Glucoselysine, a unique advanced glycation end-product of the polyol pathway and its association with vascular complications in type 2 diabetes.

Glucoselysine (GL) is a unique advanced glycation end-product derived from fructose. The main source of fructose in vivo is the polyol pathway, and an increase in its activity leads to diabetic complications. Here, we aimed to demonstrate that GL can serve as an indicator of the polyol pathway activity. Additionally, we propose a novel approach for detecting GL in peripheral blood samples using LC-MS/MS and evaluate its clinical usefulness. We successfully circumvent interference from fructoselysine, which shares the same molecular weight as GL, by performing ultrafiltration and hydrolysis without reduction, successfully generating adequate peaks for quantification in serum. Furthermore, using immortalized aldose reductase knockout mouse Schwann cells, we demonstrate that GL reflects the downstream activity of the polyol pathway and that GL produced intracellularly is released into the extracellular space. Clinical studies reveal that GL levels in patients with type 2 diabetes are significantly higher than those in healthy participants, while Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1) levels are significantly lower. Both GL and MG-H1 show higher values among patients with vascular complications; however, GL varies more markedly than MG-H1 as well as hemoglobin A1c, fasting plasma glucose, and estimated glomerular filtration rate. Furthermore, GL remains consistently stable under various existing drug treatments for type 2 diabetes, whereas MG-H1 is impacted. To the best of our knowledge, we provide important insights in predicting diabetic complications caused by enhanced polyol pathway activity via assessment of GL levels in peripheral blood samples from patients.

[Pathogenic Mechanisms of Diabetic Neuropathy].

Diabetes stands as the predominant cause of peripheral neuropathy, and diabetic neuropathy (DN) is an early-onset and most frequent complication of diabetes. Distal symmetric polyneuropathy is the major form of DN; however, various patterns of nerve injury can manifest. Growing evidence suggests that hyperglycemia-related metabolic disorders in neurons, Schwann cells, and vascular endothelial cells play a major role in the development and progression of DN; however, its pathogenesis and development of disease-modifying therapies warrant further investigation. Herein, recent studies regarding the possible pathogenic factors of DN (polyol and other collateral glycolysis pathways, glycation, oxidative stress, Rho/Rho kinase signaling pathways, etc.) and therapeutic strategies targeting these factors are introduced.

Advantages of omics approaches for elucidating metabolic changes in diabetic peripheral neuropathy.

Various animal and cell culture models of diabetes mellitus (DM) have been established and utilized to study diabetic peripheral neuropathy (DPN). The divergence of metabolic abnormalities among these models makes their etiology complicated despite some similarities regarding the pathological and neurological features of DPN. Thus, this study aimed to review the omics approaches toward DPN, especially on the metabolic states in diabetic rats and mice induced by chemicals (streptozotocin and alloxan) as type 1 DM models and by genetic mutations (MKR, db/db and ob/ob) and high-fat diet as type 2 DM models. Omics approaches revealed that the pathways associated with lipid metabolism and inflammation in dorsal root ganglia and sciatic nerves were enriched and controlled in the levels of gene expression among these animal models. Additionally, these pathways were conserved in human DPN, indicating the pivotal pathogeneses of DPN. Omics approaches are beneficial tools to better understand the association of metabolic changes with morphological and functional abnormalities in DPN.

A Drosophila model of diabetic neuropathy reveals a role of proteasome activity in the glia.

Diabetic peripheral neuropathy (DPN) is the most common chronic, progressive complication of diabetes mellitus. The main symptom is sensory loss; the molecular mechanisms are not fully understood. We found that Drosophila fed a high-sugar diet, which induces diabetes-like phenotypes, exhibit impairment of noxious heat avoidance. The impairment of heat avoidance was associated with shrinkage of the leg neurons expressing the Drosophila transient receptor potential channel Painless. Using a candidate genetic screening approach, we identified proteasome modulator 9 as one of the modulators of impairment of heat avoidance. We further showed that proteasome inhibition in the glia reversed the impairment of noxious heat avoidance, and heat-shock proteins and endolysosomal trafficking in the glia mediated the effect of proteasome inhibition. Our results establish Drosophila as a useful system for exploring molecular mechanisms of diet-induced peripheral neuropathy and propose that the glial proteasome is one of the candidate therapeutic targets for DPN.

