The Differential Expression of Circular RNAs in Type 2 Diabetes Mellitus and Latent Autoimmune Diabetes in Adults.

Objective: Expression of circular RNAs (circRNAs) in the peripheral blood of individuals with latent autoimmune diabetes in adults (LADA) and type 2 diabetes mellitus (T2DM) were quantified to identify dysregulated circRNAs compared with control individuals. Methods: circRNAs were obtained from the peripheral blood serum of 12 healthy adults and 12 individuals with LADA and 12 type 2 diabetics. The circRNA expression profiles were analyzed by high-throughput RNA sequencing. The most highly dysregulated circular RNAs were validated by quantitative real-time polymerase chain reaction. A circular RNA-microRNA (miRNA) network diagram predicted the interactions of circular RNAs, miRNAs, and coding genes. Results: A total of 2334 differentially expressed circRNAs were detected among the three groups, with 277 circRNAs in the Group DM versus Group NG; 992 circRNAs in the Group LADA versus Group NG and 1065 circRNAs in the Group DM versus Group LADA. Six circRNAs were identified as the most distinctive differentially expressed targets (p < 0.05). The proposed molecular functions of these differentially expressed circRNAS included the tumor necrosis factor signaling pathway, the FoxO signaling pathway, cellular senescence, and long-term potentiation (all false discovery rate p < 0.05) which may contribute to T2DM and LADA. Conclusion: circRNAs are aberrantly expressed in the peripheral blood of patients with T2DM and LADA and may interact with miRNA and circRNA-derived peptides in the development of diabetes. Further investigations may illustrate the partial pathogenesis of diabetes mellitus. Clinical Trial Registration number: ChiCTR1900020644.

Full recovery from chronic headache and hypopituitarism caused by lymphocytic hypophysitis: A case report.

BACKGROUND: Lymphocytic hypophysitis (LYH) is an important condition to consider in the differential diagnosis of patients with a pituitary mass. The main clinical manifestations of LYH include headache, symptoms related to sellar compression, hypopituitarism, diabetes insipidus and hyperprolactinemia. Headache, which is a frequent complaint of patients with LYH, is thought to be related to the occupying effect of the pituitary mass and is rapidly resolved with a good outcome after timely and adequate glucocorticoid treatment or surgery. CASE SUMMARY: Here, we report a patient with LYH whose initial symptom was headache and whose pituitary function assessment showed the presence of secondary hypoadrenalism, central hypothyroidism and hypogonadotropic hypogonadism. Pituitary magnetic resonance imaging showed symmetrical enlargement of the pituitary gland with suprasellar extension in a dumbbell shape with significant homogeneous enhancement after gadolinium enhancement. The size of the gland was approximately 17.7 mm × 14.3 mm × 13.8 mm. The pituitary stalk was thickened without deviation, and there was an elevation of the optimal crossing. The lesion grew bilaterally toward the cavernous sinuses, and the parasternal dural caudal sign was visible. The patient presented with repeatedly worsening and prolonged headaches three times even though the hypopituitarism had fully resolved after glucocorticoid treatment during this course. CONCLUSION: This rare headache regression suggests that patients with chronic headaches should also be alerted to the possibility of LYH.

Alterations in plantar vessel blood flow in patients with mild diabetic peripheral neuropathy.

INTRODUCTION: Early identification and treatment of diabetic peripheral neuropathy (DPN) are crucial. Presently, the mechanism of DPN is not very clear, and there are inconclusive conclusions about the influencing factors of vascular dynamic characteristics in DPN. This study aims to detect and compare the hemodynamic characteristics of plantar blood vessels in patients with mild DPN and healthy participants to explore a simple and reliable new idea and a potential method for early assessment of DPN and to investigate the influence of gender and age on hemodynamic characteristics. RESEARCH DESIGN AND METHODS: Sixty age-matched and gender-matched patients with mild DPN (30 men and 30 women) and 60 healthy participants were randomly recruited. Color Doppler ultrasound was used to measure and analyze the hemodynamic characteristics of plantar-related vessels. RESULTS: Ultrasonic measurements had good test-retest reliability. There may be no statistically significant differences in the blood flow velocity and blood flow in the plantar-related blood vessels of participants, irrespective of their gender and age. For patients with mild DPN, color Doppler ultrasound may indicate early hemodynamic abnormalities when there are no obvious abnormalities in the large arteries of the lower limbs, which are specifically manifested as increased blood flow velocity and blood flow in the distal small vessels. CONCLUSIONS: Our study provides in vivo data support for the dynamic characteristics of the plantar blood vessel biomechanical model and provides a new idea of in vivo and non-invasive early diagnosis of DPN.

