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PubMed1976

Oxidative side reactions during dansylation of SH-compounds.

Dansyl chloride can act as an oxidizing agent on compounds which are easily oxidized. During the reaction of mercaptanes, e.g. cysteine, homocysteine, cysteamine, with dansyl chloride, the corresponding disulfides are formed and dansyl chloride is reduced to 5-dimethylaminonaphthalene 1-sulfinic acid. This reaction is so rapid that the normal dansylation can take place only after complete oxidation of all SH-compounds. Therefore only the dansyl derivatives of the corresponding disulfides are formed during normal dansylation of SH-compounds. If different SH-compounds are present in the reaction mixture mixed disulfides are formed as well. These can be separated by microchromatography on 3 X 3 cm micropolyamide sheets. Dependent on the concentration of dansyl chloride, 6 or even 15 different dansylated disulfides are formed from three different SH-compounds so that interpretation of these chromatograms is difficult. The actual dansylmercaptanes (e.g., dansylcysteine, dansylhomocysteine, dansylcysteamine) can be prepared by reduction of the dansylated disulfides with suitable reducing agents.

Amino Acids↗
PubMed1992

[Role of sulfhydryl compounds in the oxygen radical induced injury of isolated gastric mucosal cells].

Gastric mucosal cells were separated by pronase-EDTA method and cultured. The cellular injury was produced by oxygen radicals provided by xanthine oxidase(XO)-xanthine(X) system. When the cells were subjected to the action of XO-X system, the cellular viability was decreased and leakage of lactate dehydrogenase (LDH) from the cells was significantly increased. In addition, the cellular contents of nonprotein sulfhydryls (NPSH) and protein sulfhydryls (PSH) were decreased. When the intracellular sulfhydryl content was decreased by N-ethylmaleimide (NEM, a depletor of endogenous sulfhydryls), the cell mortality and LDH leakage were increased in a time-dependent and dose-dependent manner. If glutathione or cysteamine (compounds containing-SH) was administered into the media, the cellular injury induced by XO-X system was notably inhibited, also in a dose-dependent manner. The above results suggest that sulfhydryls may play an important role in the cell defending mechanism against injury of gastric mucosal cells by oxygen radicals.

Animals↗
PubMed1992

Effects of AET and MEA on the lysosomal hydrolase activities in the mouse organs.

The adult male Swiss mice were injected intraperitoneally with AET (2-aminoethylisothiouronium Br.HBr) or MEA (cysteamine HCl), in a toxic dose of 400 mg/kg body weight. The acid phosphatase (E.C. 3.1.3.2) and arylsulphatase (E. C. 3.1.6.1) activities in crude homogenates of liver and kidneys were assessed every fourth hour throughout a 24-h period. Different patterns of temporal changes in the acid phosphatase and arylsulphatase activities in liver and kidneys expressed in nkat per 1 mg of protein, 1 g of fresh tissue and per the whole organ weight, were found. The extent and timing of the alterations in the activity of each of the lysosomal hydrolases were dependent on the particular organ chosen and aminothiol compound given.

Acid Phosphatase↗
PubMedDate not supplied

[An experimental approach to determining the protective properties of drugs against ionizing radiation in low and sublethal doses].

In experiments with mice, the efficiency of radioprotective agents against acute gamma-irradiation with nonlethal and low doses (0.5-4 Gy) was estimated by nine parameters. The treatment with cystamine, cysteamine and riboxine prior to irradiation (< 2 Gy) did not influence the postirradiation values of the parameters under study. With a dose of up to 4 Gy, the effect of riboxine was noted. The determinations of the number of aberrant mitoses, cellularity and mitotic activity of the bone marrow have proved to be most informative. The data obtained are discussed with due regard for the specific effect of low-level radiation and mechanisms of the protective action of the agents under study.

Animals↗
PubMed1976

[The correlations between aging and drug effects (author's transl)].

