In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation.

1998 ◽  
Vol 9 (7) ◽  
pp. 1213-1224 ◽  
Author(s):  
M Abbate ◽  
C Zoja ◽  
D Corna ◽  
M Capitanio ◽  
T Bertani ◽  
...  
Keyword(s):  
Time Course ◽  
Early Stage ◽  
Protein Accumulation ◽  
Glomerular Injury ◽  
Cellular Mechanisms ◽  
Proinflammatory Response ◽  
Glomerular Permeability ◽  
Tubular Cells ◽  
Interstitial Inflammation ◽  
Tubulointerstitial Lesions

Progression to end-stage renal failure is the final common pathway of many forms of glomerular disease, independent of the type of initial insult. Progressive glomerulopathies have in common persistently high levels of urinary protein excretion and tubulointerstitial lesions at biopsy. Among the cellular mechanisms that may determine progression regardless of etiology, the traffic of excess proteins filtered from glomerulus in renal tubule may have functional importance by initiating interstitial inflammation in the early phase of parenchymal injury. This study analyzes the time course and sites of protein accumulation and interstitial cellular infiltration in two different models of proteinuric nephropathies. In remnant kidneys after 5/6 renal mass ablation, albumin and IgG accumulation by proximal tubular cells was visualized in the early stage, preceding interstitial infiltration of MHC-II-positive cells and macrophages. By double-staining, infiltrates developed at or near tubules containing intracellular IgG or luminal casts. This relationship persisted thereafter despite more irregular distribution of infiltrate. Similar patterns were found in an immune model (passive Heymann nephritis), indicating that the interstitial inflammatory reaction develops at the sites of protein overload, regardless of the type of glomerular injury. Osteopontin was detectable in cells of proximal tubules congested with protein in both models at sites of interstitial infiltration, and by virtue of its chemoattractive action this is likely mediator of a proximal tubule-dependent inflammatory pathway in response to protein load. Protein overload of tubules is a key candidate process translating glomerular protein leakage into cellular signals of interstitial inflammation. Mechanisms underlying the proinflammatory response of tubular cells to protein challenge in diseased kidney should be explored, as well as ways of limiting protein reabsorption/deposition to prevent consequent inflammation and progressive disease.

scholarly journals Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?

2021 ◽  
Author(s):  
Fabiola De Marchi ◽  
◽  
Claudia Carrarini ◽  
Antonio De Martino ◽  
Luca Diamanti ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Time Course ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Multisystem Disorder ◽  
Behavioral Impairment ◽  
Behavioral Impairments ◽  
Als Patients ◽  
Disease Stages ◽  
Lateral Sclerosis

Abstract Background and aim Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline. Conclusions To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.

Dynamic coupling among neocortical neurons during evoked and spontaneous spike-wave seizure activity

1994 ◽  
Vol 72 (5) ◽  
pp. 2051-2069 ◽  
Author(s):  
M. Steriade ◽  
F. Amzica
Keyword(s):  
Cortical Neurons ◽  
Time Course ◽  
Early Stage ◽  
Field Potential ◽  
Time Lags ◽  
Temporal Relations ◽  
Intracellular Recordings ◽  
Field Potentials ◽  
Thalamic Nuclei ◽  
Spike Wave

