scholarly journals Nephrotoxic Effects of Paraoxon in Three Rat Models of Acute Intoxication

2021 ◽  
Vol 22 (24) ◽  
pp. 13625
Author(s):  
Vladislav E. Sobolev ◽  
Margarita O. Sokolova ◽  
Richard O. Jenkins ◽  
Nikolay V. Goncharov
Keyword(s):  
Specific Inhibitor ◽  
Acute Poisoning ◽  
Acute Intoxication ◽  
Ultrastructural Changes ◽  
Apical Surface ◽  
Delayed Effects ◽  
Specific Effects ◽  
Nitrophenyl Phosphate ◽  
Species Characteristics ◽  
Distal Tubules

The delayed effects of acute intoxication by organophosphates (OPs) are poorly understood, and the various experimental animal models often do not take into account species characteristics. The principal biochemical feature of rodents is the presence of carboxylesterase in blood plasma, which is a target for OPs and can greatly distort their specific effects. The present study was designed to investigate the nephrotoxic effects of paraoxon (O,O-diethyl O-(4-nitrophenyl) phosphate, POX) using three models of acute poisoning in outbred Wistar rats. In the first model (M1, POX2x group), POX was administered twice at doses 110 µg/kg and 130 µg/kg subcutaneously, with an interval of 1 h. In the second model (M2, CBPOX group), 1 h prior to POX poisoning at a dose of 130 µg/kg subcutaneously, carboxylesterase activity was pre-inhibited by administration of specific inhibitor cresylbenzodioxaphosphorin oxide (CBDP, 3.3 mg/kg intraperitoneally). In the third model (M3), POX was administered subcutaneously just once at doses of LD16 (241 µg/kg), LD50 (250 µg/kg), and LD84 (259 µg/kg). Animal observation and sampling were performed 1, 3, and 7 days after the exposure. Endogenous creatinine clearance (ECC) decreased in 24 h in the POX2x group (p = 0.011). Glucosuria was observed in rats 24 h after exposure to POX in both M1 and M2 models. After 3 days, an increase in urinary excretion of chondroitin sulfate (CS, p = 0.024) and calbindin (p = 0.006) was observed in rats of the CBPOX group. Morphometric analysis revealed a number of differences most significant for rats in the CBPOX group. Furthermore, there was an increase in the area of the renal corpuscles (p = 0.0006), an increase in the diameter of the lumen of the proximal convoluted tubules (PCT, p = 0.0006), and narrowing of the diameter of the distal tubules (p = 0.001). After 7 days, the diameter of the PCT lumen was still increased in the nephrons of the CBPOX group (p = 0.0009). In the M3 model, histopathological and ultrastructural changes in the kidneys were revealed after the exposure to POX at doses of LD50 and LD84. Over a period from 24 h to 3 days, a significant (p = 0.018) expansion of Bowman’s capsule was observed in the kidneys of rats of both the LD50 and LD84 groups. In the epithelium of the proximal tubules, stretching of the basal labyrinth, pycnotic nuclei, and desquamation of microvilli on the apical surface were revealed. In the epithelium of the distal tubules, partial swelling and destruction of mitochondria and pycnotic nuclei was observed, and nuclei were displaced towards the apical surface of cells. After 7 days of the exposure to POX, an increase in the thickness of the glomerular basement membrane (GBM) was observed in the LD50 and LD84 groups (p = 0.019 and 0.026, respectively). Moreover, signs of damage to tubular epithelial cells persisted with blockage of the tubule lumen by cellular detritus and local destruction of the surface of apical cells. Comparison of results from the three models demonstrates that the nephrotoxic effects of POX, evaluated at 1 and 3 days, appear regardless of prior inhibition of carboxylesterase activity.

Changes in H+-translocating vacuolar-type ATPase in the anterior silk gland cell of Bombyx mori during metamorphosis.

