Accelerated wound healing by S-methylmethionine sulfonium: evidence of dermal fibroblast activation via the ERK1/2 pathway.

S-Methylmethionine sulfonium (SMMS) is a derivative of the amino acid methionine, and is synthesized in a variety of plants. SMMS is widely referred to as vitamin U because of its potent therapeutic effect on gastrointestinal ulceration. Skin wounds are accompanied by mucosal erosion and share similar histopathological aspects with gastric ulcers, so it is plausible that SMMS may promote skin wound healing. In animal models, topical administration of SMMS for a given period of time, to both physical and chemical wounds, facilitated wound closure and promoted re-epithelialization compared with a control. In addition, single SMMS treatment was sufficient to promote the growth of human dermal fibroblasts (hDFs) as well as the migration of hDFs, which are indispensable steps for skin wound healing. The promotion of hDF proliferation and migration resulted from considerable activation of ERK1/2 by SMMS, and inhibition of ERK activity by a chemical inhibitor significantly abrogated both the promoted proliferation and migration of hDFs. Therefore, we concluded that SMMS facilitated the repair process of skin damage by activation of dermal fibroblasts, which suggests that SMMS has potential as a skin wound-healing agent.

Effects of combination treatment with famotidine and methylmethionine sulfonium chloride on the mucus barrier of rat gastric mucosa.

BACKGROUND AND AIM: In Japan, peptic ulcer disease (PUD) is treated clinically with a combination of a mucosal protectant and acid suppressants, but there is scant information regarding the effects of these drugs on normal gastric mucus cells. In the present study, the effects of co-administration of methylmethionine sulfonium chloride (MMSC) and famotidine on rat gastric mucus cells were investigated using both biochemical and histological methods. METHODS: Rats were divided into four groups: controls were given carboxymethylcellulose orally once daily for 7 days and the second, third and fourth groups were treated similarly with famotidine (famotidine group), MMSC (MMSC group) or famotidine plus MMSC (combination group). After killing the rats on the 8th day, the stomachs were removed and the biosynthesis and amount of mucin in different areas of the gastric mucosa were compared among groups. Using anti-mucin monoclonal antibodies, the mucin content and immunoreactivity were also compared. RESULTS: Both the biosynthesis and accumulation of mucin were significantly decreased in the famotidine group, but increased in the MMSC and combination groups. The amount and immunoreactivity of surface mucus cell-derived mucin were both reduced in the famotidine group, and increased in the MMSC and combination groups. There was no difference among the groups in the content and immunoreactivity of gland mucus cell-derived mucin. CONCLUSION: Famotidine-induced suppression of gastric surface mucus cell function is prevented by combined treatment with MMSC, raising the possibility of a more effective cure of PUD.

[Positron emission tomography with L-[S-methyl-11C]-methioine and its biodistribution].

OBJECTIVE: To study the biodistribution of L-[S-methyl-(11)C]-methioine ((11)C-MET) and explore its clinical application in positron emission tomography (PET) for brain tumor detection. METHODS: Twenty-four Wistar rats and divided into 6 equal groups and injected with (11)C-MET through the tail vein and killed by decollation at 5, 10, 20, 30 and 40 min after injection, respectively. The liver, brain, blood, heart, lung, kidney, and spleen were harvested to measure the radioactivity and calculate the biodistribution of (11)C-MET. PET imaging with (11)C-MET was performed in 6 normal volunteers and 30 patients with pathologically confirmed brain gliomas. RESULTS AND CONCLUSION: (11)C-MET showed high blood uptake and a long retention in the tumor mass, therefore can be a valuable tracer for PET imaging of brain tumor and the hypophysis.

Comparative species utilization and toxicity of sulfur amino acids.

Animal studies have shown that several methionine (Met) and cysteine (Cys) analogs or precursors have L-Met- and L-Cys-sparing activity. Relative oral bioavailability (RBV) values, with the L-isomer of Met and Cys set at 100% (isosulfurous basis), are near 100% for D-Met for animals but only about 30% for humans. Both the OH and keto analogs of Met have high RBV-sparing values, as does N-acetyl-L-Met (the D-isomer of acetylated Met has no bioactivity). L-Homocysteine has an RBV value of about 65% for Met sparing in rats and chicks, but D-homocysteine has little if any Met-sparing activity. S-Methyl-L-Met can partially spare Met, but only when fed under dietary conditions of choline/betaine deficiency. Relative to L-Cys, high RBV values exist for L-cystine, N-acetyl-L-Cys, L-homocysteine, L-Met, and glutathione, but D-cystine, the keto analog of Cys, L-cysteic acid, and taurine have no Cys-sparing activity. l-2-Oxothiazolidine-4-carboxylate has an RBV value of 75%, D-homocysteine 70%, and DL-lanthionine 35% as Cys precursors. Under dietary conditions of Cys deficiency and very low inorganic sulfate (SO4) ingestion, dietary SO4 supplementation has been shown to reduce the Cys requirement of several animal species as well as humans. Excessive ingestion of Met, Cys, or cystine has also been studied extensively in experimental animals, and these sulfur amino acids (SAA) are well established as being among the most toxic of all amino acids that have been studied. Even though Cys and its oxidized product (cystine) are equally efficacious at levels at or below their dietary requirements for maximal growth, Cys is far more toxic than cystine when administered orally in the pharmacologic dosing range. Isosulfurous (excess) levels of cystine, N-acetyl-L-Cys, or glutathione are far less growth depressing than L-Cys when 6 to 10 times the minimally required level of these SAA compounds are fed to chicks.

Protection against chronic gastric ulceration in the rat with sulfhydryl-containing agents.