1. We investigated the development from patterns of electroencephalogram (EEG) synchronization to paroxysms consisting of spike-wave (SW) complexes at 2–4 Hz or to seizures at higher frequencies (7–15 Hz). We used multisite, simultaneous EEG, extracellular, and intracellular recordings from various neocortical areas and thalamic nuclei of anesthetized cats. 2. The seizures were observed in 25% of experimental animals, all maintained under ketamine and xylazine anesthesia, and were either induced by thalamocortical volleys and photic stimulation or occurred spontaneously. Out of unit and field potential recordings within 370 cortical and 65 thalamic sites, paroxysmal events occurred in 70 cortical and 8 thalamic sites (approximately 18% and 12%, respectively), within which a total of 181 neurons (143 extracellular and 38 intracellular) were simultaneously recorded in various combinations of cell groups. 3. Stimulus-elicited and spontaneous SW seizures at 2–4 Hz lasted for 15–35 s and consisted of barrages of action potentials related to the spiky depth-negative (surface-positive) field potentials, followed by neuronal silence during the depth-positive wave component of SW complexes. The duration of inhibitory periods progressively increased during the seizure, at the expense of the phasic excitatory phases. 4. Intracellular recordings showed that, during such paroxysms, cortical neurons displayed a tonic depolarization (approximately 10–20 mV), sculptured by rhythmic hyperpolarizations. 5. In all cases, measures of synchrony demonstrated time lags between discharges of simultaneously recorded cortical neurons, from as short as 3–10 ms up to 50 ms or even longer intervals. Synchrony was assessed by cross-correlograms, by a method termed first-spike-analysis designed to detect dynamic temporal relations between neurons and relying on the detection of the first action potential in a spike train, and by a method termed sequential-field-correlation that analyzed the time course of field potentials simultaneously recorded from different cortical areas. 6. The degree of synchrony progressively increased from preseizure sleep patterns to the early stage of the SW seizure and, further, to its late stage. In some cases the time relation between neurons during the early stages of seizures was inversed during late stages. 7. These data show that, although the common definition of SW seizures, regarded as suddenly generalized and bilaterally synchronous activities, may be valid at the macroscopic EEG level, cortical neurons display time lags between their rhythmic spike trains, progressively increased synchrony, and changes in the temporal relations between their discharges during the paroxysms.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Complement Components C3 and C4 Indicate Vasculitis Manifestations to Distinct Renal Compartments in ANCA-Associated Glomerulonephritis

2021 ◽  
Vol 22 (12) ◽  
pp. 6588
Author(s):  
Samy Hakroush ◽  
Désirée Tampe ◽  
Peter Korsten ◽  
Philipp Ströbel ◽  
Björn Tampe
Keyword(s):  
Current Knowledge ◽  
Systemic Disease ◽  
Kidney Injury ◽  
Scoring Systems ◽  
Antineutrophil Cytoplasmic Antibodies ◽  
Glomerular Injury ◽  
Tubulointerstitial Injury ◽  
Complement Components ◽  
Tubulointerstitial Lesions ◽  
Low Levels

Background: Acute kidney injury (AKI) is a common and severe complication of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) causing progressive chronic kidney disease (CKD), end-stage renal disease (ESRD) or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN), a common manifestation of glomerular injury in AAV. However, there is growing evidence that activation of the complement pathway contributes to the pathogenesis and progression of AAV. We here aimed to compare glomerular and tubulointerstitial lesions in ANCA GN and extrarenal manifestation of AAV in association with levels of circulating complement components C3c and C4. Methods: Plasma levels of C3c and C4 in a total number of 53 kidney biopsies with ANCA GN were retrospectively included between 2015 and 2020. Glomerular and tubulointerstitial lesions were evaluated according to established scoring systems for ANCA GN and analogous to the Banff classification. Results: We here show that circulating levels of C3c and C4 in ANCA GN were comparable to the majority of other renal pathologies. Furthermore, hypocomplementemia was only detectable in a minor subset of ANCA GN and not correlated with renal or extrarenal AAV manifestations. However, low levels of circulating C3c correlated with AKI severity in ANCA GN independent of systemic disease activity or extrarenal AAV manifestation. By systematic scoring of glomerular and tubulointerstitial lesions, we provide evidence that low levels of circulating C3c and C4 correlated with vasculitis manifestations to distinct renal compartments in ANCA GN. Conclusions: We here expand our current knowledge about distinct complement components in association with vasculitis manifestations to different renal compartments in ANCA GN. While low levels of C4 correlated with glomerulitis, our observation that low levels of circulating complement component C3c is associated with interstitial vasculitis manifestation reflected by intimal arteritis implicates that C3c contributes to tubulointerstitial injury in ANCA GN.

