scholarly journals Gene Expression Profiling of the Sciatic Nerve in Streptozotocin-Induced Diabetic Rats with Peripheral Neuropathy

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Yiji Tu ◽  
Zenggan Chen ◽  
Feng Zhang ◽  
Zhenglin Di ◽  
Junhui Zhang ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Sciatic Nerve ◽  
Signaling Pathway ◽  
Early Phase ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Motor Nerve ◽  
Motor Nerve Conduction Velocity ◽  
Sprague Dawley ◽  
Cell Cycle Protein

Aims. To investigate the candidate biomarkers and molecular mechanisms involved in the early phase of experimental diabetic peripheral neuropathy (DPN). Methods. Diabetes in Sprague-Dawley rats was induced with streptozotocin (STZ) treatment, followed with neurological tests and histological examinations to assess the neuropathic symptoms of DPN. Microarray was performed on the sciatic nerve tissues from control rats and DPN rats at then6th week after diabetes induction, and differentially expressed genes (DEGs) between them were identified and applied for further bioinformatic analyses. Results. Experimental DPN rats were successfully constructed, presenting significantly decreased withdrawal threshold and motor nerve conduction velocity, and typical histological changes in the sciatic nerve. 597 DEGs (186 up- and 411 downregulated) were identified in DPN rats. DEGs from the 3 most highly connected clusters in the protein-protein interaction network were enriched for biological processes or pathways such as “cell division,” “cell cycle,” “protein phosphorylation,” “chemokine signaling pathway,” “neuropeptide signaling pathway,” “response to drug,” “cellular response to insulin stimulus,” “PPAR signaling pathway,” and “glycerophospholipid metabolism.” Thirteen genes were identified as the hub DEGs in the PPI network. Eleven transcriptional factors (TFs) targeting 9 of the 13 hub DEGs were predicted. Conclusions. The present study identified a pool of candidate biomarkers such as Cdk1, C3, Mapk12, Agt, Adipoq, Cxcl2, and Mmp9 and molecular mechanisms which may be involved in the early phase of experimental DPN. The findings provide clues for exploring new strategies for the early diagnosis and treatment of DPN.

scholarly journals Effects of Long-Term Treatment with Ranirestat, a Potent Aldose Reductase Inhibitor, on Diabetic Cataract and Neuropathy in Spontaneously Diabetic Torii Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Ayumi Ota ◽  
Akihiro Kakehashi ◽  
Fumihiko Toyoda ◽  
Nozomi Kinoshita ◽  
Machiko Shinmura ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Aldose Reductase ◽  
Reductase Inhibitor ◽  
Motor Nerve ◽  
Positive Control ◽  
Aldose Reductase Inhibitor ◽  
Motor Nerve Conduction Velocity ◽  
Sprague Dawley ◽  
Diabetic Cataract ◽  
Long Term Treatment

We evaluated ranirestat, an aldose reductase inhibitor, in diabetic cataract and neuropathy (DN) in spontaneously diabetic Torii (SDT) rats compared with epalrestat, the positive control. Animals were divided into groups and treated once daily with oral ranirestat (0.1, 1.0, 10 mg/kg) or epalrestat (100 mg/kg) for 40 weeks, normal Sprague-Dawley rats, and untreated SDT rats. Lens opacification was scored from 0 (normal) to 3 (mature cataract). The combined scores (0–6) from both lenses represented the total for each animal. DN was assessed by measuring the motor nerve conduction velocity (MNCV) in the sciatic nerve. Sorbitol and fructose levels were measured in the lens and sciatic nerve 40 weeks after diabetes onset. Cataracts developed more in untreated rats than normal rats (P<0.01). Ranirestat significantly (P<0.01) inhibited rapid cataract development; epalrestat did not. Ranirestat significantly reversed the MNCV decrease (40.7 ± 0.6 m/s) in SDT rats dose-dependently (P<0.01). Epalrestat also reversed the prevented MNCV decrease (P<0.05). Sorbitol levels in the sciatic nerve increased significantly in SDT rats (2.05 ± 0.10 nmol/g), which ranirestat significantly suppressed dose-dependently, (P<0.05, <0.01, and <0.01); epalrestat did not. Ranirestat prevents DN and cataract; epalrestat prevents DN only.