Four examples (Methamphetamine, Testosterone, Caffeine, Cysteamine) have demonstrated that the response of the organism to a drug is primarily dependent upon the functional status of the organ concerned. If this functional status changes with age, then accordingly the reaction to the drug also changes. If, however, one alters the functional status of an organ in the elderly organism, e.g. inducing increased production of DNA in the liver by partial hepatectomy, the reaction of the organ now follows a pattern comparable to the juvenile organism, rather than being dependent on chronological age.

Age Factors↗
PubMed1992

[Infantile cystinosis. A new Tunisian case].

A case of cystinosis in a three and a half-year-old is reported. Suggestive manifestations included severe rickets, small stature, and complex renal tubule dysfunction meeting the criteria for secondary Fanconi syndrome. Diagnosis was established by the discovery of retinal lesions upon ophtalmologic evaluation and, above all, by the finding that intracellular leukocyte cystine levels were increased to 16 mumol of 1/2 cystine per gram protein. Cystinosis is severe because it inevitably leads to renal failure. Much hope is currently placed in the use of cysteamine to delay this and other complications. At present, early antenatal diagnosis during the first ten weeks of pregnancy is needed in high-risk families to allow elective termination of pregnancy within the legal time limit.

Child, Preschool↗
PubMed2004

Intermittent hypoxia causes a suppressed pituitary growth hormone through somatostatin.

OBJECTIVES: The aim of this study was to investigate the response of the growth hormone (GH) in rat anterior pituitary to intermittent hypoxia (IH) and its modulation by hypothalamic somatostatin (SS). SETTING AND DESIGN: To observe the hypoxic response, rats were exposed to simulated altitude hypoxia (2 km or 5 km) in a hypobaric chamber for various days (4 h/d); to clarify SS-involvement, rats were pretreated with SS antagonist (cysteamine, CSH, 200 mg/kg/d, s.c.) then exposed to IH (5 km) for 2d. The GH mRNA and immunostaining GH in pituitary as well as immunostaining SS in median eminence (ME) of hypothalamus were assayed by RT-PCR and immuno-histochemistry, respectively. RESULTS: IH of 5 km altitude (IH5) markedly suppressed the body weight gain (BWG) of rats from 1d to 10d, and it was returned to control level henceforth, while no significant influence was showed in the group of IH of 2 km altitude (IH2). IH5 for 2 and 5d significantly decreased GH mRNA expression in the pituitary. The pituitary immunostaining GH was remarkably increased in groups of IH2 for 5, 10, and 15 d, and in groups of IH5 for 2, 5, and 10d. Immunostaining SS in ME was significantly reduced in group of IH2 for 5d, and in groups of IH5 for 2d and 5d. Pretreatments (s.c.) with SS antagonist (CSH) significantly reversed IH5-caused increase of immunostaining GH and reduction of mRNA levels in pituitary. CONCLUSIONS: IH may cause a short-term and recoverable suppression of GH release, and reduce GH mRNA expression in anterior pituitary, which may depend on the intensity and duration of the hypoxia. This suppression may be due to a modulation of hypoxia-activated SS.

Altitude↗
PubMedDate not supplied

[Cystinosis: an infrequent cause of distal myopathy].

INTRODUCTION: Cystinosis is a hereditary disease with clinical symptoms that are caused by the accumulation of cystine crystals in different tissues. Distal vacuolar myopathy has been reported as one of its later complications. CASE REPORT: Here, we present the case of a 20-year-old male diagnosed with cystinosis at the age of 2 years, with severe renal involvement that required a transplant. The patient gradually developed weakness and atrophy of the muscles in his hands. Neurophysiological and histological studies enabled a diagnosis of distal vacuolar myopathy to be established, and electron microscopy revealed deposits of cystine crystals. CONCLUSIONS: Cystinosis must be included within the differential diagnosis of distal myopathies. Timely treatment with cysteamine could prevent the development of this complication.

Adult↗
PubMed2006

The presentation and organization of adaptive cytoprotection in the rat stomach, duodenum, and colon. Dedicated to André Robert the founder of the concept of cytoprotection and adaptive cytoprotection.