1998 ◽  
Vol 201 (4) ◽  
pp. 479-486
Author(s):  
M Azuma ◽  
Y Ohta
Keyword(s):  
Bombyx Mori ◽  
Gland Cell ◽  
Specific Inhibitor ◽  
Instar Larva ◽  
Silk Gland ◽  
Ultrastructural Changes ◽  
Immunocytochemical Staining ◽  
Apical Plasma Membrane ◽  
Apical Surface ◽  
Silkworm Larvae

A proton-translocating vacuolar-type ATPase (V-ATPase) was identified and characterized in the anterior silk gland of Bombyx mori. By incubating the intact tissue with the fluorescent dye Acridine Orange, the acidified compartment was detected at the apical pole of the epithelial cells. This was observed throughout the feeding period of the fifth-instar larva until the onset of spinning. Acidification was prevented completely and reversibly by 0.8 micromol l-1 bafilomycin A1, a specific inhibitor of V-ATPase. The presence of V-ATPase in a microsomal fraction was verified by immunoblots using an antiserum to the V-ATPase holoenzyme from Manduca sexta midgut. The antiserum localized the V-ATPase to the apical plasma membrane of the anterior silk gland cells, suggesting that the enzyme is functionally active in pumping protons out of the cell towards the glandular lumen of feeding silkworm larvae. In spinning larvae, the acidification produced by the V-ATPase appears to cease, because acidic compartments were seen rarely and only in the periphery of basal cytoplasm, and because immunocytochemical staining for the V-ATPase was greatly reduced at the apical surface. The metamorphic changes in relation to the occurrence of V-ATPase corresponded well with the ultrastructural changes in the anterior silk gland cell of Bombyx mori larvae.

Carbon monoxide: mechanism of toxic action, pathogenesis and clinical manifestations of acute intoxication

2021 ◽  
pp. 4-9
Author(s):  
A. N. Grebenyuk ◽  
V. N. Bykov
Keyword(s):  
Carbon Monoxide ◽  
Clinical Manifestations ◽  
Acute Poisoning ◽  
Toxic Action ◽  
Acute Intoxication ◽  
Emergency Situations ◽  
Common Causes ◽  
The Central Nervous System ◽  
Regulatory Effects ◽  
Mitochondrial Cytochrome Oxidase

Introduction. Carbon monoxide (CO) remains one of the most common causes of acute poisoning and death, both in everyday life and in emergency situations, especially in fires.Material and methods. The paper summarizes information about the regulatory effects, mechanisms of toxic action, pathogenesis and clinical picture of intoxication, as well as predictors of the severity of CO poisoning.Results. The main mechanism of the toxic effect of CO is due to its ability to bind to the protohemal iron of hemoglobin (Hb) to form carboxyhemoglobin (HbCO). The toxicity of CO may also be enhanced by impaired functions of the myoglobin of the myocardium and skeletal muscles, mitochondrial cytochrome oxidase, and iron-containing enzymes of the antioxidant system. The leading link in the pathogenesis of acute CO intoxication is a violation of the oxygen transport function of hemoglobin and the associated development of hemic and tissue hypoxia. CO-induced cell and tissue damage due to the induction of mitochondrial dysfunction, oxidative stress, free radical hyperproduction, lipid peroxidation, inflammation, and apoptosis also play a role in the pathogenesis of intoxication.Conclusion. The mechanism of toxic action of CO, associated primarily with the formation of carboxyhemoglobin and the development of hypoxia, determines the clinical manifestations of acute intoxication, which depend on the concentration of CO and the duration of exposure, but are almost always associated with the central nervous system and cardiovascular system.

Mechanism of acidification along cortical distal tubule of the rat

1994 ◽  
Vol 266 (2) ◽  
pp. F218-F226 ◽  
Author(s):  
R. Fernandez ◽  
M. J. Lopes ◽  
R. F. de Lira ◽  
W. F. Dantas ◽  
E. J. Cragoe Junior ◽  
...  
Keyword(s):  
Channel Blocker ◽  
Exchange Resin ◽  
Rat Kidney ◽  
Specific Inhibitor ◽  
Distal Tubule ◽  
Ringer Solution ◽  
Na Channel ◽  
Bafilomycin A1 ◽  
Bicarbonate Reabsorption ◽  
Distal Tubules