Severe metabolic disorders coexisting with Werner syndrome: a case report.

Werner syndrome, also called adult progeria, is a heritable autosomal recessive human disorder characterized by the premature onset of numerous age-related diseases including juvenile cataracts, dyslipidemia, diabetes mellitus (DM), osteoporosis, atherosclerosis, and cancer. Werner syndrome is a segmental progeroid syndrome whose presentation resembles accelerated aging. The most common causes of death for WS patients are atherosclerosis and cancer. A 40-year-old female presented with short stature, bird-like facies, canities with alopecia, scleroderma-like skin changes, and non-healing foot ulcers. The patient reported a history of delayed puberty, abortion, hypertriglyceridemia, and juvenile cataracts. A clinical diagnosis of WS was made and subsequently confirmed. We discovered two WRN gene mutations in the patient, Variant 1 was the most common WRN mutation, nonsense mutation (c.1105C>T:p.R369Ter) in exon 9, which caused a premature termination codon (PTC) at position 369. Variant 2 was a frameshift mutation (c.1134delA:p.E379KfsTer5) in exon 9, which caused a PTC at position 383 and has no published reports describing. Patients with WS can show a wide variety of clinical and biological manifestations in endocrine-metabolic systems (DM, thyroid dysfunction, and hyperlipidemia). Doctors must be cognizant of early manifestations of WS and treatment options.

Comparative proteomics analysis of human osteosarcoma by 2D DIGE with MALDI-TOF/TOF MS.

Osteosarcoma (OS) is the most common primary malignant tumor of bone and the third most common cancer in childhood and adolescence. However, controversy concerning the ideal combination of chemotherapy agents ensued throughout the last quarter of the 20th century because of conflicting and often nonrandomized data. Collaborative efforts to increase understanding of the biology of osteosarcoma and the use of preclinical models to test novel protein targets will be critical to identify the path toward improving outcomes for patients. We attempted to identify potential protein markers or therapy targets of osteosarcoma and give a glance at tumorigenesis of osteosarcoma. A sensitive and accurate method was employed in comparative proteomic analysis between benign tumor and osteosarcoma. Tumor tissues obtained by open biopsy before induction chemotherapy were investigated With 2D DIGE and MALDI-TOF/TOF MS, 22 differentially expressed proteins were identified after database searching, including 8 up-regulated and 14 down-regulated proteins. We also validated the expression levels of interesting proteins(have higher Ratios(tumor/normal)) by Western blotting assay. Annotating by bioinformatic tools, we found structural and signal transduction associated proteins were in large percentage among altered level proteins. In particular, some low abundant proteins involving translation and transcription, such as EEF2(Elongation Factor 2), LUM Lumican 23 kDa Protein) and GTF2A2(Transcription Initiation Factor Iia Gamma Chain.), were firstly reported by our study comparing to previous observations. Our findings suggest that these differential proteins may be potential biomarkers for diagnosis or molecules for understanding of osteosarcoma tumorigenesis, coming with biologic, preclinical, and clinical trial efforts being described to improve outcomes for patients.

Fine motor skill training enhances functional plasticity of the corticospinal tract after spinal cord injury.