BACKGROUND: Adaptive cytoprotection could be demonstrated in lesion attenuation within the whole gastrointestinal tract, in particular sequences, with onset and duration longer than the initial short-lasting period (i.e. one hour) defined by Robert in the stomach only. MATERIAL/METHODS: Adaptive cytoprotection possibly appeared and lesions were attenuated when the stomach, duodenum or colon, in various combinations and sequences, were challenged with initial (mild) and/or final (strong) irritants over a two-week period. Rats were challenged with the mild or strong irritants 25% or 96% ethanol intragastrically 1 ml/rat (stomach) and cysteamine 40 mg or 400 mg/kg subcutaneously (duodenum), or intrarectally (colon). To postulate the prostaglandin relationship known in Robert's cytoprotection and adaptive cytoprotection, indomethacin (1 mg/kg subcutaneously) was given simultaneously with the second challenge. RESULTS: Administering the mild and strong irritant protocols within the same part of the gastrointestinal tract, adaptive cytoprotection presents in the stomach (1 h to 14 days), duodenum (2 h to 14 days), but not in the colon. With these protocols applied to different parts of the gastrointestinal tract, adaptive cytoprotection cross-reaction was evident in the stomach-duodenum, duodenum-stomach (1 h-14 days and 2 h-14 days), stomach-colon, and duodenum-colon (both 2-24 hours), but not in the colon-stomach or colon-duodenum. This protection was fully antagonized with indomethacin. CONCLUSIONS: As observed for a day and even weeks, stomach-duodenum-colon adaptive cytoprotection is an important new defensive phenomenon.

Adaptation, Physiological↗
PubMed1991

Acid phosphatase and arylsulphatase activities in testes after AET or MEA treatment of adult mice.

Temporal changes of acid phosphatase (E.C. 3.1.3.2) and arylsulphatase (E.C. 3.1.6.1) activities in testes of adult Swiss mice after AET (2-amino-ethylisothiouronium Br. HBr) or MEA (cysteamine HCl) treatment, were studied. The animals were injected intraperitoneally with the S-containing substances in a single dose of 400 mg/kg body weight. The enzyme activities in crude organ homogenates were assessed every four hours during a 24-hour period. Administration of the aminothiol agents to mouse organism caused greater changes in the acid phosphatase activity than in the arylsulphatase activity, and the two chemical compounds AET and MEA given, influenced the enzyme activities in testes in a different way. Treatment of mice with AET resulted in a decrease of the acid phosphatase activity related to 1 g of fresh tissue at 16.00 and the whole organ weight at 24.00 and 16.00 as well as in a decrease of the arylsulphatase activity expressed per the whole weight of testes at 08.00. After MEA injection, the acid phosphatase activity related to 1 mg of protein, 1 g of fresh tissue and the whole organ weight was decreased at 20.00(1), and the enzyme activity expresse per 1 mg of protein and 1 g of fresh tissue was increased at 24.00, but the arylsulphatase activity related to both 1 mg of protein at 08.00, 12.00 and to the whole weight of testes at 08.00, was reduced.

Acid Phosphatase↗
PubMed1991

Mediated calcium transport by isolated human fibroblast lysosomes.