The cellular mechanism of luminal acidification (bicarbonate reabsorption) was studied in cortical distal tubules of rat kidney. The stopped-flow microperfusion technique was applied to early distal (ED) and late distal (LD) segments, perfused with bicarbonate Ringer solution to which specific inhibitors were added, to measure bicarbonate reabsorption [HCO3 flux (JHCO3)]. pH and transepithelial potential difference (Vt) were recorded by double-barreled H+ exchange resin/reference (1 M KCl) electrodes. Amiloride increased stationary pH and reduced Vt in both early and late segments. Hexamethylene-amiloride (HMA), a specific Na(+)-H+ exchange blocker, reduced JHCO3 in both segments (ED by 43.6 and LD by 40.3%) without affecting Vt. Benzamil, an Na(+)-channel blocker, reduced Vt by 75.9 in ED and 74.9% in LD but had no significant effect on acidification in both segments. The specific inhibitor of H(+)-ATPase, bafilomycin A1, inhibited LD JHCO3 at a concentration of 2 x 10(-7) M by 49%, but ED was inhibited by 24% only at 2 x 10(-6) M. Sch-28080, an inhibitor of gastric H(+)-K(+)-ATPase, reduced JHCO3 by 35% in LD of K(+)-depleted rats but not in control rats and had no effect on ED. These data indicate that, in ED, bicarbonate reabsorption is mediated mostly by Na(+)-H+ exchange. In LD, there is evidence for contribution of Na(+)-H+ exchange, vacuolar H(+)-ATPase, and H(+)-K(+)-ATPase (in K(+)-depleted rats) to bicarbonate reabsorption.

scholarly journals Multiple non-specific effects of sphingosine on adenylate cyclase and cyclic AMP accumulation in S49 lymphoma cells preclude its use as a specific inhibitor of protein kinase C

1990 ◽  
Vol 268 (2) ◽  
pp. 507-511 ◽  
Author(s):  
J A Johnson ◽  
R B Clark
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Mammalian Cells ◽  
Specific Inhibitor ◽  
Lymphoma Cells ◽  
Specific Effects ◽  
Kinase C ◽  
Cyclic Amp Accumulation

Recent studies with phorbol esters have suggested that protein kinase C (PKC) may play a role in the regulation of adenylate cyclase in mammalian cells. Since D-sphingosine has been reported to specifically inhibit PKC in many cell types, we evaluated its effects on stimulation of cyclic AMP accumulation by adrenaline in S49 lymphoma cells. We found sphingosine to have multiple non-specific effects which could not be explained by an inhibition of PKC. These effects included: (i) inhibition by sphingosine (50 microM) of adrenaline-stimulated cyclic AMP accumulation and sphingosine permeation of the cells which rendered them leaky to ATP; (iii) sphingosine (20 microMs) augmentation of adrenaline-stimulated cyclic AMP accumulation; (iii) inhibition by sphingosine of adrenaline-stimulated adenylate cyclase in isolated membranes by up to 95%; and (iv) sphingosine (20 microM) inhibition of cellular mechanisms for the elimination of cyclic AMP. These results demonstrate the importance of evaluating the non-specific effects of sphingosine before concluding that its actions are the consequences of a specific inhibition of PKC.

Ultrastructural changes in posterior midgut cells associated with blood feeding in adult female Rhodnius prolixus Stal (Hemiptera: Reduviidae)

1983 ◽  
Vol 61 (11) ◽  
pp. 2574-2586 ◽  
Author(s):  
P. F. Billingsley ◽  
A. E. R. Downe
Keyword(s):  
Endoplasmic Reticulum ◽  
Rough Endoplasmic Reticulum ◽  
Blood Meal ◽  
Apical Cell ◽  
Blood Feeding ◽  
Rhodnius Prolixus ◽  
Ultrastructural Changes ◽  
Dense Matrix ◽  
Apical Surface ◽  
Posterior Midgut

Modifications of posterior midgut cells of Rhodnius prolixus following a meal of rabbit blood are described. Prominent stacks and whorls of rough endoplasmic reticulum become redistributed following a blood meal but later reform during the postfeeding period. Lysosomes undergo internal structural changes and apparent fluctuations in their number per cell as a result of blood meal ingestion. Before blood feeding, the apical surface of the midgut cells show a typical arrangement of a plasma membrane covered on the lumenal surface by a glycocalyx. After a blood meal, a more complex organisation appears, consisting of two plasma membranes separated by an electron-dense matrix. The lumenal apical membrane proliferates during the digestion period to form loosely organised extracellular membrane layers which may function as a peritrophic membrane. Changes in the rough endoplasmic reticulum and lysosomes and modifications to the apical cell surface appear to coincide with previously described proteinase activity cycles in the posterior midgut of R. prolixus. The implications of these results are discussed and are compared with similar ultrastructural events from haematophagous Diptera.