C1orf194 deficiency leads to incomplete early embryonic lethality and dominant intermediate Charcot–Marie–Tooth disease in a knockout mouse model

2020 ◽  
Vol 29 (15) ◽  
pp. 2471-2480
Author(s):  
Cheng Huang ◽  
Zong Rui Shen ◽  
Jin Huang ◽  
Shun Chang Sun ◽  
Di Ma ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Schwann Cells ◽  
Molecular Mechanisms ◽  
Compound Muscle Action Potential ◽  
Motor Nerve ◽  
Motor Nerve Conduction Velocity ◽  
Embryonic Lethality ◽  
Internodal Length ◽  
Transmission Electron Microscopy Analysis ◽  
Charcot Marie Tooth

Abstract Charcot–Marie–Tooth (CMT) disease is the most common inherited peripheral neuropathy and shows clinical and genetic heterogeneity. Mutations in C1orf194 encoding a Ca2+ regulator in neurons and Schwann cells have been reported previously by us to cause CMT disease. In here, we further investigated the function and pathogenic mechanism of C1or194 by generating C1orf194 knockout (KO) mice. Homozygous mutants of C1orf194 mice exhibited incomplete embryonic lethality, characterized by differentiation abnormalities and stillbirth on embryonic days 7.5–15.5. Heterozygous and surviving homozygous C1orf194 KO mice developed motor and sensory defects at the age of 4 months. Electrophysiologic recordings showed decreased compound muscle action potential and motor nerve conduction velocity in the sciatic nerve of C1orf194-deficient mice as a pathologic feature of dominant intermediate-type CMT. Transmission electron microscopy analysis revealed demyelination and axonal atrophy in the sciatic nerve as well as swelling and loss of mitochondrial matrix and other abnormalities in axons and Schwann cells. A histopathologic examination showed a loss of motor neurons in the anterior horn of the spinal cord and muscle atrophy. Shorter internodal length between nodes of Ranvier and Schmidt–Lanterman incisures was detected in the sciatic nerve of affected animals. These results indicate that C1orf194 KO mice can serve as an animal model of CMT with a severe dominant intermediate CMT phenotype that can be used to investigate the molecular mechanisms of the disease and evaluate the efficacy of therapeutic strategies.

scholarly journals TSH Combined with TSHR Aggravates Diabetic Peripheral Neuropathy by Promoting Oxidative Stress and Apoptosis in Schwann Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-23
Author(s):  
Jingwen Fan ◽  
Qi Pan ◽  
Qun Gao ◽  
Wenqing Li ◽  
Fei Xiao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Peripheral Neuropathy ◽  
Diabetic Peripheral Neuropathy ◽  
Cell Model ◽  
Cell Damage ◽  
Motor Nerve ◽  
Thyroid Stimulating Hormone ◽  
Motor Nerve Conduction Velocity ◽  
The Impact

Subclinical hypothyroidism (SCH) is associated with diabetic peripheral neuropathy (DPN); however, the mechanism underlying this association remains unknown. This study is aimed at examining neurofunctional and histopathological alterations in a type 2 diabetes (T2DM) mouse model of SCH and investigating the impact of thyroid-stimulating hormone (TSH) in an in vitro DPN cell model established using RSC96 cells under high glucose (HG) and palmitic acid (PA) stimulation. Our results indicated that T2DM, in combination with SCH, aggravated abnormal glucose and lipid metabolism in T2DM and dramatically destroyed the peripheral nervous system by increasing paw withdrawal latency, decreasing motor nerve conduction velocity, and exacerbating ultrastructural deterioration of the damaged sciatic nerve caused by diabetes. Furthermore, the results of our in vitro experiments showed that TSH intensified HG/PA-induced RSC96 cell damage by inducing oxidative stress, mitochondrial dysfunction, and apoptosis. More importantly, TSHR knockout or inhibition of PA-induced TSHR palmitoylation could alleviate the apoptosis induced by TSH. Overall, in this study, the novel mechanisms by which TSH, as an independent risk factor for DPN progression, aggravating Schwann cell apoptosis and demyelination, are elucidated. These findings indicate that TSHR could be a potential target for both the prevention and treatment of DPN and, possibly, other microvascular diseases, and have implication in the clinical management of patients with DPN.

scholarly journals Genome-Wide Regulation of Acupuncture and Moxibustion on Ulcerative Colitis Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Zhaoqin Wang ◽  
Yan Huang ◽  
Di Wang ◽  
Rumeng Wang ◽  
Kunshan Li ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Signaling Pathway ◽  
Differentially Expressed Genes ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Mapk Signaling ◽  
Differentially Expressed ◽  
Clinical Effects ◽  
Sprague Dawley ◽  
Acupuncture And Moxibustion

