scholarly journals Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wataru Shiraishi ◽  
Ryo Yamasaki ◽  
Yu Hashimoto ◽  
Senri Ko ◽  
Yuko Kobayakawa ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Peripheral Nerves ◽  
Disease Onset ◽  
Green Fluorescence Protein ◽  
Macrophage Infiltration ◽  
Fluorescence Protein ◽  
End Stage ◽  
Als Patients

AbstractMacrophages expressing C–C chemokine receptor type 2 (CCR2) infiltrate the central and peripheral neural tissues of amyotrophic lateral sclerosis (ALS) patients. To identify the functional role of CCR2+ macrophages in the pathomechanisms of ALS, we used an ALS animal model, mutant Cu/Zn superoxide dismutase 1G93A (mSOD1)-transgenic (Tg) mice. To clarify the CCR2 function in the model, we generated SOD1G93A/CCR2Red fluorescence protein (RFP)/Wild type (WT)/CX3CR1Green fluorescence protein (GFP)/WT-Tg mice, which heterozygously express CCR2-RFP and CX3CR1-GFP, and SOD1G93A/CCR2RFP/RFP-Tg mice, which lack CCR2 protein expression and present with a CCR2-deficient phenotype. In mSOD1-Tg mice, mSOD1 accumulated in the sciatic nerve earlier than in the spinal cord. Furthermore, spinal cords of SOD1G93A/CCR2RFP/WT/CX3CR1GFP/WT mice showed peripheral macrophage infiltration that emerged at the end-stage, whereas in peripheral nerves, macrophage infiltration started from the pre-symptomatic stage. Before disease onset, CCR2+ macrophages harboring mSOD1 infiltrated sciatic nerves earlier than the lumbar cord. CCR2-deficient mSOD1-Tg mice showed an earlier onset and axonal derangement in the sciatic nerve than CCR2-positive mSOD1-Tg mice. CCR2-deficient mSOD1-Tg mice showed an increase in deposited mSOD1 in the sciatic nerve compared with CCR2-positive mice. These findings suggest that CCR2+ and CX3CR1+ macrophages exert neuroprotective functions in mSOD1 ALS via mSOD1 clearance from the peripheral nerves.

Dysautonomia as Onset Symptom of Myotonic Dystrophy Type 2

2018 ◽  
Vol 79 (3-4) ◽  
pp. 166-170
Author(s):  
Salvatore Rossi ◽  
Angela Romano ◽  
Anna Modoni ◽  
Francesco Perna ◽  
Valentina Rizzo ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Peripheral Nerves ◽  
Autosomal Dominant ◽  
Disease Onset ◽  
Clinical Signs ◽  
Myotonic Dystrophy Type ◽  
Multisystem Disorder ◽  
Myotonic Dystrophy Type 2 ◽  
Cctg Repeat

Myotonic dystrophy type 2 (DM2) is an autosomal dominant muscular dystrophy caused by the expansion of an intronic tetranucleotide CCTG repeat in CNBP on chromosome 3. As DM1, DM2 is a multisystem disorder affecting, beside the skeletal muscle, various other tissues, including peripheral nerves. Indeed, a subclinical involvement of peripheral nervous system has been described in several cohorts of DM2 patients, whereas DM2 patients manifesting clinical signs and/or symptoms of neuropathy have been only rarely reported. Here, we describe 2 related DM2 patients both of whom displayed an atypical disease onset characterized by dysautonomic symptoms, possibly secondary to peripheral neuropathy.

scholarly journals Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes

2012 ◽  
Vol 216 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Lucy M Hinder ◽  
Anuradha Vivekanandan-Giri ◽  
Lisa L McLean ◽  
Subramaniam Pennathur ◽  
Eva L Feldman
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Sciatic Nerve ◽  
Peripheral Nerves ◽  
Sural Nerve ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Diabetic Mice ◽  
Type 2 Diabetic

