Calcimimetic restores diabetic peripheral neuropathy by ameliorating apoptosis and improving autophagy

Chung, You Chul; Lim, Ji Hee; Oh, Hyun Mi; Kim, Hyung Wook; Kim, Min Young; Kim, Yaeni; Chang, Yoon Sik; Park, Cheol Whee

doi:10.1038/s41419-018-1192-7

Cited by 50 publications

(39 citation statements)

References 32 publications

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“…LC3 and P62 are the main proteins regulating cell autophagy that were down-regulated in the sciatic nerves of diabetic mice and high glucose-treated RSC96 cells vs. the normal control group in the present study, which suggests the dysregulation of cell autophagy. In line with our findings, Chung et al (13) revealed that the LC3-II/LC3-I ratio and beclin-1 were decreased in the sciatic nerves of db/db mice compared with db/m mice. Similarly, high glucose induced the decreases in beclin-1 expression, LC3-II/LC3-I ratio, and LC3 punctate in human Schwann cells.…”

Section: Discussionsupporting

confidence: 93%

“…Additionally, the LC3-II/LC3-I ratio was decreased in the sciatic nerves of diabetic mice vs. normal mice. In line with this, the LC3-II/LC3-I ratio and number of LC3 punctate were reduced in human Schwann cells grown in a highglucose medium in comparison with those grown in a lowglucose medium (13). Qu et al (14) also revealed that there were fewer autophagosomes in immortalized rat Schwann cell 96 (RSC96) cells and primary rat Schwann cells under high-glucose conditions than under control conditions.…”

mentioning

confidence: 76%

“…Chung et al (13) reported that LC3 expression was significantly decreased in SRY-box10-positive cells (a marker of Schwann cells) of the sciatic nerves in diabetic mice (db/db mice) compared with nondiabetic mice (db/m mice). Additionally, the LC3-II/LC3-I ratio was decreased in the sciatic nerves of diabetic mice vs. normal mice.…”

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confidence: 99%

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STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy

Wang

et al. 2019

FASEB j.

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Schwann cells are the main supportive cells of the peripheral nerves. Schwann cells suffer inhibition of autophagy under hyperglycemia treatment in diabetic peripheral neuropathy (DPN). However, the exact mechanism is still not fully elucidated. We first observed the decrease of autophagy markers (LC3‐II/LC3‐I, P62) in the sciatic nerves of diabetic mice vs. normal mice, accompanied with the loss of myelinated nerve fibers and abnormal myelin sheath. In line with this, LC3‐II/LC3‐I and P62 were also significantly reduced in high glucose—treated rat Schwann cell 96 (RSC96) cells compared with normal glucose—treated cells. Furthermore, we found that trichostatin A [an inhibitor of histone deacetylase (HDAC)] evidently improved LC3‐II/LC3‐I in high glucose—treated RSC96 cells, without an effect on P62 expression. Again, HDAC1 and HDAC5 were revealed to be increased in RSC96 cells stimulated with high glucose. Inhibition of HDAC1 but not HDAC5 by small hairpin RNA vector enhanced LC3‐II/LC3‐I in high glucose—cultured RSC96 cells. In addition, LC3‐II conversion regulators [autophagy‐related protein (Atg)3, Atg5, and Atg7] were detected in high glucose—treated and HDAC1‐knockdown RSC96 cells, and Atg3 was proven to be the key target of HDAC1. The presuppression of Atg3 offset the improvement of LC3‐II/LC3‐I resulting from HDAC1 inhibition in high glucose—treated RSC96 cells. The Janus kinase (JAK)—signal transducer and activator of transcription (STAT) signaling pathway was activated in RSC96 cells treated with high glucose, which was indicated by increased STAT3 phosphorylation. Blocking STAT3 phosphorylation by chemical inhibitor AG490 induced HDAC1 down‐regulation followed by increases in Atg3 and LC3‐II/LC3‐I. Interestingly, we also found that AG490 treatment enhanced P62 expression in high glucose—stimulated RSC96 cells. Taken together, our findings demonstrate that hyperglycemia inhibits LC3‐II/LC3‐I in an HDAC1‐Atg3—dependent manner and decreases P62 expression in an HDAC‐independent manner via the JAK‐STAT3 signaling pathway in the Schwann cells of DPN.—Du, W., Wang, N., Li, F. Jia, K., An, J., Liu, Y., Wang, Y., Zhu, L., Zhao, S. Hao, J. STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy. FASEB J. 33, 8008–8021 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 93%

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confidence: 76%

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STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy

Wang

et al. 2019

FASEB j.

