PMID- 38334676
OWN - NLM
STAT- MEDLINE
DCOM- 20240214
LR  - 20240226
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 13
IP  - 3
DP  - 2024 Feb 5
TI  - Imeglimin Exhibits Novel Anti-Inflammatory Effects on High-Glucose-Stimulated 
      Mouse Microglia through ULK1-Mediated Suppression of the TXNIP-NLRP3 Axis.
LID - 10.3390/cells13030284 [doi]
LID - 284
AB  - Type 2 diabetes mellitus (T2DM) is an epidemiological risk factor for dementia 
      and has been implicated in multifactorial pathologies, including 
      neuroinflammation. In the present study, we aimed to elucidate the potential 
      anti-inflammatory effects of imeglimin, a novel antidiabetic agent, on 
      high-glucose (HG)-stimulated microglia. Mouse microglial BV2 cells were 
      stimulated with HG in the presence or absence of imeglimin. We examined the 
      effects of imeglimin on the levels of proinflammatory cytokines, intracellular 
      reactive oxygen species (ROS), mitochondrial integrity, and components related to 
      the inflammasome or autophagy pathways in these cells. Our results showed that 
      imeglimin suppressed the HG-induced production of interleukin-1beta (IL-1beta) by 
      reducing the intracellular ROS levels, ameliorating mitochondrial dysfunction, 
      and inhibiting the activation of the thioredoxin-interacting protein 
      (TXNIP)-NOD-like receptor family pyrin domain containing 3 (NLRP3) axis. 
      Moreover, the inhibitory effects of imeglimin on the TXNIP-NLRP3 axis depended on 
      the imeglimin-induced activation of ULK1, which also exhibited novel 
      anti-inflammatory effects without autophagy induction. These findings suggest 
      that imeglimin exerted novel suppressive effects on HG-stimulated microglia 
      through the ULK1-TXNIP-NLRP3 axis, and may, thereby, contribute to the 
      development of innovative strategies to prevent T2DM-associated cognitive 
      impairment.
FAU - Kato, Hisashi
AU  - Kato H
AUID- ORCID: 0000-0003-4395-8369
AD  - Department of Endocrinology, Metabolism and Hypertension Research, Clinical 
      Research Institute, NHO Kyoto Medical Center, Kyoto 612-8555, Japan.
FAU - Iwashita, Kaori
AU  - Iwashita K
AD  - Department of Endocrinology, Metabolism and Hypertension Research, Clinical 
      Research Institute, NHO Kyoto Medical Center, Kyoto 612-8555, Japan.
FAU - Iwasa, Masayo
AU  - Iwasa M
AUID- ORCID: 0000-0001-8761-9698
AD  - Department of Endocrinology, Metabolism and Hypertension Research, Clinical 
      Research Institute, NHO Kyoto Medical Center, Kyoto 612-8555, Japan.
FAU - Kato, Sayaka
AU  - Kato S
AD  - Department of Endocrinology, Metabolism and Hypertension Research, Clinical 
      Research Institute, NHO Kyoto Medical Center, Kyoto 612-8555, Japan.
AD  - Department of Endocrinology and Metabolism, Graduate School of Medical Science, 
      Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
FAU - Yamakage, Hajime
AU  - Yamakage H
AD  - Department of Endocrinology, Metabolism and Hypertension Research, Clinical 
      Research Institute, NHO Kyoto Medical Center, Kyoto 612-8555, Japan.
FAU - Suganami, Takayoshi
AU  - Suganami T
AUID- ORCID: 0000-0002-1918-0465
AD  - Department of Molecular Medicine and Metabolism, Research Institute of 
      Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
AD  - Department of Immunometabolism, Nagoya University Graduate School of Medicine, 
      Nagoya 464-8601, Japan.
AD  - Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, 
      Nagoya University, Nagoya 464-8601, Japan.
AD  - Center for One Medicine Innovative Translational Research (COMIT), Nagoya 
      University, Nagoya 464-8601, Japan.
FAU - Tanaka, Masashi
AU  - Tanaka M
AUID- ORCID: 0000-0003-0719-8972
AD  - Department of Endocrinology, Metabolism and Hypertension Research, Clinical 
      Research Institute, NHO Kyoto Medical Center, Kyoto 612-8555, Japan.
AD  - Department of Rehabilitation, Health Science University, Minamitsuru-gun 
      401-0380, Japan.
FAU - Satoh-Asahara, Noriko
AU  - Satoh-Asahara N
AUID- ORCID: 0000-0002-8645-3144
AD  - Department of Endocrinology, Metabolism and Hypertension Research, Clinical 
      Research Institute, NHO Kyoto Medical Center, Kyoto 612-8555, Japan.
AD  - Department of Metabolic Syndrome and Nutritional Science, Research Institute of 
      Environmental Medicine, Nagoya University, Nagoya 466-8550, Japan.
LA  - eng
GR  - JP21K17557/Japan Society for the Promotion of Science/
GR  - JP22K07411/Japan Society for the Promotion of Science/
GR  - JP22K11720/Japan Society for the Promotion of Science/
GR  - JP22K07456/Japan Society for the Promotion of Science/
GR  - JP21H02835/Japan Society for the Promotion of Science/
GR  - JP22K19723/Japan Society for the Promotion of Science/
GR  - H29-NHO-01/the National Hospital Organization for collaborative clinical 
      research/
PT  - Journal Article
DEP - 20240205
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Anti-Inflammatory Agents)
RN  - IY9XDZ35W2 (Glucose)
RN  - UU226QGU97 (imeglimin)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Triazines)
RN  - EC 2.7.11.1 (Ulk1 protein, mouse)
RN  - EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog)
RN  - 0 (Txnip protein, mouse)
RN  - 52500-60-4 (Thioredoxins)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Anti-Inflammatory Agents/pharmacology
MH  - *Diabetes Mellitus, Type 2/complications/drug therapy
MH  - Glucose/pharmacology
MH  - Microglia/metabolism
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - *Triazines
MH  - Autophagy-Related Protein-1 Homolog/drug effects/metabolism
MH  - Thioredoxins/drug effects/metabolism
PMC - PMC10854746
OTO - NOTNLM
OT  - ULK1
OT  - hyperglycemia
OT  - imeglimin
OT  - microglia
OT  - neuroinflammation
OT  - type 2 diabetes mellitus
COIS- The authors declare no conflicts of interest. The funders and Sumitomo Pharma Co. 
      Ltd. had no role in the design of the study; in the collection, analyses, or 
      interpretation of data; in the writing of the manuscript; or in the decision to 
      publish the results.
EDAT- 2024/02/09 12:44
MHDA- 2024/02/09 18:42
PMCR- 2024/02/05
CRDT- 2024/02/09 10:15
PHST- 2023/11/29 00:00 [received]
PHST- 2024/01/30 00:00 [revised]
PHST- 2024/02/02 00:00 [accepted]
PHST- 2024/02/09 18:42 [medline]
PHST- 2024/02/09 12:44 [pubmed]
PHST- 2024/02/09 10:15 [entrez]
PHST- 2024/02/05 00:00 [pmc-release]
AID - cells13030284 [pii]
AID - cells-13-00284 [pii]
AID - 10.3390/cells13030284 [doi]
PST - epublish
SO  - Cells. 2024 Feb 5;13(3):284. doi: 10.3390/cells13030284.