Lysosomes purified by Percoll gradient from normal human fibroblasts (GM0010A) show uptake of Ca2+ in a mediated manner. The uptake is linear over the first 1.5 min and approaches a steady state by 10 min. Uptake is saturable, displaying a Vmax of about 10 pmol/min/unit hexosaminidase at 20 mM Ca2+ (7 nmol/min/mg protein), and a Km of 5.7 mM. Ca2+ uptake increases with increasing extralysosomal pH from 5.0 to 8.5. The Q10 is 1.6, and Ea 8.7 kcal/mol. Uptake of 0.1 mM Ca2+ was inhibited to the extent indicated by 1.0 mM of the following: Cd2+, 100%; Hg2+, 100%; Zn2+, 89%; Mg2+, 77%; Ba2+, 60%; Sr2+, 37%; Fe2+, 20%; Cu2+, 0%. Mono- and trivalent cations had no effect. ATP (1.0 mM) inhibited uptake by 80%, and chloroquine (0.1 mM) inhibited by 60%, as did 1.0 mM L-cystine. Cysteamine, N-ethylmaleimide, and the anions Cl-, SO(2-)4, and acetate had no effect. The calcium ionophore A23187 augmented uptake by 10-fold at 10 microM. Surprisingly, Pb2+ greatly augmented lysosomal Ca2+ uptake in a concentration-dependent manner. Pb2+, however, adversely affected lysosomal latency. Lysosomal calcium uptake was not affected by inositol 1,4,5-triphosphate, and calcium-induced calcium release from lysosomes was not observed. A role for lysosomes in cellular calcium homeostasis has not been previously suggested. This work shows that Ca2+ can be transported into and out of lysosomes and could assist in lysosomal proteolysis. The extent of further lysosomal participation in cellular calcium regulation is unclear.

Adenosine Triphosphate↗
PubMed1991

[Protective effects of SH-compounds on ischemia reperfusion induced arrhythmias in the isolated rat heart].

Protective effects of cysteine (Cys), N-acetylcysteine (NAC), cysteamine (MEA), cystamine (CSSC) and aminopropylmethylisothiourea (APMT) on ischemia/reperfusion induced arrhythmias were studied in isolated Langendorff perfused rat hearts. The arrhythmias were caused by ligation of the anterior descending branch of the left coronary artery for 10 min and reperfused for 5 min. The drugs were dissolved in saline (NS) and perfused through a peristaltic pump system at 0.1, 0.6 or 3.6 mumol/min (n = 10), starting from 10 min before ligation up to 5 min after reperfusion. The control hearts were perfused with NS. The results showed that Cys, NAC and MEA pursued at 0.6-3.6 mumol/min significantly reduced the incidence of ventricular fibrillation (VF), which were 80-90% in control and 0-20% in 3 treated groups, with P less than 0.01-0.001. The duration of ventricular tachycardia (VT) + VF was 3.0 +/- 1.6 min in control and were 0.2 +/- 0.2, 0.2 +/- 0.1 and 1.2 +/- 2.1 min in Cys, NAC and MEA groups, respectively (with P less than 0.01-0.001). Coronary flow (CF) were remarkably reduced to about 50% during ligation in NS, but remained at normal levels in three treated groups. There were no significant protective effects on arrhythmias in CSSC and APMT perfused hearts. CF of CSSC and APMT groups were even less than those of control. The structure-activity analysis suggested that the SH group may play a crucial role in the protective effect of SH compounds on ischemia/reperfusion induced arrhythmias. The mechanism of protection was briefly discussed in this paper.

Acetylcysteine↗
PubMed1991

Temporary changes of protein level in liver after AET or MEA treatment prior to 60Co gamma-irradiation of male mice.

The adult male Swiss mice were either whole-body gamma-irradiated with a single dose of 10 Gy from 60Co source, always at 19.00 or, 15 minutes before irradiation injected intraperitoneally with AET (2-aminoethylisothiouronium Br. HBr), or MEA (cysteamine HCl), in a dose of 400 mg/kg body weight. The measurements of the protein level in crude homogenates of liver were done in four-hour internals during a 24-hour period, starting at 20.00. The protein concentration in liver was calculated per 1 g of fresh tissue and the whole organ weight. The body and liver weight was also studied. There were no fluctuations in the liver weight and concentration of protein in the control and irradiated only mice. Temporary changes in the liver weight and level of protein expressed in mg per 1 g of fresh tissue and the whole organ weight could be found in the group of males treated with AET, and daily changes in the liver weight and concentration of protein related to mg per 1 g of fresh tissue, in the group of male mice injected with MEA prior to irradiation, could be recorded. Differences in the liver weight at 20.00, 24.00 and 04.00, as well as in the protein level expressed in mg per 1 g fresh tissue at 04.00, 12.00, 16.00, and the whole liver weight at 24.00, 04.00, and 16.00, of between the particular groups of mice, were observed. There were no temporary changes in the body weight in any of the groups and there were no differences in this value between the groups of mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1990

The physiology of somatostatin in the rabbit retina.