Diabetic neuropathy (DN) is the most common complication of diabetes and is characterized by distal-to-proximal loss of peripheral nerve axons. The idea of tissue-specific pathological alterations in energy metabolism in diabetic complications-prone tissues is emerging. Altered nerve metabolism in type 1 diabetes models is observed; however, therapeutic strategies based on these models offer limited efficacy to type 2 diabetic patients with DN. Therefore, understanding how peripheral nerves metabolically adapt to the unique type 2 diabetic environment is critical to develop disease-modifying treatments. In the current study, we utilized targeted liquid chromatography–tandem mass spectrometry (LC/MS/MS) to characterize the glycolytic and tricarboxylic acid (TCA) cycle metabolomes in sural nerve, sciatic nerve, and dorsal root ganglia (DRG) from male type 2 diabetic mice (BKS.Cg-m+/+Leprdb;db/db) and controls (db/+). We report depletion of glycolytic intermediates in diabetic sural nerve and sciatic nerve (glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate (sural nerve only), 3-phosphoglycerate, 2-phosphoglycerate, phosphoenolpyruvate, and lactate), with no significant changes in DRG. Citrate and isocitrate TCA cycle intermediates were decreased in sural nerve, sciatic nerve, and DRG from diabetic mice. Utilizing LC/electrospray ionization/MS/MS and HPLC methods, we also observed increased protein and lipid oxidation (nitrotyrosine; hydroxyoctadecadienoic acids) indb/dbtissue, with a proximal-to-distal increase in oxidative stress, with associated decreased aconitase enzyme activity. We propose a preliminary model, whereby the greater change in metabolomic profile, increase in oxidative stress, and decrease in TCA cycle enzyme activity may cause distal peripheral nerves to rely on truncated TCA cycle metabolism in the type 2 diabetes environment.

The role of renal anemia and cardiovascular disease in the progression of chronic glomerulonephritis

2016 ◽  
Vol 88 (12) ◽  
pp. 57-61 ◽  
Author(s):  
I T Murkamilov ◽  
I G Gordeev ◽  
R R Kaliev
Keyword(s):  
Cardiovascular Disease ◽  
Disease Onset ◽  
Hemoglobin Concentration ◽  
Chronic Glomerulonephritis ◽  
Bicycle Ergometry ◽  
Reactive Protein ◽  
Persistent Proteinuria ◽  
Cell Counts ◽  
End Stage

Aim. To study the rate of chronic glomerulonephritis progression when added by anemia and cardiovascular disease (CVD). Subjects and methods. 231 patients (133 men and 98 women) with predialysis chronic glomerulonephritis (CGN) were examined. The patients’ mean age of was 35.8±11.8 years; the disease duration was 1 to 17 years. The disease onset was the date when urinalysis showed evidence of persistent proteinuria and (or) hematuria. Besides, the time when anemia developed and the clinical and instrumental signs of CVD appeared was taken as the initial reference point; the time when end-stage renal failure was diagnosed was taken to be the endpoint. Red blood cell counts with the inclusion of its indices, hemoglobin concentration, hematocrit values, daily proteinuria values, and glomerular filtration rate were analyzed. The biochemical parameters included the concentrations of electrolytes, creatinine, fibrinogen, iron, cholesterol, total protein and C-reactive protein (CRP). Electrocardiography and echocardiography, bicycle ergometry and 24-hour ECG monitoring were used to detect CVD. Results. The presence of anemia and CVD in patients with predialysis CGN versus those without anemia and CVD was associated with an increase in the concentrations of CRP [36.2 and 12.6%; respectively; (p

scholarly journals Actin-dependent Lamellipodia Formation and Microtubule-dependent Tail Retraction Control-directed Cell Migration

2000 ◽  
Vol 11 (9) ◽  
pp. 2999-3012 ◽  
Author(s):  
Christoph Ballestrem ◽  
Bernhard Wehrle-Haller ◽  
Boris Hinz ◽  
Beat A. Imhof
Keyword(s):  
Cell Migration ◽  
Cell Body ◽  
Actin Polymerization ◽  
Green Fluorescence Protein ◽  
Time Lapse ◽  
Dependent Manner ◽  
Directed Cell Migration ◽  
Cell Front ◽  
Fluorescence Protein

Migrating cells are polarized with a protrusive lamella at the cell front followed by the main cell body and a retractable tail at the rear of the cell. The lamella terminates in ruffling lamellipodia that face the direction of migration. Although the role of actin in the formation of lamellipodia is well established, it remains unclear to what degree microtubules contribute to this process. Herein, we have studied the contribution of microtubules to cell motility by time-lapse video microscopy on green flourescence protein-actin- and tubulin-green fluorescence protein–transfected melanoma cells. Treatment of cells with either the microtubule-disrupting agent nocodazole or with the stabilizing agent taxol showed decreased ruffling and lamellipodium formation. However, this was not due to an intrinsic inability to form ruffles and lamellipodia because both were restored by stimulation of cells with phorbol 12-myristate 13-acetate in a Rac-dependent manner, and by stem cell factor in melanoblasts expressing the receptor tyrosine kinase c-kit. Although ruffling and lamellipodia were formed without microtubules, the microtubular network was needed for advancement of the cell body and the subsequent retraction of the tail. In conclusion, we demonstrate that the formation of lamellipodia can occur via actin polymerization independently of microtubules, but that microtubules are required for cell migration, tail retraction, and modulation of cell adhesion.