Recovery of subjective visual horizontal after unilateral vestibular deafferentation by intratympanic instillation of gentamicin

2006 ◽  
Vol 16 (1-2) ◽  
pp. 69-73 ◽  
Author(s):  
Yoshinari Takai ◽  
Toshihisa Murofushi ◽  
Munetaka Ushio ◽  
Shinichi Iwasaki
Keyword(s):  
Healthy Subjects ◽  
Time Course ◽  
Early Stage ◽  
Ccd Camera ◽  
The Other ◽  
Spontaneous Nystagmus ◽  
Vestibular Evoked Myogenic Potentials ◽  
Normal Range ◽  
Intratympanic Gentamicin ◽  
Unilateral Vestibular Deafferentation

The time course of the recovery of subjective visual horizontal (SVH) after unilateral vestibular deafferentation by intratympanic instillation of gentamicin was studied. Six patients who underwent intratympanic gentamicin instillation therapy for Meniere's disease (1 man and 5 women, 32 to 69 years of age) were enrolled in this study. For comparison, SVH in 23 healthy subjects (12 men and 11 woman, 23 to 48 years of age) was also measured. The mean ± SD of SVH in healthy subjects was 0.0 ± 1.1 deg. All of the 6 patients showed significantly deviated SVH toward the injected side-down at the early stage after the therapy. Although one patient showed recovery of SVH to the normal range 25 days after the injection, the other patients required more time for recovery. Three patients did not show recovery to the normal range after 1 year. On the other hand, spontaneous nystagmus observed using an infrared CCD camera in total dark disappeared after 35 days (median). Patients who had normal vestibular evoked myogenic potentials before the therapy showed a tendency of delay of recovery of SVH. The reasons why the recovery of SVH took longer than the disappearance of spontaneous nystagmus are discussed in this report.

Copper metabolism in the kidney of rats administered copper and copper-metallothionein

1998 ◽  
Vol 274 (4) ◽  
pp. F783-F790 ◽  
Author(s):  
Masaaki Kurasaki ◽  
Masashi Okabe ◽  
Shigeru Saito ◽  
Mika Suzuki-Kurasaki
Keyword(s):  
Time Course ◽  
Copper Metabolism ◽  
Degradation Process ◽  
High Concentration ◽  
Tubular Cells ◽  
Microscopic Studies

To gain a greater understanding of the mechanism of Cu metabolism in kidneys of rats, using autofluorescence of Cu-metallothioneins (Cu-MTs) we revealed the behavior of Cu-MT in the kidneys of rats administered Cu-MT. Yellow and orange fluorescent signals of Cu-MT were observed in the cortex. By microscopic studies, Cu-MT was dominant in the proximal convolute tubular cells of the cortex. A high concentration of Cu-MT presented in the lysosome-like organelles of the proximal convolute tubular adjacent to the glomeruli. During the time course after the injection, the orange signal in lysosome-like organelles gradually converted to a yellow signal, indicating that the Cu-MT was involved in a degradation process in lysosomes by oxidation, and the MT mRNA increased in the cortex, although the immunoreactivity of MT was almost constant in the same region. These results suggested that Cu bound to the injected MT was released in lysosomes and became a new inducer of MT biosynthesis in the cortex. In conclusion, the biosynthesis and degradation of Cu-MT occur repeatedly in the proximal convolute tubular cells.

scholarly journals The key features of SARS-CoV-2 leader and NSP1 required for viral escape of NSP1-mediated repression

2021 ◽  
Author(s):  
Lucija Bujanic ◽  
Olga Shevchuk ◽  
Nicolai von Kuegelgen ◽  
Katarzyna Ludwik ◽  
David Koppstein ◽  
...  
Keyword(s):  
Drug Targets ◽  
Early Stage ◽  
Nonstructural Protein ◽  
Viral Escape ◽  
Cellular Mechanisms ◽  
Viral Mrnas ◽  
Stem Loop ◽  
Nonstructural Protein 1 ◽  
Global Pandemic ◽  
Cellular Mrnas

