DW14006 as a direct AMPKα activator ameliorates diabetic peripheral neuropathy in mice

10.2337/figshare.12583115.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Xu Xu ◽

Wei Wang ◽

Zhengyu Wang ◽

Jianlu Lv ◽

...

Keyword(s):

Oxidative Stress ◽

Peripheral Neuropathy ◽

Diabetic Peripheral Neuropathy ◽

Diabetic Mice ◽

Adeno Associated Virus ◽

Multiple Risk Factors ◽

Underlying Mechanisms ◽

Amp Activated Protein Kinase

<a>Diabetic peripheral neuropathy</a> (DPN) is a long-term complication of diabetes with a complicated pathogenesis. <a></a><a>AMP-activated protein kinase (</a><a></a><a>AMPK) </a>senses oxidative stress <a></a><a>and </a><a>mitochondrial function</a> playing a central role in the regulation of DPN. Here, we reported that DW14006 <a></a><a></a><a></a><a>(</a><a>2-(3-(7-chloro-6-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinolin-3-yl)phenyl)acetic acid)</a> as a direct AMPKα activator efficiently ameliorated <a>DPN in both</a><a> streptozotocin</a> (STZ)-induced type 1 and BKS <i>db/<a></a><a></a><a>db</a></i> type 2 diabetic mice. <a></a><a></a><a>DW14006 administration highly enhanced neurite outgrowth of dorsal root </a><a>ganglion</a> (DRG) neuron and <a></a><a>improved neurological function</a> in diabetic mice. <a></a><a></a><a>The underlying mechanisms have been intensively investigated. DW14006 treatment improved mitochondrial </a><a></a><a>bioenergetics</a> profiles and <a></a><a>restrained </a>oxidative stress and inflammation in <a>diabetic mice</a> by targeting AMPKa, which has been verified by assay against the STZ-induced diabetic mice injected with <a></a><a>adeno associated virus AAV</a>8-AMPKa-RNAi. <a></a>To our knowledge, our work might be the first report on the amelioration of direct AMPKa activator on DPN by counteracting <a>multiple risk factors</a> including <a>mitochondrial dysfunction, oxidative stress and inflammation</a>, and DW14006 has been highlighted as a potential leading compound in the treatment of DPN.

Download Full-text

Long Non-coding RNA XIST Attenuates Diabetic Peripheral Neuropathy by Inducing Autophagy Through MicroRNA-30d-5p/sirtuin1 Axis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.655157 ◽

2021 ◽

Vol 8 ◽

Author(s):

Bei-Yan Liu ◽

Lin Li ◽

Li-Wei Bai ◽

Chang-Shui Xu

Keyword(s):

Oxidative Stress ◽

Peripheral Neuropathy ◽

Schwann Cells ◽

Diabetic Peripheral Neuropathy ◽

Beclin 1 ◽

Diabetic Mice ◽

Non Coding Rna ◽

Non Coding Rnas ◽

Long Non Coding Rna

Diabetic peripheral neuropathy (DPN) is a prevalent diabetes mellitus (Feldman et al., 2017) complication and the primary reason for amputation. Meanwhile, long non-coding RNAs (lncRNAs) are a type of regulatory non-coding RNAs (ncRNAs) that broadly participate in DPN development. However, the correlation of lncRNA X-inactive specific transcript (XIST) with DPN remains unclear. In this study, we were interested in the role of XIST in the modulation of DPN progression. Significantly, our data showed that the expression of XIST and sirtuin1 (SIRT1) was inhibited, and the expression of microRNA-30d-5p (miR-30d-5p) was enhanced in the trigeminal sensory neurons of the diabetic mice compared with the normal mice. The levels of LC3II and Beclin-1 were inhibited in the diabetic mice. The treatment of high glucose (HG) reduced the XIST expression in Schwann cells. The apoptosis of Schwann cells was enhanced in the HG-treated cells, but the overexpression of XIST could block the effect in the cells. Moreover, the levels of LC3II and Beclin-1 were reduced in the HG-treated Schwann cells, while the overexpression of XIST was able to reverse this effect. The HG treatment promoted the production of oxidative stress, while the XIST overexpression could attenuate this result in the Schwann cells. Mechanically, XIST was able to sponge miR-30d-5p and miR-30d-5p-targeted SIRT1 in the Schwann cells. MiR-30d-5p inhibited autophagy and promoted oxidative stress in the HG-treated Schwann cells, and SIRT1 presented a reversed effect. MiR-30d-5p mimic or SIRT1 depletion could reverse XIST overexpression-mediated apoptosis and autophagy of the Schwann cells. Thus, we concluded that XIST attenuated DPN by inducing autophagy through miR-30d-5p/SIRT1 axis. XIST and miR-30d-5p may be applied as the potential targets for DPN therapy.

Download Full-text

A Novel TNF-α Converting Enzyme (TACE) Selective Inhibitor JTP-96193 Prevents Insulin Resistance in KK-Ay Type 2 Diabetic Mice and Diabetic Peripheral Neuropathy in Type 1 Diabetic Mice

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.b19-00526 ◽

2019 ◽

Vol 42 (11) ◽

pp. 1906-1912 ◽

Cited By ~ 1

Author(s):

Mariko Maekawa ◽

Hironobu Tadaki ◽

Daisuke Tomimoto ◽

Chihiro Okuma ◽

Ryuhei Sano ◽

...

Keyword(s):

Insulin Resistance ◽

Peripheral Neuropathy ◽

Diabetic Peripheral Neuropathy ◽

Selective Inhibitor ◽

Converting Enzyme ◽

Diabetic Mice ◽

Tnf Α ◽

Type 2 Diabetic

Download Full-text

Blood–brain barrier disruption and ventricular enlargement are the earliest neuropathological changes in rats with repeated sub-concussive impacts over 2 weeks

Scientific Reports ◽

10.1038/s41598-021-88854-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bailey Hiles-Murison ◽

Andrew P. Lavender ◽

Mark J. Hackett ◽

Joshua J. Armstrong ◽

Michael Nesbit ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Brain Barrier ◽

Hippocampal Formation ◽

Brain Barrier ◽

Lateral Ventricles ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Brain Barrier Disruption ◽

Underlying Mechanisms

AbstractRepeated sub-concussive impact (e.g. soccer ball heading), a significantly lighter form of mild traumatic brain injury, is increasingly suggested to cumulatively alter brain structure and compromise neurobehavioural function in the long-term. However, the underlying mechanisms whereby repeated long-term sub-concussion induces cerebral structural and neurobehavioural changes are currently unknown. Here, we utilised an established rat model to investigate the effects of repeated sub-concussion on size of lateral ventricles, cerebrovascular blood–brain barrier (BBB) integrity, neuroinflammation, oxidative stress, and biochemical distribution. Following repeated sub-concussion 3 days per week for 2 weeks, the rats showed significantly enlarged lateral ventricles compared with the rats receiving sham-only procedure. The sub-concussive rats also presented significant BBB dysfunction in the cerebral cortex and hippocampal formation, whilst neuromotor function assessed by beamwalk and rotarod tests were comparable to the sham rats. Immunofluorescent and spectroscopic microscopy analyses revealed no significant changes in neuroinflammation, oxidative stress, lipid distribution or protein aggregation, within the hippocampus and cortex. These data collectively indicate that repeated sub-concussion for 2 weeks induce significant ventriculomegaly and BBB disruption, preceding neuromotor deficits.

Download Full-text