ADF/cofilin mediates actin cytoskeletal alterations in LLC-PK cells during ATP depletion

2003 ◽  
Vol 284 (4) ◽  
pp. F852-F862 ◽  
Author(s):  
Sharon L. Ashworth ◽  
Erica L. Southgate ◽  
Ruben M. Sandoval ◽  
Peter J. Meberg ◽  
James R. Bamburg ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Three Dimensional ◽  
Green Fluorescence Protein ◽  
Atp Depletion ◽  
Green Fluorescence ◽  
Short Term ◽  
Fluorescence Protein ◽  
Cytoskeleton Disruption ◽  
Constitutively Active

Ischemic injury induces actin cytoskeleton disruption and aggregation, but mechanisms affecting these changes remain unclear. To determine the role of actin-depolymerizing factor (ADF)/ cofilin participation in ischemic-induced actin cytoskeletal breakdown, we utilized porcine kidney cultured cells, LLC-PKA4.8, and adenovirus containing wild-type (wt), constitutively active, and inactive Xenopus ADF/cofilin linked to green fluorescence protein [XAC(wt)-GFP] in an ATP depletion model. High adenoviral infectivity (70%) in LLC-PKA4.8 cells resulted in linearly increasing XAC(wt)-GFP and phosphorylated (p)XAC(wt)-GFP (inactive) expression. ATP depletion rapidly induced dephosphorylation, and, therefore, activation, of endogenous pcofilin as well as pXAC(wt)-GFP in conjunction with the formation of fluorescent XAC(wt)-GFP/actin aggregates and rods. No significant actin cytoskeletal alterations occurred with short-term ATP depletion of LLC-PKA4.8 cells expressing GFP or the constitutively inactive mutant XAC(S3E)-GFP, but cells expressing the constitutively active mutant demonstrated nearly instantaneous actin disruption with aggregate and rod formation. Confocal image three-dimensional volume reconstructions of normal and ATP-depleted LLC-PKA4.8 cells demonstrated that 25 min of ATP depletion induced a rapid increase in XAC(wt)-GFP apical and basal signal in addition to XAC-GFP/actin aggregate formation. These data demonstrate XAC(wt)-GFP participates in ischemia-induced actin cytoskeletal alterations and determines the rate and extent of these ATP depletion-induced cellular alterations.

scholarly journals Effect of vasodilator PGE1 on sciatic nerve function, VEGF level, vascular permeability and peripheral nerve in type 2 diabetic rats

2021 ◽  
Vol 18 (7) ◽  
pp. 1481-1485
Author(s):  
Fang Wang ◽  
Yufang Liu ◽  
Xiue Xu ◽  
Yuan Chen ◽  
Guiyan Chen
Keyword(s):  
Sciatic Nerve ◽  
Vascular Permeability ◽  
Peripheral Nerves ◽  
Post Treatment ◽  
Control Group ◽  
Study Group ◽  
Nerve Function ◽  
Untreated Control Group ◽  
Vegf Level

Purpose: To investigate the effect of vasodilator prostaglandin E1 (PGE1) on sciatic nerve function, vascular endothelial growth factor (VEGF), vascular permeability and peripheral nerve in type 2 diabetes mellitus (T2DM) rats. Methods: Twenty-one rats in the study group were intraperitoneally injected with PGE1, while rats in T2DM untreated group (n = 21) were injected with an equivalent amount of normal saline. Seven rats were randomly selected from the study and the control groups every seven days for 21 days for determination of changes in sciatic nerve function, VEGF level, vascular permeability and peripheral nerves. Results: Sciatic nerve motor nerve conduction velocity (MNCV) was significantly higher in the study group than in T2DM untreated control group at the three time-points post-treatment (p < 0.01). The level of VEGF in the study group decreased, relative to the T2DM untreated control group on the 7th 14th and 21st days post- treatment (p < 0.05) while the water content of sciatic nerve tissue in study group was markedly decreased, relative to control value on day 21 (p < 0.05). Rats in the study group showed decreased TTT, relative to those in T2DM untreated group on days 7, 14 and 21 post-treatment (p < 0.01). Conclusion: PGE1 improves the sciatic nerve function of T2DM rats, reduces the level of serum VEGF and vascular permeability, and protects peripheral nerves. These findings provide a basis for the development of new T2DM drugs

scholarly journals Peripheral hypersensitivity to subthreshold stimuli persists after resolution of acute experimental disc-herniation neuropathy

2015 ◽  
Vol 42 (S1) ◽  
pp. S49-S49
Author(s):  
MF Shamji ◽  
Y Tu ◽  
MW Salter
Keyword(s):  
Sciatic Nerve ◽  
Disc Herniation ◽  
Thermal Sensitivity ◽  
Motor Dysfunction ◽  
Macrophage Infiltration ◽  
Cobalt Staining ◽  
Inflammatory Neuropathy ◽  
Patients Experience

