Inhibitory effects of xanthine oxidase inhibitor, topiroxostat, on development of neuropathy in db/db mice

Takahashi, Kazuhisa; Mizukami, Hiroki; Osonoi, Sho; Ogasawara, Saori; Hara, Yutaro; Kudoh, Kazuhiro; Takeuchi, Yuki; Sasaki, Takanori; Daimon, Makoto; Yagihashi, Soroku

doi:10.1016/j.nbd.2021.105392

Cited by 13 publications

(15 citation statements)

References 40 publications

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“…Subsequently, cDNA was generated with the SuperScript ® VILO cDNA Synthesis Kit (Thermo Fisher Scientific). Quantitative PCR (qPCR) was performed with a previously described method [ 52 , 53 ]. Commercially available probe sets of mice (Gene expression assays, Thermo Fisher Scientific) for TGF−β, αSMA, collagen Type 1A1, RAGE, IL−6 and an internal standard of β2 microglobulin were mixed with cDNA Thunderbird Probe qPCR Mix (Toyobo Co. Ltd., Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma

Uchida

Mizukami

Hara

et al. 2021

IJMS

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Pancreatic stellate cells (PSCs) mainly consist of cancer-associating fibroblasts in pancreatic ductal adenocarcinoma (PDAC). The receptor for advanced glycation end products (RAGE) is implicated in the pathophysiology of diabetic complications. Here, we studied the implication of RAGE in PSC activation in PDAC. The activation of cultured mouse PSCs was evaluated by qPCR. The induction of epithelial mesenchymal transition (EMT) in PDAC cell lines was assessed under stimulation with culture supernatant from activated PSCs. A total of 155 surgically resected PDAC subjects (83 nondiabetic, 18 with ≦3-years and 54 with >3-years history of diabetes) were clinicopathologically evaluated. A high-fat diet increased the expression of activated markers in cultured PSCs, which was abrogated by RAGE deletion. Culture supernatant from activated PSCs facilitated EMT of PDAC cells with elevation of TGF−β and IL−6, but not from RAGE−deleted PSCs. Diabetic subjects complicated with metabolic syndrome, divided by cluster analysis, showed higher PSC activation and RAGE expression. In such groups, PDAC cells exhibited an EMT nature. The complication of metabolic syndrome with diabetes significantly worsened disease−free survival of PDAC subjects. Thus, RAGE in PSCs can be viewed as a new promoter and a future therapeutic target of PDAC in diabetic subjects with metabolic syndrome.

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Section: Methodsmentioning

confidence: 99%

Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma

Uchida

Mizukami

Hara

et al. 2021

IJMS

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“…Decreased insulin or dysregulation of insulin signaling could be therapeutic targets in DPN in T1D, because insulin resistance is characteristic in the SN and DRG in both T1D and T2D ( 21 , 23 ). Our previous study revealed that the activation of plasma xanthine oxidase induces M1 macrophage polarization and exacerbates DPN in db/db mice ( 19 ). Our results first showed that M1 macrophage polarization via RAGE induced insulin resistance in the peripheral nervous system in the early stage of T1D DPN.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, macrophages have more detailed categorizations based on disease type ( 61 ). Macrophage infiltration in the SN is also thought to be a pathogenic mechanism in the advanced stage of DPN, and the population can change during the progression of DPN ( 19 ). Therefore, to establish a treatment for DPN using RAGE in macrophages, a more detailed analysis is required to classify infiltrated macrophages, depending on the stage of DPN in the future.…”

Section: Discussionmentioning

confidence: 99%

“…Then, 20 μL of the mixture was loaded onto an optical reaction plate in duplicate. An established reverse transcription PCR (RT-PCR) assay using the relative quantification method ( ΔΔ Ct ) was conducted in an ABI PRISM 7000 Sequence Detection System (Thermo Fisher Scientific) ( 19 ). If mRNA expression of the examined genes was not observed during 1 assay, the thereshold value was regarded as 45 cycles.…”

Section: Methodsmentioning

confidence: 99%

“…Such inflammatory conditions are associated with insulin resistance, particularly in the fatty tissue of T2D patients ( 14 ). Moreover, low-grade inflammation exerted by M1 characterizes the pathology of DPN ( 15 – 19 ). Although inflammation and the dysregulation of insulin signaling are thought to be mechanistic factors of DPN, few studies have explored their detailed associations with the pathophysiology of DPN in type 1 diabetes (T1D) ( 2 , 20 – 23 ).…”

Section: Introductionmentioning

confidence: 99%

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RAGE activation in macrophages and development of experimental diabetic polyneuropathy

Osonoi¹,

Mizukami²,

Takeuchi³

et al. 2022

JCI Insight

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It is suggested that activation of receptor for advanced glycation end products (RAGE) induces proinflammatory response in diabetic nerve tissues. Macrophage infiltration is invoked in the pathogenesis of diabetic polyneuropathy (DPN), while the association between macrophage and RAGE activation and the downstream effects of macrophages remain to be fully clarified in DPN. This study explored the role of RAGE in the pathogenesis of DPN through the modified macrophages. Infiltrating proinflammatory macrophages impaired insulin sensitivity, atrophied the neurons in dorsal root ganglion, and slowed retrograde axonal transport (RAT) in the sciatic nerve of type 1 diabetic mice. RAGE-null mice showed an increase in the population of antiinflammatory macrophages, accompanied by intact insulin sensitivity, normalized ganglion cells, and RAT. BM transplantation from RAGE-null mice to diabetic mice protected the peripheral nerve deficits, suggesting that RAGE is a major determinant for the polarity of macrophages in DPN. In vitro coculture analyses revealed proinflammatory macrophage–elicited insulin resistance in the primary neuronal cells isolated from dorsal root ganglia. Applying time-lapse recording disclosed a direct impact of proinflammatory macrophage and insulin resistance on the RAT deficits in primary neuronal cultures. These results provide a potentially novel insight into the development of RAGE-related DPN.

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A strategy for inhibitors screening of xanthine oxidase based on colorimetric sensor combined with affinity chromatography technology

Chen,

Zhang,

Wang

et al. 2024

Biosensors and Bioelectronics

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Inhibitory effects of xanthine oxidase inhibitor, topiroxostat, on development of neuropathy in db/db mice

Cited by 13 publications

References 40 publications

Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma

Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma

RAGE activation in macrophages and development of experimental diabetic polyneuropathy

A strategy for inhibitors screening of xanthine oxidase based on colorimetric sensor combined with affinity chromatography technology

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