Acupuncture and moxibustion have definite clinical effects on treating ulcerative colitis (UC), but their mechanism is still unclear. To investigate the molecular mechanisms, we applied herb-partitioned moxibustion or electroacupuncture at the Tianshu (ST25) points on UC rats and used RNA sequencing to identify molecular consequences. Male Sprague Dawley (SD) rats were divided into 6 groups randomly: the normal control (NC) group, the control + herb-partitioned moxibustion (NCHM) group, the control + electroacupuncture (NCEA) group, the model (UC) group, the model + herb-partitioned moxibustion (UCHM) group, and the model + electroacupuncture (UCEA) group. Compared to the UC group, HE staining in the UCHM group and UCEA group indicated that colitis was relieved, the histopathological score and MPO were both significantly reduced, and the serum hs-CRP concentration was decreased significantly. The results of RNA-seq suggested that, compared to the NC group, 206 upregulated genes and 167 downregulated genes were identified in colon tissues from the UC group; compared to the UC group, the expression levels of some genes were both affected in the UCHM group and the UCEA group (684 differentially expressed genes were identified in the UCHM group, and 1182 differentially expressed genes were identified in the UCEA group). KEGG signal pathway analysis indicated that the differentially expressed genes in the UCHM group were associated with the JAK-STAT signaling pathway and cell adhesion molecule (CAM); the differentially expressed genes in the UCEA group were associated with the NF-κB signaling pathway, the toll-like receptor signaling pathways, the PI3K-Akt signaling pathway, the MAPK signaling pathway, and the Wnt signaling pathway. This is the first study to reveal the gene expression characteristics of the anti-inflammatory effect of UC rats from the perspective of acupuncture and moxibustion control, which provide a clue for further investigation into the molecular mechanisms of UC treatment by acupuncture and moxibustion.

scholarly journals Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction

2021 ◽  
Vol 23 (1) ◽  
pp. 169
Author(s):  
Lisa A. Walter ◽  
Lauren P. Blake ◽  
Yann S. Gallot ◽  
Charles J. Arends ◽  
Randall S. Sozio ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sciatic Nerve ◽  
Neuromuscular Junction ◽  
Molecular Mechanisms ◽  
Skeletal Muscle Atrophy ◽  
Sprague Dawley ◽  
Unfolded Protein ◽  
Potential Therapeutic Role ◽  
The Unfolded Protein Response ◽  
Protein Response

Denervation of skeletal muscle is a debilitating consequence of injury of the peripheral nervous system, causing skeletal muscle to experience robust atrophy. However, the molecular mechanisms controlling the wasting of skeletal muscle due to denervation are not well understood. Here, we demonstrate that transection of the sciatic nerve in Sprague–Dawley rats induced robust skeletal muscle atrophy, with little effect on the neuromuscular junction (NMJ). Moreover, the following study indicates that all three arms of the unfolded protein response (UPR) are activated in denervated skeletal muscle. Specifically, ATF4 and ATF6 are elevated in the cytoplasm of skeletal muscle, while XBP1 is elevated in the nuclei of skeletal muscle. Moreover, XBP1 is expressed in the nuclei surrounding the NMJ. Altogether, these results endorse a potential role of the UPR and, specifically, XBP1 in the maintenance of both skeletal muscle and the NMJ following sciatic nerve transection. Further investigations into a potential therapeutic role concerning these mechanisms are needed.

scholarly journals Ataxia with loss of Purkinje cells in a mouse model for Refsum disease

2008 ◽  
Vol 105 (46) ◽  
pp. 17712-17717 ◽  
Author(s):  
Sacha Ferdinandusse ◽  
Anna W. M. Zomer ◽  
Jasper C. Komen ◽  
Christina E. van den Brink ◽  
Melissa Thanos ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Purkinje Cells ◽  
Calcium Binding ◽  
Phytanic Acid ◽  
Clinical Symptoms ◽  
Motor Nerve ◽  
Motor Nerve Conduction Velocity ◽  
Testicular Atrophy ◽  
Refsum Disease ◽  
Acid Accumulation

Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal α-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigmentosa. To study the pathogenesis of Refsum disease, we generated and characterized a Phyh knockout mouse. We studied the pathological effects of phytanic acid accumulation in Phyh−/− mice fed a diet supplemented with phytol, the precursor of phytanic acid. Phytanic acid accumulation caused a reduction in body weight, hepatic steatosis, and testicular atrophy with loss of spermatogonia. Phenotype assessment using the SHIRPA protocol and subsequent automated gait analysis using the CatWalk system revealed unsteady gait with strongly reduced paw print area for both fore- and hindpaws and reduced base of support for the hindpaws. Histochemical analyses in the CNS showed astrocytosis and up-regulation of calcium-binding proteins. In addition, a loss of Purkinje cells in the cerebellum was observed. No demyelination was present in the CNS. Motor nerve conduction velocity measurements revealed a peripheral neuropathy. Our results show that, in the mouse, high phytanic acid levels cause a peripheral neuropathy and ataxia with loss of Purkinje cells. These findings provide important insights in the pathophysiology of Refsum disease.

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