Objective: While acute disc-herniation radiculopathy frequently resolves without clinical sequelae, some patients experience long-term sensory or motor dysfunction. This study examined chronic sensitivity of the rodent hindpaw after resolution of an acute inflammatory neuropathy. Methods: C57BL/6 mice underwent mid-thigh sciatic nerve exposure, with sham animals exposed and experimental animals injured by placement of littermate tail nucleus pulposus (NP). Animals were evaluated for mechanical allodynia (Von Frey), thermal sensitivity (heat withdrawal and acetone latency), and gait stability (RotaRod), until the acute nociceptive phenotype resolved. Thereafter, animals were injected with intraplantar subthreshold capsaicin or vehicle followed by the same testing. At sacrifice, sciatic nerves were assessed for macrophage infiltration by immunohistochemistry, and dorsal root ganglion (DRG) explants were assessed for capsaicin sensitivity using cobalt staining. Results: NP-treated animals were allodynic after subthreshold capsaicin delivery compared with sham-operated controls and NP-treated animals delivered vehicle only. Early intraneural macrophage infiltration at one week dissipated by this three week timepoint. DRGs derived from NP-treated animals exhibited greater cobalt staining upon capsaicin exposure compared with shams. Conclusion: Non-compressive disc herniation creates long-term sensitization in the sciatic nerve distribution. This persists despite resolution of acute intraneural macrophage migration, and the demonstrated role of TRPV1 provides insight into the transformation of acute inflammatory pain into chronic neuropathic pain.

scholarly journals Role of Heme Oxygenase in Inflammation, Insulin-Signalling, Diabetes and Obesity

2010 ◽  
Vol 2010 ◽  
pp. 1-18 ◽  
Author(s):  
Joseph Fomusi Ndisang
Keyword(s):  
Heme Oxygenase ◽  
Chronic Conditions ◽  
Insulin Signalling ◽  
Common Denominator ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
End Stage ◽  
Diabetes And Obesity

Diabetes and obesity are chronic conditions associated with elevated oxidative/inflammatory activities with a continuum of tissue insults leading to more severe cardiometabolic and renal complications including myocardial infarction and end-stage-renal damage. A common denominator of these chronic conditions is the enhanced the levels of cytokines like tumour necrosis factor-alpha (TNF-α), interleukin (IL-6), IL-1βand resistin, which in turn activates the c-Jun-N-terminal kinase (JNK) and NF-κB pathways, creating a vicious cycle that exacerbates insulin resistance, type-2 diabetes and related complications. Emerging evidence indicates that heme oxygenase (HO) inducers are endowed with potent anti-diabetic and insulin sensitizing effects besides their ability to suppress immune/inflammatory response. Importantly, the HO system abates inflammation through several mechanisms including the suppression of macrophage-infiltration and abrogation of oxidative/inflammatory transcription factors like NF-κB, JNK and activating protein-1. This review highlights the mechanisms by which the HO system potentiates insulin signalling, with particular emphasis on HO-mediated suppression of oxidative and inflammatory insults. The HO system could be explored in the search for novel remedies against cardiometabolic diseases and their complications.

scholarly journals Natural history and risk factors for diabetic nephropathy in Italy: insights from AMD Annals initiative

2019 ◽  
Vol 22 (4) ◽  
pp. 178
Author(s):  
Piscitelli, P.
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Natural History ◽  
Disease Onset ◽  
Diabetic Patients ◽  
Increased Risk ◽  
End Stage

Diabetic patients have a high risk to develop diabetic nephropathy. Diabetic nephropathy represents non only a risk factor for progression toward end stage renal disease but it is also associates with an increased risk to have of major cardiovascular events. Over the last few years, analysis of the AMD annals dataset has contributed several important insights on the clinical features of type 2 diabetes kidney disease and their prognostic and therapeutic implications. First, non-albuminuric renal impairment is the predominant clinical phenotype. Even though associated with a lower risk of progression compared to overt albuminuria, it contributes significantly to the burden of end-stage renaldisease morbidity. Second, optimal blood pressure control provides significant but incomplete renal protection. It reduces albuminuria but there may be a J curve phenomenon with eGFR at very low blood pressure values. Third, hyperuricemia and diabetic hyperlipidemia, namely elevated triglycerides and low HDL cholesterol, are strong independent predictorsof chronic kidney disease onset in diabetes, although the pathogenetic mechanisms underlying these associationsremain uncertain. These data help clarify the natural history of CKD in patients with type 2 diabetes and provide important clues for designing futureinterventional studies. KEY WORDS albuminuria; glomerular filtration rate; hypertension; uric acid; type2 diabetes mellitus.

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