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At least 757 records · Page 42Linked to original sources
PubMed2004

Testosterone induces cytoprotection by activating ATP-sensitive K+ channels in the cardiac mitochondrial inner membrane.

BACKGROUND: Whereas in the past, androgens were mainly believed to exert adverse effects on the cardiovascular system, recent experimental data postulate a benefit of testosterone for recovery of myocardial function after ischemia/reperfusion injury. Thus, we examined whether testosterone might improve myocardial tolerance to ischemia due to activation of mitochondrial (mitoK(ATP)) and/or sarcoplasmatic (sarcK(ATP)) K(ATP) channels. METHODS AND RESULTS: In a cellular model of ischemia, testosterone significantly decreased the rate of ischemia-induced death of cardiomyocytes that could be prevented by 5-hydroxydecainoic acid but was unaffected by the sarcK(ATP) blocker HMR1098 and the testosterone receptor antagonist flutamide. To index mitoK(ATP), mitochondrial flavoprotein fluorescence was measured. Testosterone induced a highly significant increase in mitochondrial flavoprotein fluorescence in intact myocytes and isolated mitoplasts that could be abolished by 5-hydroxydecainoic acid. Testosterone-mediated flavoprotein oxidation of mitoplasts was K+ dependent and ATP sensitive. In mitoplast-attached single-channel recordings, testosterone directly activated an ATP-sensitive K+ channel of the inner mitochondrial membrane. Addition of the K(ATP) channel opener diazoxide and pinacidil to the cytosolic solution activated the ATP-sensitive K+ current comparable to testosterone, whereas 5-hydroxydecainoic acid and glibenclamide inhibited the testosterone-induced current. Patch-clamp experiments of intact myocytes in whole-cell configuration did not demonstrate any effect of testosterone on sarcK(ATP) channels. CONCLUSIONS: Our results provide direct evidence for the existence of cardiac mitoK(ATP) and a link between testosterone-induced cytoprotection and activation of mitoK(ATP). Endogenous testosterone might play a more important role in recovery after myocardial infarction than is currently assumed.

Adenosine Triphosphate↗
PubMed2003

Wall stiffness suppresses Akt/eNOS and cytoprotection in pulse-perfused endothelium.

Increased steady shear stress stimulates nitric oxide synthase (eNOS) in part by Akt-dependent phosphorylation. Arteries in vivo are exposed to pulse perfusion (PP) combining phasic shear with stretch. In compliant vessels, enhancing PP lowers vascular tone by stimulating eNOS; whereas in aged, stiff arteries, flow-mediated dilation declines and PP is a prominent risk factor. Here, we tested the hypothesis that reduced wall distensibility alters PP-induced eNOS/Akt mechano-signaling. Bovine aortic endothelial cells cultured within distensible tubes were exposed to physiological nonreversing steady or PP (7 dynes/cm(2) mean shear, pulse pressure 0 or 90 mm Hgx2 hours) in a custom servo-system. In compliant tubes, PP doubled Akt phosphorylation above nonpulsatile flow levels, whereas P-Akt declined to static levels from PP in stiffer tubes. eNOS phosphorylation (S-1179) similarly increased with PP in compliant tubes but was nearly undetectable with increased PP in stiffer tubes. After PP, brief exposure of cells to ultraviolet irradiation (oxidant stress) and subsequent culture revealed cytoprotection in compliant tubes but diffuse cytotoxicity and cell detachment in stiffer tubes. NOS inhibition by L-NAME converted compliant-tube post-UV behavior to that of stiffer tubes. These data provide novel evidence that wall compliance can directionally mediate endothelial Akt/eNOS phosphorylation and mechano-signaling. This may help explain increased vascular risks resulting from artery stiffening.

Animals↗
PubMed2001

Cytoprotection by Jun kinase during nitric oxide-induced cardiac myocyte apoptosis.

Nitric oxide (NO) induces apoptosis in cardiac myocytes through an oxidant-sensitive mechanism. However, additional factors appear to modulate the exact timing and rate of NO-dependent apoptosis. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated kinase [ERK] 1/2, c-Jun N-terminal kinase [JNK] 1/2, and p38MAPK) in NO-mediated apoptotic signaling. The NO donor S:-nitrosoglutathione (GSNO) induced caspase-dependent apoptosis in neonatal rat cardiac myocytes, preceded by a rapid (<10-minute) and significant (approximately 50-fold) activation of JNK1/2. Activation of JNK was cGMP dependent and was inversely related to NO concentration; it was maximal at the lowest dose of GSNO (10 micromol/L) and negligible at 1 mmol/L. NO slightly increased ERK1/2 beginning at 2 hours but did not affect p38MAPK activity. Inhibitors of ERK and p38MAPK activation did not affect cell death rates. In contrast, expression of dominant-negative JNK1 or MKK4 mutants significantly increased NO-induced apoptosis at 5 hours (56.77% and 57.37%, respectively, versus control, 40.5%), whereas MEKK1, an upstream activator of JNK, sharply reduced apoptosis in a JNK-dependent manner. Adenovirus-mediated expression of dominant-negative JNK1 both eliminated the rapid activation of JNK by NO and accelerated NO-mediated apoptosis by approximately 2 hours. These data indicate that NO activates JNK as part of a cytoprotective response, concurrent with initiation of apoptotic signaling. Early, transient activation of JNK serves both to delay and to reduce the total extent of apoptosis in cardiac myocytes.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Continuing postischemic neuronal death in CA1: influence of ischemia duration and cytoprotective doses of NBQX and SNX-111 in rats.