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“…RSC 96 cells, which maintain the attributes of SCs, are cultivated in medium with high glucose (HG) to simulate SCs in DPN mice . In addition, SCs damage induced by HG includes morphological changes, for instance swelling and vacuolation, leading to destruction of organelles . This process is also accompanied by the occurrence of intracellular autophagy and apoptosis .…”

Section: Introductionmentioning

confidence: 99%

Muscone ameliorates diabetic peripheral neuropathy through activating AKT/mTOR signalling pathway

Dong

Bai

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Emerging evidence showed that muscone could improve chronic inflammation after myocardial infarction and protect alcohol‐induced osteonecrosis of the femoral head. However, the function of muscone on diabetic peripheral neuropathy (DPN) is obscure. Methods The neuronal Schwann cell RSC 96 cells were treated with 125 mmol/l glucose to simulate the cells in DPN. The RSC 96 cell viability was detected by cell counting kit‐8. The RSC 96 cell cycle and apoptosis were determined by flow cytometry. The expression of marker proteins of apoptosis, autophagy and AKT/mTOR signalling pathway was assessed by Western blot. Key findings We observed that after high glucose (HG) treatment, the number of cell apoptosis was increased, cell proliferation was decreased, as well as the expression of apoptosis‐related proteins and autophagy‐related proteins were changed. However, this phenomenon can be reversed by muscone. Meanwhile, the expression of phosphorylated AKT and mammalian target of rapamycin (mTOR) was down‐regulated with HG treatment, while the expression quantity was up‐regulated after disposed with muscone. Conclusions Our outcomes demonstrated that autophagy and apoptosis of RSC 96 cells induced by HG can be alleviated by muscone through modulating AKT/mTOR signalling pathway, suggesting that muscone might be a potential molecule with influence in connection to DPN.

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“…The International Diabetes Federation has estimated that 415 million people have been diagnosed with DM worldwide and anticipates an increase of up to 640 million by 2040 (1). Diabetic neuropathy (DN) is one of the most common diabetic complications and is characterized by complex changes in functional and sensorimotor parameters (2). The pathophysiology of DN involves a complex cascade of specific interrelated mechanisms (3,4).…”

Section: Introductionmentioning

confidence: 99%

The combined effect of mesenchymal stem cells and resveratrol on type 1 diabetic neuropathy

et al. 2019

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Diabetic neuropathy (DN) is one of the most common diabetic complications that results in an increase in patient discomfort and pain. The present study demonstrated that mesenchymal stem cells (MSCs) or resveratrol (RSV) may improve diabetic hyperglycemia and neuropathy. The aim of the present study was to investigate the combined effect of MSCs and RSV on DN. A total of 100 non-obese diabetic mice were divided into the following six groups: Normal control, MSCs, RSV, MSCs + RSV, insulin and diabetic control groups. Following homologous therapy, the levels of blood glucose and C-peptide, islets, nuclear factor (NF)-κB, nerve growth factor (NGF) and myelin basic protein (MBP), and the sciatic nerve structure in each group were examined and evaluated. Following the administration of therapy, the levels of blood glucose and C-peptide in mice in the MSCs + RSV group were significantly improved when compared with the other diabetic groups, and the dosage of insulin therapy required was the lowest among the six experimental groups (P<0.05). The levels of NGF, MBP and NF-κB in the MSCs + RSV group were significantly improved compared with the MSCs and RSV groups (P<0.05). Furthermore, the diameter of the axon, number of myelinated nerve fibers and the depth of the myelin sheath in the MSCs + RSV group were greatest among the five examined groups (excluding the control). The combination of RSV and MSCs could relieve hyperglycemia and improve DN. This indicated that the combination of RSV and MSCs may be a novel therapeutic method for the treatment of DN.

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Calcimimetic restores diabetic peripheral neuropathy by ameliorating apoptosis and improving autophagy

Cited by 50 publications

References 32 publications

STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy

STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy

Muscone ameliorates diabetic peripheral neuropathy through activating AKT/mTOR signalling pathway

The combined effect of mesenchymal stem cells and resveratrol on type 1 diabetic neuropathy

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