Reserpine (intraperitoneal, 5 mg/kg every day for 5 days) produced chronic ulceration of the rat stomach 2 weeks postdose. Gavage with 1% DL-cysteine or DL-methionine-S-methylsulfonium chloride at 1 mL/day for 2 weeks and 5 days protected against ulceration in 30% of the rats, and this protection extended to 80% of cases with 2% solutions. Similar gavage with 5% solutions protected all rats against ulceration without significantly influencing the basal H+ output [13.1 +/- 0.3 and 14.2 +/- 0.2 mumol for DL-cysteine and DL-methionine-S-methylsulfonium chloride, respectively, versus 15.1 +/- 0.4 mumol (mean +/- standard error of the mean; n = 10)]; that is, cytoprotection was achieved.

[The nutritional prevention of postradiation effects]. / Alimentarnaia profilaktika postradiatsionnykh éffektov.

Radioprotective effects of vitamin complexes were shown. Author issued the possible mechanisms of the phenomena.

Sulphydryl-containing agents stimulate the healing of duodenal ulceration in man.

This prospective randomized double-blind study examined whether sulphydryl-containing agents stimulate the healing and prevent the recurrence of duodenal ulceration in man. To this end, DL-methionine methyl sulphonium chloride (MMSC, 500 mg four times daily) or DL-cysteine (200 mg four times daily) were orally administered with cimetidine. Symptomatic endoscopy-proven duodenal ulcer patients who were smokers and social drinkers were randomized to receive for 8 weeks cimetidine (400 mg b.d.), cimetidine (400 mg b.d.) with MMSC, or cimetidine (400 mg b.d.) with cysteine. These patients were then kept on their respective oral regimens (except for cimetidine which was changed to 400 mg at bedtime) for 1 year (maintenance) and followed up for another. After 8 weeks of treatment, the ulceration healed in 65 patients (74%) given cimetidine alone but in all the patients given MMSC (n = 87) or cysteine (n = 86) with cimetidine (p less than 0.01). During the maintenance year, 15 patients (29%) given cimetidine at night relapsed. Addition of MMSC or cysteine to cimetidine incurred a significantly (p less than 0.001) lower relapse rate. During the year following maintenance therapy, the relapse rate in the group that had been previously treated with cimetidine alone (63%, n = 51) was significantly (p less than 0.001) higher than that in the groups previously treated with MMSC and cimetidine (6%, n = 67) or cysteine with cimetidine (6%, n = 64). The results suggest that sulphydryl-containing agents stimulate the healing and protect against the recurrence of duodenal ulceration.

Role of sulfhydryl-containing agents in the healing of erosive gastritis and chronic gastric ulceration in the rat.

One milliliter of 1, 2, or 5% DL-cysteine (cysteine) or DL-methionine methylsulfonium chloride (MMSC) was instilled into the rat stomach 1, 24, and 48 h after giving ethanol (1 mL of 40% solution) by gavage. One hour following the administration of ethanol, gastric mucosal injury was seen in all the animals (22.6 +/- 1.1 mm2, mean +/- SEM; n = 10). Twenty-four hours after giving the ethanol, all the rats treated with cysteine or MMSC still had the mucosal injury. Treatment with 2% cysteine or MMSC significantly (p less than 0.01) reduced the extent of this injury (10.2 +/- 0.6 and 10.1 +/- 0.5 mm2, respectively, versus 20.7 +/- 1.2 mm2, mean +/- SEM; n = 10), an action that was similarly achieved by the 5% solutions (10.1 +/- 0.5 and 9.9 +/- 0.3 mm2, respectively, versus 20.7 +/- 1.2 mm2, mean +/- SEM; n = 10). Forty-eight hours following the administration of ethanol, 30% of the animals given 1% cysteine or MMSC still had gastric mucosal injury, which was significantly (p less than 0.001) less extensive than that seen with ethanol alone (3.8 +/- 0.3 and 4.1 +/- 0.3 mm2, respectively, versus 13.1 +/- 0.8 mm2, mean +/- SEM; n = 10). At this time period, however, none of the animals treated with 2 or 5% solutions of cysteine or MMSC still had any injury. Healing of the ethanol-induced injury was confirmed microscopically and was achieved by regeneration.(ABSTRACT TRUNCATED AT 250 WORDS)

[The effect of methylation on the carnitine synthesis]. / Vliianie protsessov metilirovaniia na sintez karnitina.

The effect of vitamin B12, its analogs and donors of methyl groups on the coupling of methylation and carnitine accumulation in rats was studied. Biological active forms of vitamin B12 (methylcobalamine, cyanocobalamine, hydroxycobalamine) are shown to stimulate the carnitine synthesis in liver. The donor of methyl groups S-methylmethionine, also has a positive effect. Factor B does not influence the carnitine level. The stimulating effect of vitamin B12 and donors in methyl groups on the carnitine synthesis seems to result from activation of methylation.

[Anti-inflammatory effect of methylmethionine sulfonium chloride (vitamin U)].

Tests conducted on mice demonstrated that methylmethionine-sulfonium chloride (vitamin U) is capable of lowering the permeability of the skin capillaries following the action of stimulants. It greatly potentiates the antiphlogistic effect of acetylsalicylic acid, this action being more pronounced with vitamin U administered one hour before intake of acetlsaliclic acid than when both are taken simultaneously. Given in a dose of 1000 mg/kg vitamin U helps reduce exudation in aseptic serosites in rats. The antiphlogistic effect of vitamin U comes in conjunction with its ability to exercise a protective action against lesion of the gastric mucosa produced by acetylsalicylic acid.