The neuropeptide somatostatin (SS) has been localized to neurons of the rabbit retina by immunochemical and biochemical methods (Sagar et al., 1982, 1986; Marshak and Yamada 1984). We examined the effects of bath-applied SS on neurons of the rabbit retina, using intra- and extracellular electrophysiological techniques in an in vitro retina eyecup preparation. All commonly encountered ganglion cell receptive field types were affected by SS, and the effects were of 3 kinds: The first was a general excitation, occurring with a threshold concentration of about 100 nM; the onset of the excitation was too slow (seconds) for SS to participate in any rapid light-evoked responses. The second SS effect was an increase in the "signal-to-noise ratio," defined here as the ratio of light-evoked to spontaneous spiking, which resulted from a decrease in spontaneous activity and, usually, a concomitant increase in light-evoked spiking. The third effect was a shift in center-surround balance towards a more dominant center. The signal-to-noise and center-surround effects were evident at concentrations as low as 0.5 nM; both were slow onset (tens of seconds) and long lasting (tens of minutes). SS acted at multiple levels within the retinal circuitry to produce the observed changes in ganglion cell output. These effects included direct actions on ganglion and amacrine cells, and a decrease in the efficiency with which horizontal cells could drive the retinal network. At least part of these SS actions on third-order neurons resulted from a decrease in conductance to ions with an equilibrium potential more positive than dark membrane potential. The degradation-resistant SS agonist SMS201-995 had effects qualitatively and quantitatively similar to those of SS, suggesting that SS may be degraded slowly enough to act at a distance from its sites of release. While no adequate SS antagonist is available, the greater sensitivity to exogenous SS, in retinas depleted of their SS content (with cysteamine), suggests a role for endogenous SS. The potency of SS also reinforces this view. The results of this study suggest that SS may be a neuromodulator in the rabbit retina, producing long-lasting changes in the "signal-to-noise" discharge pattern and center-surround balance of ganglion cells.

Action Potentials↗
PubMedDate not supplied

Pharmacokinetics and disposition of WR-1065 in the rhesus monkey.

The pharmacokinetics of WR-1065 [S-2-(3-aminopropylamino)ethanethiol] were investigated following iv, intraduodenal, and intraportal administrations in the rhesus monkey. Pharmacokinetic parameters were estimated by compartmental modeling of plasma concentration data from 10-min and 120-min iv infusions. Higher apparent volumes of distribution (Vc and Vss) and higher mean residence time (MRT) were observed at the slower infusion rate but a constant total dose. The values reflect a change in the distribution of WR-1065, possibly due to to saturation of binding in plasma and tissue. However, clearance remained unchanged. For a monkey administered approximately twice the 60 mg/kg dose infused over 120 min, data analysis indicates a disproportional increase in AUC and a substantial decrease in clearance. Low and erratic plasma concentrations of free drug (analytically determined without reductive cleavage) were observed following intraduodenal administration of WR-1065, demonstrating the drug's poor oral bioavailability. Results of intraduodenal administrations of radiolabeled drug indicated than an appreciable amount of the radiolabel in the dose reached the systemic circulation. However, after either intraduodenal or iv administration, only 31% of the AUC (radiolabel) could be accounted for as total (free and disulfide-bound) WR-1065 by specific analysis in separate experiments. Low levels of total cysteamine strongly suggest it to be a minor contributor to the disposition of the drug. Free WR-1065 AUC values following intraportal administration were similar to values obtained after iv administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Induction of sperm head abnormalities by incorporated radionuclides: dependence on subcellular distribution, type of radiation, dose rate, and presence of radioprotectors.