Negative pressure pulmonary edema due to upper airway obstruction after general anesthesia in a patient with Parkinson's disease: A case report.

In a patient with Parkinson's disease (PD) who underwent spine surgery 13 h after the last anti-Parkinson medications, negative pressure pulmonary edema from upper airway obstruction developed immediately after extubation. Although oxygenation improved with high-flow nasal cannula therapy, such complications might develop due to abrupt discontinuation of medication for PD.

Motor skills training-induced activation of descending pathways mediating cortical command to hindlimb motoneurons in experimental diabetic rats.

Diabetes disrupts the corticospinal tract (CST) system components that control hindlimb and trunk movement, resulting in weakness of the lower extremities. However, there is no information about a method to improve these disorders. This study aimed to investigate the rehabilitative effects of 2 weeks of aerobic training (AT) and complex motor skills training (ST) on motor disorders in streptozotocin-induced type 1 diabetic rats. In this study, electrophysiological mapping of the motor cortex showed that the diabetes mellitus (DM)-ST group had a larger motor cortical area compared to the DM-AT group and sedentary diabetic animals. Moreover, hand grip strength and rotarod latency increased in the DM-ST group; however, these two parameters did not change in the DM-AT group, as well as in control and sedentary diabetic rats. Furthermore, in the DM-ST group, cortical stimulation-induced and motor-evoked potentials were preserved after the interception of the CST; however, this potential disappeared after additional lesions were made on lateral funiculus, suggesting that their function extends to activating motor descending pathways other than the CST locating lateral funiculus. According to immunohistochemical analysis, the larger fibers present on the dorsal part of the lateral funiculus, which corresponds to the rubrospinal tract of the DM-ST group, expressed the phosphorylated growth-associated protein, 43 kD, which is a specific marker of axons with plastic changes. Additionally, electrical stimulation of the red nucleus revealed expansion of the hindlimb-responsible area and increased motor-evoked potentials of the hindlimb in the DM-ST group, suggesting a strengthening of synaptic connections between the red nucleus and spinal interneurons driving motoneurons. These results reveal that ST induces plastic changes in the rubrospinal tract in a diabetic model, which can compensate for diabetes by disrupting the CST system components that control the hindlimb. This finding suggests that ST can be a novel rehabilitation strategy to improve motor dysfunctions in diabetic patients.

Rhabdomyolysis secondary to hypervirulent Klebsiella pneumoniae infection: A case report.

Hypervirulent Klebsiella pneumoniae (hvKP) is recognized as a lifethreatening community-acquired infection associated with pyogenic liver abscess. However, rhabdomyolysis secondary to hvKP infection is rare. To the best of our knowledge, we report the first case of rhabdomyolysis due to hvKP infection in a patient who survived septic shock syndrome.

Glucagon-Like Peptide-1 Receptor Agonists as Potential Myelination-Inducible and Anti-Demyelinating Remedies.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were developed as insulinotropic and anti-hyperglycemic agents for the treatment of type 2 diabetes, but their neurotrophic and neuroprotective activities have been receiving increasing attention. Myelin plays a key role in the functional maintenance of the central and peripheral nervous systems, and recent in vivo and in vitro studies have shed light on the beneficial effects of GLP-1RAs on the formation and protection of myelin. In this article, we describe the potential efficacy of GLP-1RAs for the induction of axonal regeneration and remyelination following nerve lesions and the prevention and alleviation of demyelinating disorders, particularly multiple sclerosis.

Docosahexaenoic Acid Suppresses Oxidative Stress-Induced Autophagy and Cell Death via the AMPK-Dependent Signaling Pathway in Immortalized Fischer Rat Schwann Cells 1.