Following central nervous system injury, axonal sprouts form distal to the injury site and extend into the denervated area, reconstructing neural circuits through neural plasticity. How to facilitate this plasticity has become the key to the success of central nervous system repair. It remains controversial whether fine motor skill training contributes to the recovery of neurological function after spinal cord injury. Therefore, we established a rat model of unilateral corticospinal tract injury using a pyramidal tract cutting method. Horizontal ladder crawling and food ball grasping training procedures were conducted 2 weeks before injury and 3 days after injury. The neurological function of rat forelimbs was assessed at 1, 2, 3, 4, and 6 weeks after injury. Axon growth was observed with biotinylated dextran amine anterograde tracing in the healthy corticospinal tract of the denervated area at different time periods. Our results demonstrate that compared with untrained rats, functional recovery was better in the forelimbs and forepaws of trained rats. The number of axons and the expression of growth associated protein 43 were increased at the injury site 3 weeks after corticospinal tract injury. These findings confirm that fine motor skill training promotes central nervous system plasticity in spinal cord injury rats.

Factors affecting directional migration of bone marrow mesenchymal stem cells to the injured spinal cord.

Microtubule-associated protein 1B plays an important role in axon guidance and neuronal migration. In the present study, we sought to discover the mechanisms underlying microtubule-associated protein 1B mediation of axon guidance and neuronal migration. We exposed bone marrow mesenchymal stem cells to okadaic acid or N-acetyl-D-erythro-sphingosine (an inhibitor and stimulator, respectively, of protein phosphatase 2A) for 24 hours. The expression of the phosphorylated form of type I microtubule-associated protein 1B in the cells was greater after exposure to okadaic acid and lower after N-acetyl-D-erythro-sphingosine. We then injected the bone marrow mesenchymal stem cells through the ear vein into rabbit models of spinal cord contusion. The migration of bone marrow mesenchymal stem cells towards the injured spinal cord was poorer in cells exposed to okadaic acid- and N-acetyl-D-erythro-sphingosine than in non-treated bone marrow mesenchymal stem cells. Finally, we blocked phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways in rabbit bone marrow mesenchymal stem cells using the inhibitors LY294002 and U0126, respectively. LY294002 resulted in an elevated expression of phosphorylated type I microtubule-associated protein 1B, whereas U0126 caused a reduction in expression. The present data indicate that PI3K and ERK1/2 in bone marrow mesenchymal stem cells modulate the phosphorylation of microtubule-associated protein 1B via a cross-signaling network, and affect the migratory efficiency of bone marrow mesenchymal stem cells towards injured spinal cord.

Stress protein expression in early phase spinal cord ischemia/reperfusion injury.

Spinal cord ischemia/reperfusion injury is a stress injury to the spinal cord. Our previous studies using differential proteomics identified 21 differentially expressed proteins (n > 2) in rabbits with spinal cord ischemia/reperfusion injury. Of these proteins, stress-related proteins included protein disulfide isomerase A3, stress-induced-phosphoprotein 1 and heat shock cognate protein 70. In this study, we established New Zealand rabbit models of spinal cord ischemia/reperfusion injury by abdominal aorta occlusion. Results demonstrated that hind limb function initially improved after spinal cord ischemia/reperfusion injury, but then deteriorated. The pathological morphology of the spinal cord became aggravated, but lessened 24 hours after reperfusion. However, the numbers of motor neurons and interneurons in the spinal cord gradually decreased. The expression of protein disulfide isomerase A3, stress-induced-phosphoprotein 1 and heat shock cognate protein 70 was induced by ischemia/reperfusion injury. The expression of these proteins increased within 12 hours after reperfusion, and then decreased, reached a minimum at 24 hours, but subsequently increased again to similar levels seen at 6-12 hours, showing a characterization of induction-inhibition-induction. These three proteins were expressed only in cytoplasm but not in the nuclei. Moreover, the expression was higher in interneurons than in motor neurons, and the survival rate of interneurons was greater than that of motor neurons. It is assumed that the expression of stress-related proteins exhibited a protective effect on neurons.

Neural plasticity after spinal cord injury.