In contrast to the biological effects caused by exposure to external beams of radiation, the effects of tissue-incorporated radionuclides are highly dependent on the type of radiation emitted and on their distribution at the macroscopic, microscopic, and subcellular levels, which are in turn determined by the chemical nature of the radionuclides administered. Induction of abnormalities of sperm heads in mice is investigated in this work after the injection of a variety of radiochemicals including alpha emitters. When the initial slopes of the dose-response curves are used to compare the relative biological effectiveness (RBE) of different radiocompounds, the alpha particles emitted in the decay of 210Po are more effective than Auger electrons emitted by 125I incorporated in the DNA of the spermatogonial cells, and both emissions are more effective than X rays. It is also shown that the Auger emitters (125I, 111In) distributed in the cell nucleus are more efficient in producing abnormalities than the same radionuclides localized in the cytoplasm. These findings are consistent with our earlier observations, where spermatogonial cell survival is assayed as a function of the testicular absorbed dose. Further, chronic irradiation of testis with gamma rays from intratesticularly administered 7Be is about three times more effective in causing abnormalities than a single acute exposure to 120-kVp X rays. The resulting RBE values correlate well with our data on sperm head survival with the same radiocompounds. Finally, the radioprotector cysteamine, when administered in small, nontoxic amounts, significantly reduces the incidence of sperm abnormalities from alpha-particle radiation as well as emissions from 125I incorporated into DNA, the dose reduction factors being 10 and 14, respectively.

Alpha Particles↗
PubMed1990

Effects of radical scavengers on the development of experimental diabetes.

The possible value of radical scavengers in the prevention of beta cell destruction was studied in two animal models of type I diabetes. Eight compounds were tested alone or in combinations. In the low-dose streptozotocin model treatment started 24 hr after the last injection of the beta cell toxin, in the BB rat daily administration was started at 50 days of age (i.e., 20-70 days before diabetes onset). No effect was seen in the low-dose streptozotocin model for 3-aminobenzamide, N-acetyl-DL-homocysteine thiolactone, ebselen, and butylated hydroxyanisole whereas partial suppression of hyperglycaemia was seen in mice receiving cysteamine. In BB rats diabetes development was delayed and partially suppressed by administration of ebselen plus vitamin E plus MaxEPA (fish lipid concentrate), but not when ebselen was replaced by nicotinamide. We conclude that the disease process is not readily modifiable by treatment with exogenous radical scavengers.

Aging↗
PubMed1990

Temporary changes of arylsulphatase activity in liver after exposure of AET or MEA pre-treated mice to 60Co gamma-irradiation.

The adult male Swiss mice were either whole-body 60Co gamma-irradiated with a single dose of 10 Gy at 1900, or treated intraperitoneally with AET (2-aminoethylisothiouronium bromide hydrobromide) or MEA (cysteamine hydrochloride), in a dose of 400 mg/kg body weight, 15 minutes before irradiation. The measurements of the arylsulphatase (E.C. 3.1.6.1) activity in crude homogenate of liver were done every four hours during 24-hour period, starting at 2000. The enzyme activity towards the artificial substrate p-nitrocatechol sulphate was related to 1 mg of protein, 1 g of fresh tissue and to the whole organ weight. No fluctuations in the activity of arylsulphatase in the control mice were found. There were temporary changes in the enzyme activity expressed in nkat per 1 mg of protein and 1 g of fresh tissue in the irradiated only males, in that related to 1 g of fresh tissue and the whole organ weight in mice injected with AET before irradiation, as well as that calculated in nkat per 1 mg of protein in animals pre-treated with MEA to exposure of gamma rays. Between the particular groups of males, differences in the arylsulphatase activity related to 1 g of fresh tissue and the whole liver weight at 0400 were only observed. 60Co gamma-irradiation influenced the activity of arylsulphatase in liver. AET and MEA modified the effect of exposure of mice to gamma rays on the enzyme activity in a different way.

Animals↗