Autophagy is the process by which intracellular components are degraded by lysosomes. It is also activated by oxidative stress; hence, autophagy is thought to be closely related to oxidative stress, one of the major causes of diabetic neuropathy. We previously reported that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) induced antioxidant enzymes and protected Schwann cells from oxidative stress. However, the relationship between autophagy and oxidative stress-induced cell death in diabetic neuropathy has not been elucidated. Treatment with tert-butyl hydroperoxide (tBHP) decreased the cell survival rate, as measured by an MTT assay in immortalized Fischer rat Schwann cells 1 (IFRS1). A DHA pretreatment significantly prevented tBHP-induced cytotoxicity. tBHP increased autophagy, which was revealed by the ratio of the initiation markers, AMP-activated protein kinase, and UNC51-like kinase phosphorylation. Conversely, the DHA pretreatment suppressed excessive tBHP-induced autophagy signaling. Autophagosomes induced by tBHP in IFRS1 cells were decreased to control levels by the DHA pretreatment whereas autolysosomes were only partially decreased. These results suggest that DHA attenuated excessive autophagy induced by oxidative stress in Schwann cells and may be useful to prevent or reduce cell death in vitro. However, its potentiality to treat diabetic neuropathy must be validated in in vivo studies.

Continuing versus withholding angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) combination tablets during perioperative periods in patients undergoing minor surgery: a single-blinded randomized controlled trial.

PURPOSE: This trial was conducted to compare effects of continuing versus withholding single-pill combination tablets consisting of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) on perioperative hemodynamics and clinical outcomes. METHODS: Patients undergoing minor abdominal or urological surgery (n = 106) were randomly assigned to Group C, in which ARB/CCB combination tablets were continued until surgery, or Group W, in which they were withheld within 24 h of surgery. Perioperative hemodynamics and clinical outcomes were compared between the Groups. RESULTS: The incidence of hypotension during anesthesia requiring repeated treatment with vasoconstrictors was higher in Group C than Group W (p = 0.0052). Blood pressure during anesthesia was generally lower in Group C than Group W (p < 0.05) despite significantly more doses of ephedrine and phenylephrine administrated in Group C (p = 0.0246 and p = 0.0327, respectively). The incidence of postoperative hypertension did not differ between Groups (p = 0.3793). Estimated glomerular filtration rate (eGFR) on the preoperative day did not differ between Groups (p = 0.7045), while eGFR was slightly lower in Group C than Group W on the first and third postoperative days (p = 0.0400 and p = 0.0088, respectively), although clinically relevant acute kidney injury did not develop. CONCLUSIONS: Continuing ARB/CCB combination tablets preoperatively in patients undergoing minor surgery increased the incidence of hypotension during anesthesia, increased requirements of vasoconstrictors to treat hypotension, and might deteriorate postoperative renal function, albeit slightly. These results suggest that withholding ARB/CCB tablets preoperatively is preferable to continuing them. CLINICAL TRIAL REGISTRATION: This trial is registered with the Japan Registry of Clinical Trials (jRCT) at Japanese Ministry of Health, Labour, and Welfare (Trial ID: jRCT1031190027).

Role of pyruvate in maintaining cell viability and energy production under high-glucose conditions.

Pyruvate functions as a key molecule in energy production and as an antioxidant. The efficacy of pyruvate supplementation in diabetic retinopathy and nephropathy has been shown in animal models; however, its significance in the functional maintenance of neurons and Schwann cells under diabetic conditions remains unknown. We observed rapid and extensive cell death under high-glucose (> 10 mM) and pyruvate-starved conditions. Exposure of Schwann cells to these conditions led to a significant decrease in glycolytic flux, mitochondrial respiration and ATP production, accompanied by enhanced collateral glycolysis pathways (e.g., polyol pathway). Cell death could be prevented by supplementation with 2-oxoglutarate (a TCA cycle intermediate), benfotiamine (the vitamin B1 derivative that suppresses the collateral pathways), or the poly (ADP-ribose) polymerase (PARP) inhibitor, rucaparib. Our findings suggest that exogenous pyruvate plays a pivotal role in maintaining glycolysis-TCA cycle flux and ATP production under high-glucose conditions by suppressing PARP activity.

Exendin-4 Promotes Schwann Cell Survival/Migration and Myelination In Vitro.