BACKGROUND AND PURPOSE: Transient forebrain ischemia results in a 24- to 72-hour delayed loss of CA1 neurons. Previous work has not assessed whether insult durations can vary the degree and maturation rate of CA1 injury and whether there are different ultrastructural features of death after brief or severe ischemia. We also tested whether known cytoprotective drugs achieve permanent or transient neuroprotection. METHODS: In the first experiment, ischemia was induced for 5, 15, or 30 minutes with the use of the 4-vessel occlusion rat model with 1- to 28-day survival. Others subjected to 5 or 15 minutes of ischemia and allowed to survive for 14 or 7 days, respectively, were examined with electron microscopy. Finally, we determined whether NBQX (30 mg/kg x3 at 0 or 6 hours after ischemia), an AMPA antagonist, and SNX-111 (5 mg/kg at 6 hours after ischemia), an N-type Ca2+ channel antagonist, provided enduring CA1 protection against 10 minutes of ischemia. RESULTS: CA1 damage was not detected at 24 hours. Thirty minutes of ischemia produced 47% and 84% CA1 damage at 2 and 3 days, respectively. A 15-minute occlusion yielded 11%, 74%, and 86% loss at 2, 3, and 7 days, respectively. Five minutes of ischemia produced an even slower progression with 24%, 52%, and 59% loss at 3, 7, and 14 days, respectively. Ultrastructural examination after 5 and 15 minutes of ischemia revealed necrosis with no morphological evidence of apoptosis. Both NBQX (P<0.021) and SNX-111 (P<0.001) significantly reduced CA1 death at 7 days (</=35%) but not at 28 days (>/=80%) compared with saline treatment ( approximately 79%). CONCLUSIONS: Brief forebrain ischemia results in a slower progression of CA1 loss than more severe insults. Nonetheless, neuronal injury had necrotic, not apoptotic, morphology. NBQX and SNX-111 only postponed CA1 injury.

Animals↗
PubMed2001

The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection.

Protease-activated receptor-2 (PAR-2), a receptor activated by trypsin/tryptase, modulates smooth muscle tone and exocrine secretion in the salivary glands and pancreas. Given that PAR-2 is expressed throughout the gastrointestinal tract, we investigated effects of PAR-2 agonists on mucus secretion and gastric mucosal injury in the rat. PAR-2-activating peptides triggered secretion of mucus in the stomach, but not in the duodenum. This mucus secretion was abolished by pretreatment with capsaicin, which stimulates and ablates specific sensory neurons, but it was resistant to cyclo-oxygenase inhibition. In contrast, capsaicin treatment failed to block PAR-2-mediated secretion from the salivary glands. Intravenous calcitonin gene-related peptide (CGRP) and neurokinin A markedly elicited gastric mucus secretion, as did substance P to a lesser extent. Specific antagonists of the CGRP1 and NK2, but not the NK1, receptors inhibited PAR-2-mediated mucus secretion. Pretreatment with the PAR-2 agonist strongly prevented gastric injury caused by HCl-ethanol or indomethacin. Thus, PAR-2 activation triggers the cytoprotective secretion of gastric mucus by stimulating the release of CGRP and tachykinins from sensory neurons. In contrast, the PAR-2-mediated salivary exocrine secretion appears to be independent of capsaicin-sensitive sensory neurons.

Animals↗
PubMed1989

Misoprostol: a prostaglandin E1 analog with antisecretory and cytoprotective properties.

Misoprostol, a methylester analog of prostaglandin E1, with antisecretory and cytoprotective properties, has undergone extensive investigation and has received Food and Drug Administration approval for the prevention of nonsteroidal-induced ulceration. The drug represents the first synthetic, orally active prostaglandin evaluated for the treatment of peptic ulcer disease. Clinical studies reveal a trend toward slightly lower healing rates with misoprostol when compared with histamine (H2)-receptor antagonists in the treatment of gastric and duodenal ulcers. In addition, misoprostol was less effective than H2-blockers in reducing ulcer pain, and caused a higher incidence of adverse reactions, particularly diarrhea occurring in up to 13 percent of the patients treated. Several studies have shown misoprostol to be superior to cimetidine and sucralfate in the prevention of alcohol- and drug-induced gastritis. This report summarizes the biopharmaceutics, pharmacokinetics, and clinical efficacy of misoprostol in the treatment of gastric and duodenal ulcers and in the prevention of mucosal injury.