PKC induces internalization and retention of the EAAC1 glutamate transporter in recycling endosomes of MDCK cells

2009 ◽  
Vol 297 (4) ◽  
pp. C835-C844 ◽  
Author(s):  
Valeria Padovano ◽  
Silvia Massari ◽  
Silvia Mazzucchelli ◽  
Grazia Pietrini
Keyword(s):  
Excitatory Amino Acid ◽  
Mdck Cells ◽  
Glutamate Transporter ◽  
Specific Inhibitor ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Metabolic Labeling ◽  
Apical Surface ◽  
Recycling Endosomes ◽  
Intracellular Compartments

Here we show that stimulation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) treatment induces a time-dependent decrease in glutamate transport activity due to relocalization of the excitatory amino acid carrier 1 (EAAC1) glutamate transporter from the apical surface of polarized epithelial Madin-Darby canine kidney (MDCK) cells to intracellular compartments. The PKC-induced internalization of EAAC1 is negatively regulated by the calcineurin inhibitor cyclosporine A and by the expression of a dominant-negative mutant of the endocytic protein dynamin 1, a well-known target of the phosphatase activity of calcineurin. Using 32P-metabolic labeling experiments, we found unchanged levels of phosphorylated EAAC1, indicating that EAAC1 relocalization does not depend on PKC and calcineurin modification of the transporter, while we found that a target of these modifications was the serine778 residue of dynamin, a calcineurin substrate that in its dephosphorylated form activates the endocytic functions of dynamin. These data suggest that PMA stimulates endogenous dynamin and that this activation is required to mediate internalization of EAAC1 in MDCK cells. By immunofluorescence experiments with endosomal markers we demonstrated that internalized EAAC1 accumulates in endosomes also containing the basolateral betaine-GABA transporter BGT1 and activated PKCα. The sustained activation of PKC was required to maintain the transporters in the endosomal compartment, while a posttreatment with a PKC-specific inhibitor induced the recycling of the transporters to their appropriate surfaces. Taken together, our data indicate that PKC activity regulates EAAC1 surface density in MDCK cells by inducing its internalization and retention in PKCα-labeled recycling endosomes common to apical and basolateral proteins.

Ultrastructural Changes in the Air—Blood Barrier of Rats in Acute Intoxication with Furoplast Pyrolysis Products

2020 ◽  
Vol 169 (2) ◽  
pp. 270-275
Author(s):  
P. G. Tolkach ◽  
V. A. Basharin ◽  
S. V. Chepur ◽  
A. N. Gorshkov ◽  
D. T. Sizova
Keyword(s):  
Acute Intoxication ◽  
Ultrastructural Changes ◽  
Pyrolysis Products

scholarly journals P0120FEATURES OF ULTRASTRUCTURAL CHANGES IN KIDNEY TISSUE IN THE PATIENTS WHO HAVE PASSED AWAY AS A RESULT OF SEPSIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Mehman Agayev ◽  
Shalala Ismayilova ◽  
Arzu Ibishova
Keyword(s):  
Renal Failure ◽  
Structural Changes ◽  
Early Stage ◽  
Kidney Tissue ◽  
Basal Layer ◽  
Basal Membrane ◽  
Renal Tissue ◽  
Ultrastructural Changes ◽  
Severe Renal Failure ◽  
Distal Tubules

Abstract Background and Aims It is believed that septicemia and septicopyemia can lead to functional failure of many organs, including the kidneys. In this regard, it is important to study the morphological features of ultrastructural changes in kidney tissue. Method Structural changes in renal tissue of 30 patients who died as a result of sepsis were investigated by electron-microscopy. The burial was carried out at an early stage (1-6 hours after death). The sections obtained for ultrasonic examination were examined on “James 100 S ” electron microscope after contrasting with uranyl acetate and lead citrate solution. Results An ultrastructural study of the cells of the cortical and medial layers of the kidneys revealed that there are changes in extracellular contacts and cell fragmentation as a result of lysis of the cytoplasmic membrane of cells. The integrity of the basal membrane of epithelial cells of the proximal and distal tubules are preserved. However, the basal layer did not have a homogeneous structure, intersected and transparent in certain areas. Numerous vacuoles, lipid supplements and fragments of lysed intracellular proteins in the cytoplasm have been identified in the cytoplasm of cells. Most of the nucleus was in the collapse phase. The lumen of tubules is narrow and most of the microvilli of the brush border are destructed. It was revealed that in sepsis renal failure and severe destructive changes and the formation of necrosis sites in the structural elements of the nephron as a result of bacterial toxins were mainly observed in areas where bacteria were localized. Conclusion Abnormalities of podocytes, of endothelial cells, disruption of the basal membrane layers as a result of abnormal damage of organelles especially mitochondria, changes of proximal and distal tubules may be caused by severe renal failure due to sepsis.