SARS-CoV-2, responsible for the ongoing global pandemic, must overcome a conundrum faced by all viruses. To achieve its own replication and spread, it simultaneously depends on and subverts cellular mechanisms. At the early stage of infection, SARS-CoV-2 expresses the viral nonstructural protein 1 (NSP1), which inhibits host translation by blocking the mRNA entry tunnel on the ribosome; this interferes with the binding of cellular mRNAs to the ribosome. Viral mRNAs, on the other hand, overcome this blockade. We show that NSP1 enhances expression of mRNAs containing the SARS-CoV-2 leader. The first stem-loop (SL1) in viral leader is both necessary and sufficient for this enhancement mechanism. Our analysis pinpoints specific residues within SL1 (three cytosine residues at the positions 15, 19 and 20) and another within NSP1 (R124) which are required for viral evasion, and thus might present promising drug targets. Additionally, we carried out analysis of a functional interactome of NSP1 using BioID and identified components of anti-viral defense pathways. Our analysis therefore suggests a mechanism by which NSP1 inhibits the expression of host genes while enhancing that of viral RNA. This analysis helps reconcile conflicting reports in the literature regarding the mechanisms by which the virus avoids NSP1 silencing.

scholarly journals Involvement of R-cadherin in the early stage of glomerulogenesis.

1998 ◽  
Vol 9 (7) ◽  
pp. 1234-1241 ◽  
Author(s):  
S Goto ◽  
E Yaoita ◽  
H Matsunami ◽  
D Kondo ◽  
T Yamamoto ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Upper Limb ◽  
Immunofluorescence Microscopy ◽  
Early Stage ◽  
Capillary Loop ◽  
Tubular Cells ◽  
Glomerular Epithelial Cells ◽  
Ureteric Buds ◽  
Parietal Epithelial Cells ◽  
E Cadherin

The earliest commitment to the formation of glomeruli is recognizable in S-shaped bodies. Although cell-cell adhesion seems likely to play a crucial role in this process, how glomerular epithelial cells segregate from the other parts of the nephron is unknown. In this study, immunofluorescence microscopy and monoclonal antibodies specific for mouse R-, E-, P- and N-cadherins were used to examine which of these adhesion molecules are involved in glomerulogenesis of the mouse kidney. Weak R-cadherin staining was first found in the vesicle stage, becoming restricted to glomerular visceral epithelial cells (VEC) during the S-shaped body stage. The intensity of this staining became stronger in the capillary loop stage, whereas parietal epithelial cells (PEC) and tubular cells did not stain. In the maturing stage, VEC gradually lost their staining for R-cadherin. E-cadherin was detected in ureteric buds and the upper limb of S-shaped bodies. From the capillary loop to the maturing stage, anti-E-cadherin stained epithelial cells in all tubule segments, but no label was seen in VEC or PEC. P-cadherin was also stained in the ureteric buds and in the upper limb of S-shaped bodies. N-Cadherin was weakly stained in cells at the vesicle stage, but thereafter staining of N-cadherin was not detected at any stage of glomerular formation. Immunoelectron microscopy of differentiating VEC was performed using antibodies specific to alpha-catenin, which is associated with cadherin. Subsequently, immunogold particles identifying alpha-catenin were localized on junctions between primary processes of VEC. These findings indicate that R-cadherin is uniquely expressed in differentiating VEC, suggesting an important role in the early stages of glomerulogenesis.

scholarly journals Sevoflurane Promotes Bactericidal Properties of Macrophages through Enhanced Inducible Nitric Oxide Synthase Expression in Male Mice

2019 ◽  
Vol 131 (6) ◽  
pp. 1301-1315 ◽  
Author(s):  
Thomas J. Gerber ◽  
Valérie C. O. Fehr ◽  
Suellen D. S. Oliveira ◽  
Guochang Hu ◽  
Randal Dull ◽  
...  
Keyword(s):  
Early Stage ◽  
No Synthase ◽  
Control Group ◽  
Male Mice ◽  
Proinflammatory Response ◽  
E Coli ◽  
Inducible No Synthase ◽  
Bactericidal Properties