Besides its insulinotropic actions on pancreatic ß cells, neuroprotective activities of glucagon-like peptide-1 (GLP-1) have attracted attention. The efficacy of a GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) for functional repair after sciatic nerve injury and amelioration of diabetic peripheral neuropathy (DPN) has been reported; however, the underlying mechanisms remain unclear. In this study, the bioactivities of Ex-4 on immortalized adult rat Schwann cells IFRS1 and adult rat dorsal root ganglion (DRG) neuron-IFRS1 co-culture system were investigated. Localization of GLP-1R in both DRG neurons and IFRS1 cells were confirmed using knockout-validated monoclonal Mab7F38 antibody. Treatment with 100 nM Ex-4 significantly enhanced survival/proliferation and migration of IFRS1 cells, as well as stimulated the movement of IFRS1 cells toward neurites emerging from DRG neuron cell bodies in the co-culture with the upregulation of myelin protein 22 and myelin protein zero. Because Ex-4 induced phosphorylation of serine/threonine-specific protein kinase AKT in these cells and its effects on DRG neurons and IFRS1 cells were attenuated by phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor LY294002, Ex-4 might act on both cells to activate PI3K/AKT signaling pathway, thereby promoting myelination in the co-culture. These findings imply the potential efficacy of Ex-4 toward DPN and other peripheral nerve lesions.

Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems.

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.

The dynamic collapse of the trachea during anesthesia for a pediatric patient with a large anterior mediastinal mass: A case report.

Anesthesia for patient with large anterior mediastinal mass might induce life-threatening complication. Maintaining the spontaneous breathing throughout the procedure and finding rescue position are the cornerstones of anesthetic management.

Glycolaldehyde induces sensory neuron death through activation of the c-Jun N-terminal kinase and p-38 MAP kinase pathways.

Glycolaldehyde (GA) is a highly reactive hydroxyaldehyde and one of the glycolytic metabolites producing advanced glycation endproducts (AGEs), but its toxicity toward neurons and Schwann cells remains unclear. In the present study, we found that GA exhibited more potent toxicity than other AGE precursors (glyceraldehyde, glyoxal, methylglyoxal and 3-deoxyglucosone) against immortalized IFRS1 adult rat Schwann cells and ND7/23 neuroblastoma × neonatal rat dorsal root ganglion (DRG) neuron hybrid cells. GA affected adult rat DRG neurons and ND7/23 cells more severely than GA-derived AGEs, and exhibited concentration- and time-dependent toxicity toward ND7/23 cells (10 < 100 < 250 < 500 µM; 6 h < 24 h). Treatment with 500 µM GA significantly up-regulated the phosphorylation of c-jun N-terminal kinase (JNK) and p-38 mitogen-activated kinase (p-38 MAPK) in ND7/23 cells. Furthermore, GA-induced ND7/23 cell death was significantly inhibited due to co-treatment with 10 µM of the JNK inhibitor SP600125 or the p-38 MAPK inhibitor SB239063. These findings suggest the involvement of JNK and p-38 MAPK-signaling pathways in GA-induced neuronal cell death and that enhanced GA production under diabetic conditions might be involved in the pathogenesis of diabetic neuropathy.

Drug-Induced Demyelinating Neuropathies.

A large variety of drugs have been reported to cause peripheral neuropathies as dose-limiting adverse effects; however, most of them primarily affect axons and/or neuronal cell bodies rather than Schwann cells and/or myelin sheaths. In this chapter, we focus on the drugs that seem to elicit the neuropathies with schwannopathy and/or myelinopathy-predominant phenotypes, such as amiodarone, dichloroacetate, and tumor necrosis factor-α antagonists. Although the pathogenesis of demyelination induced by these drugs remain largely obscure, the recent in vivo and in vitro studies have implicated the involvement of metabolic abnormalities and impaired autophagy in Schwann cells and immune system disorders in the disruption of neuron-Schwann cell contact and interactions.

Aortic Aneurysm as a Complication of Granulomatosis with Polyangiitis Successfully Treated with Prednisolone and Cyclophosphamide: A Case Report and Review of the Literature.

A 57-year-old Japanese man was admitted to the hospital with back pain and fever, multiple lung nodules, and abdominal aortic aneurysm (AAA). Laboratory tests performed at admission showed an increased proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) level. Video-associated thoracoscopic lung biopsy was performed; pathologic examination showed granulation tissue with necrosis and multinucleated giant cells. The diagnosis of granulomatosis with polyangiitis (GPA) was confirmed on the basis of the clinical presentation, laboratory findings, and lung biopsy. All symptoms were ameliorated, and the serum level of PR3-ANCA declined following treatment with prednisolone and cyclophosphamide. Although the association of GPA with AAA is rare, GPA may be included among the large vessel vasculitides that can give rise to aortic aneurysm.