scholarly journals The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Yuzuru Ninoyu ◽  
Hirofumi Sakaguchi ◽  
Chen Lin ◽  
Toshiaki Suzuki ◽  
Shigeru Hirano ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Noise Exposure ◽  
Spiral Ganglion ◽  
Cell Junctions ◽  
Ultrastructural Changes ◽  
Apical Surface ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells ◽  
Junctional Complexes

AbstractDia1, which belongs to the diaphanous-related formin family, influences a variety of cellular processes through straight actin elongation activity. Recently, novel DIA1 mutants such as p.R1213X (p.R1204X) and p.A265S, have been reported to cause an autosomal dominant sensorineural hearing loss (DFNA1). Additionally, active DIA1 mutants induce progressive hearing loss in a gain-of-function manner. However, the subcellular localization and pathological function of DIA1(R1213X/R1204X) remains unknown. In the present study, we demonstrated the localization of endogenous Dia1 and the constitutively active DIA1 mutant in the cochlea, using transgenic mice expressing FLAG-tagged DIA1(R1204X) (DIA1-TG). Endogenous Dia1 and the DIA1 mutant were regionally expressed at the organ of Corti and the spiral ganglion from early life; alongside cochlear maturation, they became localized at the apical junctional complexes (AJCs) between hair cells (HCs) and supporting cells (SCs). To investigate HC vulnerability in the DIA1-TG mice, we exposed 4-week-old mice to moderate noise, which induced temporary threshold shifts with cochlear synaptopathy and ultrastructural changes in stereocilia 4 weeks post noise exposure. Furthermore, we established a knock-in (KI) mouse line expressing AcGFP-tagged DIA1(R1213X) (DIA1-KI) and confirmed mutant localization at AJCs and the tips of stereocilia in HCs. In MDCKAcGFP-DIA1(R1213X) cells with stable expression of AcGFP-DIA1(R1213X), AcGFP-DIA1(R1213X) revealed marked localization at microvilli on the apical surface of cells and decreased localization at cell-cell junctions. The DIA1-TG mice demonstrated hazy and ruffled circumferential actin belts at AJCs and abnormal stereocilia accompanied with HC loss at 5 months of age. In conclusion, Dia1 plays a pivotal role in the development and maintenance of AJCs and stereocilia, ensuring cochlear and HC integrity. Subclinical/latent vulnerability of HCs may be the cause of progressive hearing loss in DFNA1 patients, thus suggesting new therapeutic targets for preventing HC degeneration and progressive hearing loss associated with DFNA1.

scholarly journals Ochratoxin a and Citrinin Induced Nephrosis in Beagle Dogs III. Terminal Renal Ultrastructural Alterations

1977 ◽  
Vol 14 (4) ◽  
pp. 392-406 ◽  
Author(s):  
D. N. Kitchen ◽  
W. W. Carlton ◽  
E. J. Hinsman
Keyword(s):  
Epithelial Cells ◽  
Ochratoxin A ◽  
Ultrastructural Changes ◽  
Similar Distribution ◽  
Beagle Dogs ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Distal Tubules ◽  
Renal Tubular ◽  
Myelin Figure

The extent and type of renal ultrastructural changes in Beagle dogs varied with the administration of ochratoxin A and citrinin alone and in the two dosage combinations. The three predominant changes were cytoplasmic vacuolation, myelin figure formation and lesions designated as cytoplasmic disarray. These changes were mainly of the endomembrane system of the tubular epithelial cells. Cytoplasmic vacuoles were within proximal and distal tubules and collecting ducts and were most numerous in dogs given 10 mg/kg citrinin. Vacuolation of similar distribution, but less severe, was seen in renal tubular cells of dogs given the higher dose of the combined mycotoxins (0.2 mg/kg ochratoxin A + 10 mg/kg citrinin). This damage was limited to the proximal tubular cells in dogs given only ochratoxin A (0.1 or 0.2 mg/kg). Myelin figures were in proximal epithelial cells of dogs given ochratoxin A alone or combined with citrinin. There was cytoplasmic disarray in dogs of all groups except for dogs given 5 mg/kg citrinin. This lesion was usually limited to the proximal tubules. The lesion, however, was found in cells of the distal tubules of dogs given 10 mg/kg citrinin alone.

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