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Sevoflurane with its antiinflammatory properties has shown to decrease mortality in animal models of sepsis. However, the underlying mechanism of its beneficial effect in this inflammatory scenario remains poorly understood. Macrophages play an important role in the early stage of sepsis as they are tasked with eliminating invading microbes and also attracting other immune cells by the release of proinflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α. Thus, the authors hypothesized that sevoflurane mitigates the proinflammatory response of macrophages, while maintaining their bactericidal properties. Methods Murine bone marrow–derived macrophages were stimulated in vitro with lipopolysaccharide in the presence and absence of 2% sevoflurane. Expression of cytokines and inducible NO synthase as well as uptake of fluorescently labeled Escherichia coli (E. coli) were measured. The in vivo endotoxemia model consisted of an intraperitoneal lipopolysaccharide injection after anesthesia with either ketamine and xylazine or 4% sevoflurane. Male mice (n = 6 per group) were observed for a total of 20 h. During the last 30 min fluorescently labeled E. coli were intraperitoneally injected. Peritoneal cells were extracted by peritoneal lavage and inducible NO synthase expression as well as E. coli uptake by peritoneal macrophages was determined using flow cytometry. Results In vitro, sevoflurane enhanced lipopolysaccharide-induced inducible NO synthase expression after 8 h by 466% and increased macrophage uptake of fluorescently labeled E. coli by 70% compared with vehicle-treated controls. Inhibiting inducible NO synthase expression pharmacologically abolished this increase in bacteria uptake. In vivo, inducible NO synthase expression was increased by 669% and phagocytosis of E. coli by 49% compared with the control group. Conclusions Sevoflurane enhances phagocytosis of bacteria by lipopolysaccharide-challenged macrophages in vitro and in vivo via an inducible NO synthase–dependent mechanism. Thus, sevoflurane potentiates bactericidal and antiinflammatory host-defense mechanisms in endotoxemia.

scholarly journals Regulatory Potential of bHLH-Type Transcription Factors on the Road to Rubber Biosynthesis in Hevea brasiliensis

Plants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 674
Author(s):  
Tomoko Yamaguchi ◽  
Yukio Kurihara ◽  
Yuko Makita ◽  
Emiko Okubo-Kurihara ◽  
Ami Kageyama ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Natural Rubber ◽  
Hevea Brasiliensis ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Early Stage ◽  
Rubber Biosynthesis ◽  
On The Road

Natural rubber is the main component of latex obtained from laticifer cells of Hevea brasiliensis. For improving rubber yield, it is essential to understand the genetic molecular mechanisms responsible for laticifer differentiation and rubber biosynthesis. Jasmonate enhances both secondary laticifer differentiation and rubber biosynthesis. Here, we carried out time-course RNA-seq analysis in suspension-cultured cells treated with methyljasmonic acid (MeJA) to characterize the gene expression profile. Gene Ontology (GO) analysis showed that the term “cell differentiation” was enriched in upregulated genes at 24 h after treatment, but inversely, the term was enriched in downregulated genes at 5 days, indicating that MeJA could induce cell differentiation at an early stage of the response. Jasmonate signaling is activated by MYC2, a basic helix–loop–helix (bHLH)-type transcription factor (TF). The aim of this work was to find any links between transcriptomic changes after MeJA application and regulation by TFs. Using an in vitro binding assay, we traced candidate genes throughout the whole genome that were targeted by four bHLH TFs: Hb_MYC2-1, Hb_MYC2-2, Hb_bHLH1, and Hb_bHLH2. The latter two are highly expressed in laticifer cells. Their physical binding sites were found in the promoter regions of a variety of other TF genes, which are differentially expressed upon MeJA exposure, and rubber biogenesis-related genes including SRPP1 and REF3. These studies suggest the possibilities that Hb_MYC2-1 and Hb_MYC2-2 regulate cell differentiation and that Hb_bHLH1 and Hb_bHLH2 promote rubber biosynthesis. We expect that our findings will help to increase natural rubber yield through genetic control in the future.

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