS2 expression in female mice only. Histology showed thicker 
      dermis in male mice, whereas female mice had thinner dermal layer with more 
      adiposity; and staining for HA-binding protein showed that topical 4-MU resulted 
      in breakdown in HA. Our data suggest a topical 4-MU formulation-based dermal HA 
      inhibition model that would enable elucidating the skin-specific effects of HA in 
      normal and pathologic states.
FAU - Steen, Emily H
AU  - Steen EH
AD  - Department of Surgery, Division of Pediatric Surgery, Laboratory for Regenerative 
      Tissue Repair, Texas Children's Hospital and Baylor College of Medicine, Houston, 
      TX, USA.
FAU - Short, Walker D
AU  - Short WD
AD  - Department of Surgery, Division of Pediatric Surgery, Laboratory for Regenerative 
      Tissue Repair, Texas Children's Hospital and Baylor College of Medicine, Houston, 
      TX, USA.
FAU - Li, Hui
AU  - Li H
AD  - Department of Surgery, Division of Pediatric Surgery, Laboratory for Regenerative 
      Tissue Repair, Texas Children's Hospital and Baylor College of Medicine, Houston, 
      TX, USA.
FAU - Parikh, Umang M
AU  - Parikh UM
AD  - Department of Surgery, Division of Pediatric Surgery, Laboratory for Regenerative 
      Tissue Repair, Texas Children's Hospital and Baylor College of Medicine, Houston, 
      TX, USA.
FAU - Blum, Alexander
AU  - Blum A
AD  - Department of Surgery, Division of Pediatric Surgery, Laboratory for Regenerative 
      Tissue Repair, Texas Children's Hospital and Baylor College of Medicine, Houston, 
      TX, USA.
FAU - Templeman, Natalie
AU  - Templeman N
AD  - Department of Surgery, Division of Pediatric Surgery, Laboratory for Regenerative 
      Tissue Repair, Texas Children's Hospital and Baylor College of Medicine, Houston, 
      TX, USA.
FAU - Nagy, Nadine
AU  - Nagy N
AD  - Department of Medicine, Division of Infectious Diseases, Stanford University 
      School of Medicine, Stanford, CA, USA.
FAU - Bollyky, Paul L
AU  - Bollyky PL
AD  - Department of Medicine, Division of Infectious Diseases, Stanford University 
      School of Medicine, Stanford, CA, USA.
FAU - Keswani, Sundeep G
AU  - Keswani SG
AD  - Department of Surgery, Division of Pediatric Surgery, Laboratory for Regenerative 
      Tissue Repair, Texas Children's Hospital and Baylor College of Medicine, Houston, 
      TX, USA.
FAU - Balaji, Swathi
AU  - Balaji S
AD  - Department of Surgery, Division of Pediatric Surgery, Laboratory for Regenerative 
      Tissue Repair, Texas Children's Hospital and Baylor College of Medicine, Houston, 
      TX, USA.
LA  - eng
GR  - R01 GM111808/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PL  - England
TA  - Drug Deliv
JT  - Drug delivery
JID - 9417471
RN  - 059QF0KO0R (Water)
RN  - 3K9958V90M (Ethanol)
RN  - 3T5NG4Q468 (Hymecromone)
RN  - 6DC9Q167V3 (Propylene Glycol)
RN  - 9004-61-9 (Hyaluronic Acid)
RN  - EC 3.2.1.35 (Hyaluronoglucosaminidase)
SB  - IM
MH  - Administration, Cutaneous
MH  - Animals
MH  - *Drug Delivery Systems
MH  - Ethanol/chemistry
MH  - Female
MH  - Gene Knockdown Techniques
MH  - Hyaluronic Acid/*metabolism
MH  - Hyaluronoglucosaminidase/*genetics
MH  - Hymecromone/*administration & dosage/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Propylene Glycol/chemistry
MH  - Water/chemistry
PMC - PMC7899664
OTO - NOTNLM
OT  - 4-methylumbelliferone (4-MU)
OT  - Hyaluronic acid
OT  - genetic algorithm
OT  - hyaluronan
OT  - inhibition
OT  - response surface methodology
OT  - topical
COIS- No potential conflict of interest was reported by the author(s).
EDAT- 2021/02/20 06:00
MHDA- 2022/01/06 06:00
PMCR- 2021/02/19
CRDT- 2021/02/19 08:38
PHST- 2021/02/19 08:38 [entrez]
PHST- 2021/02/20 06:00 [pubmed]
PHST- 2022/01/06 06:00 [medline]
PHST- 2021/02/19 00:00 [pmc-release]
AID - 1886376 [pii]
AID - 10.1080/10717544.2021.1886376 [doi]
PST - ppublish
SO  - Drug Deliv. 2021 Dec;28(1):422-432. doi: 10.1080/10717544.2021.1886376.