Plasticity changes of uninjured nerves can result in a novel neural circuit after spinal cord injury, which can restore sensory and motor functions to different degrees. Although processes of neural plasticity have been studied, the mechanism and treatment to effectively improve neural plasticity changes remain controversial. The present study reviewed studies regarding plasticity of the central nervous system and methods for promoting plasticity to improve repair of injured central nerves. The results showed that synaptic reorganization, axonal sprouting, and neurogenesis are critical factors for neural circuit reconstruction. Directed functional exercise, neurotrophic factor and transplantation of nerve-derived and non-nerve-derived tissues and cells can effectively ameliorate functional disturbances caused by spinal cord injury and improve quality of life for patients.

Differential protein expression in spinal cord tissue of a rabbit model of spinal cord ischemia/reperfusion injury.

New Zealand rabbits were randomly divided into an ischemia group (occlusion of the abdominal aorta for 60 minutes), an ischemia-reperfusion group (occlusion of the abdominal aorta for 60 minutes followed by 48 hours of reperfusion) and a sham-surgery group. Two-dimensional gel electrophoresis detected 49 differentially expressed proteins in spinal cord tissue from the ischemia and ischemia/ reperfusion groups and 23 of them were identified by mass spectrometry. In the ischemia group, the expression of eight proteins was up regulated, and that of the remaining four proteins was down regulated. In the ischemia/reperfusion group, the expression of four proteins was up regulated, and that of two proteins was down regulated. In the sham-surgery group, only one protein was detected. In the ischemia and ischemia/reperfusion groups, four proteins overlapped between groups with the same differential expression, including three that were up regulated and one down regulated. These proteins were related to energy metabolism, cell defense, inflammatory mechanism and cell signaling.

Effects of cytokines and chemokines on migration of mesenchymal stem cells following spinal cord injury.

We investigated the effects of cytokines and chemokines and their associated signaling pathways on mesenchymal stem cell migration after spinal cord injury, to determine their roles in the curative effects of mesenchymal stem cells. This study reviewed the effects of tumor necrosis factor-α, vascular endothelial growth factor, hepatocyte growth factor, platelet-derived growth factor, basic fibroblast growth factor, insulin like growth factor-1, stromal cell-derived factor and monocyte chemoattractant protein-1, 3 during mesenchymal stem cell migration to damaged sites, and analyzed the signal transduction pathways involved in their effects on mesenchymal stem cell migration. The results confirmed that phosphatidylinositol 3-kinase/serine/threonine protein kinases and nuclear factor-κB play crucial roles in the migration of mesenchymal stem cells induced by cytokines and chemokines.

The role of microtubule-associated protein 1B in axonal growth and neuronal migration in the central nervous system.

In this review, we discuss the role of microtubule-associated protein 1B (MAP1B) and its phosphorylation in axonal development and regeneration in the central nervous system. MAP1B exhibits similar functions during axonal development and regeneration. MAP1B and phosphorylated MAP1B in neurons and axons maintain a dynamic balance between cytoskeletal components, and regulate the stability and interaction of microtubules and actin to promote axonal growth, neural connectivity and regeneration in the central nervous system.

Neurofilament proteins in axonal regeneration and neurodegenerative diseases.

Neurofilament protein is a component of the mature neuronal cytoskeleton, and it interacts with the zygosome, which is mediated by neurofilament-related proteins. Neurofilament protein regulates enzyme function and the structure of linker proteins. In addition, neurofilament gene expression plays an important role in nervous system development. Previous studies have shown that neurofilament gene transcriptional regulation is crucial for neurofilament protein expression, especially in axonal regeneration and degenerative diseases. Post-transcriptional regulation increased neurofilament protein gene transcription during axonal regeneration, ultimately resulting in a pattern of neurofilament protein expression. An expression imbalance of post-transcriptional regulatory proteins and other disorders could lead to amyotrophic lateral sclerosis or other neurodegenerative diseases. These findings indicated that after transcription, neurofilament protein regulated expression of related proteins and promoted regeneration of damaged axons, suggesting that regulation disorders could lead to neurodegenerative diseases.