PMID- 33147798
OWN - NLM
STAT- MEDLINE
DCOM- 20210331
LR  - 20231112
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 21
DP  - 2020 Nov 2
TI  - Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone as an 
      Anti-Inflammatory Modulator of LPS-Mediated Astrocyte Responses.
LID - 10.3390/ijms21218203 [doi]
LID - 8203
AB  - Astrocytes are glial cells that play an important role in neuroinflammation. 
      Astrocytes respond to many pro-inflammatory stimuli, including lipopolysaccharide 
      (LPS), an agonist of Toll-like receptor 4 (TLR4). Regulatory specificities of 
      inflammatory signaling pathways are still largely unknown due to the ectodermal 
      origin of astrocytes. Recently, we have shown that hyaluronic acid (HA) may form 
      part of astrocyte inflammatory responses. Therefore, we tested 
      4-methylumbelliferone (4-MU), a specific inhibitor of HA synthesis, as a possible 
      regulator of LPS-mediated responses. Rat primary astrocytes were treated with LPS 
      with and without 4-MU and gene expression levels of inflammatory (interleukins 
      1beta, (IL-1beta), 6, (IL-6), tumor necrosis factor alpha TNFalpha,) and resolution 
      interleukin 10 (IL-10) markers were evaluated via real-time PCR and western blot. 
      The release of cytokines and HA was determined by ELISA. Oxylipin profiles were 
      measured by ultra-performance liquid chromatography-tandem mass spectrometry 
      (UPLC-MS/MS) analysis. Our data show that 4-MU (i) has anti-inflammatory effects 
      in the course of TLR4 activation, decreasing the cytokines level TNFalpha, IL-6 and 
      IL-1beta and increasing IL-10, (ii) downregulates prostaglandin synthesis but not 
      via cyclooxygenases COX-1 and COX-2 pathways, (iii) modulates HA synthesis and 
      decreases LPS-induced HA synthase mRNA expression (HAS-1, HAS-2) but does not 
      have an influence on HAS-3, HYAL1 and HYAL2 mRNAs; (iv) the effects of 4-MU are 
      predominantly revealed via JNK but not p38, ERK mitogen-activated protein kinases 
      (MAPKs) or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) 
      pathways. For the first time, it is shown that 4-MU possesses the useful 
      potential to regulate an inflammatory astrocyte response.
FAU - Chistyakov, Dmitry V
AU  - Chistyakov DV
AUID- ORCID: 0000-0003-0137-8585
AD  - Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State 
      University, 119992 Moscow, Russia.
AD  - SREC PFUR, Peoples' Friendship University of Russia (RUDN University), 117198 
      Moscow, Russia.
FAU - Nikolskaya, Arina I
AU  - Nikolskaya AI
AD  - Faculty of Bioengineering and Bioinformatics, Moscow Lomonosov State University, 
      119234 Moscow, Russia.
FAU - Goriainov, Sergei V
AU  - Goriainov SV
AD  - SREC PFUR, Peoples' Friendship University of Russia (RUDN University), 117198 
      Moscow, Russia.
FAU - Astakhova, Alina A
AU  - Astakhova AA
AD  - Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State 
      University, 119992 Moscow, Russia.
FAU - Sergeeva, Marina G
AU  - Sergeeva MG
AUID- ORCID: 0000-0002-7625-9110
AD  - Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State 
      University, 119992 Moscow, Russia.
LA  - eng
GR  - 16-15-10298/Russian Science Foundation/
PT  - Journal Article
DEP - 20201102
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (IL1B protein, rat)
RN  - 0 (Il6 protein, rat)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Oxylipins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 130068-27-8 (Interleukin-10)
RN  - 3T5NG4Q468 (Hymecromone)
RN  - 9004-61-9 (Hyaluronic Acid)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Astrocytes/*drug effects
MH  - Cells, Cultured
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Female
MH  - Hyaluronic Acid/*antagonists & inhibitors
MH  - Hymecromone/*pharmacology
MH  - Inflammation
MH  - Interleukin-10/metabolism
MH  - Interleukin-1beta/metabolism
MH  - Interleukin-6/metabolism
MH  - Lipopolysaccharides
MH  - MAP Kinase Signaling System
MH  - Male
MH  - NF-kappa B/metabolism
MH  - Oxylipins/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Real-Time Polymerase Chain Reaction
MH  - Tandem Mass Spectrometry
MH  - Tumor Necrosis Factor-alpha/metabolism
PMC - PMC7662953
OTO - NOTNLM
OT  - 4-methylumbelliferone (4-MU)
OT  - astrocytes
OT  - cyclooxygenase (COX)
OT  - hyaluronic acid
OT  - interleukin 10 (IL-10)
OT  - interleukin 6 (IL-6)
OT  - neuroinflammation
OT  - oxylipins
OT  - toll-like receptors (TLRs)
COIS- The authors declare no conflict of interests.
EDAT- 2020/11/06 06:00
MHDA- 2021/04/01 06:00
PMCR- 2020/11/01
CRDT- 2020/11/05 01:00
PHST- 2020/10/11 00:00 [received]
PHST- 2020/10/25 00:00 [revised]
PHST- 2020/10/30 00:00 [accepted]
PHST- 2020/11/05 01:00 [entrez]
PHST- 2020/11/06 06:00 [pubmed]
PHST- 2021/04/01 06:00 [medline]
PHST- 2020/11/01 00:00 [pmc-release]
AID - ijms21218203 [pii]
AID - ijms-21-08203 [pii]
AID - 10.3390/ijms21218203 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Nov 2;21(21):8203. doi: 10.3390/ijms21218203.