Alprostadil↗
PubMed1994

Acetylcysteine as a cytoprotective antioxidant in patients with severe sepsis: potential new use for an old drug.

OBJECTIVE: To stimulate debate regarding a potential new use for acetylcysteine as a cellular antioxidant in severely septic patients with systemic inflammatory response syndrome (SIRS). DATA SOURCES: A MEDLINE review of published animal, human, and laboratory studies relating to the cytopathogenic effects of active radicals in SIRS and the protective effects of acetylcysteine and glutathione. STUDY SELECTION: Few studies were available so all studies pertinent to the objective were reviewed. DATA EXTRACTION: Clinical and basic science data from the available trials of the effects of acetylcysteine on active radical production or active radical cell injury were extrapolated to predict the effect of acetylcysteine on human sepsis. DATA SYNTHESIS: Severe sepsis is a major cause of SIRS. Much of the cellular injury associated with SIRS is mediated by active radicals produced by inflammatory cells that overwhelm endogenous antioxidants. Reduced glutathione is a crucial intracellular antioxidant that becomes depleted during SIRS. Regeneration of glutathione can be achieved by acetylcysteine, which unlike glutathione itself penetrates cells. In animal models of sepsis and lung injury, acetylcysteine mitigates the cytopathologic effects of SIRS. In humans, clinical benefit has been demonstrated in the SIRS of established fulminant hepatic failure. CONCLUSIONS: The data do not as yet lead to any firm conclusions regarding the value of acetylcysteine in the management of SIRS in severe sepsis. The animal and human studies are, however, sufficiently encouraging to warrant formal trials to test the hypothesis that acetylcysteine therapy has a cytoprotective effect in sepsis.

Acetylcysteine↗
PubMed2005

Cytoprotective effects of carvedilol against oxygen free radical generation in rat liver.

The protective effects of carvedilol, an antihypertensive agent, against oxidative injury caused by acetaminophen were studied in rat liver. Male Wistar rats (250 +/- 30 g) were pre-treated with carvedilol (3.6 mg/kg, p.o.) for 10 days and on the 11th day received an overdose of acetaminophen (800 mg/kg, p.o.). Four hours after acetaminophen administration, blood was collected to determine serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). After that, rats were killed and the livers were excised to determine reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and carbonyl protein contents, and the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione S-transferase (GST), and also the DNA damage index. Acetaminophen significantly increased the levels of TBARS, the DNA damage and SOD, AST and ALT activities. Carvedilol was able to prevent lipid peroxidation, protein carbonilation and DNA fragmentation caused by acetaminophen. Moreover, this drug prevented increases in SOD, AST and ALT activities. These results show that carvedilol exerts cytoprotective effects against oxidative injury caused by acetaminophen in rat liver. These effects are probably related to the O2*- scavenging property of carvedilol or its metabolites.

Acetaminophen↗
PubMed2003

Antibiotic cyclic AMP signaling by "primed" leukocytes confers anti-inflammatory cytoprotection.

The mechanism underlying anti-inflammatory effects of macrolide antibiotics remains uncertain. In this study, we first show the evidences concerning the possible link between leukocytic cyclic adenosine monophosphate (cAMP) signaling and the mechanism of anti-inflammatory, cytoprotective actions of macrolides. The clinical range of macrolides (i.e., erythromycin, roxithromycin, and clarithromycin) preferentially inhibited nuclear factor-kappaB activation mediated by reactive oxygen intermediates, inducing cAMP-dependent signaling [i.e., cAMP and cAMP-responsive element-binding protein (CREB)] by "primed" but not "resting" leukocytes. In this context, cAMP/CREB inhibition with adenosine 3':5'-cyclic monophosphothioate, rp-isomer (rp-cAMPs) and CREB decoy oligonucleotides reduced the anti-inflammatory actions of macrolides. These results thus indicate that macrolide-induced cAMP/CREB signaling, selectively by primed leukocytes, plays a major role in the mechanism of anti-inflammatory actions of macrolides.

Animals↗
PubMed2005

Clinical perspectives for the use of melatonin as a chronobiotic and cytoprotective agent.

The circadian time system involves periodic gene expression at the cellular level, synchronized by a hierarchically superior structure located in the hypothalamic suprachiasmatic nuclei. Treatment of circadian rhythm disorders has led to the development of a new type of agent called "chronobiotics," among which melatonin is the prototype. In elderly insomniacs, melatonin treatment decreased sleep latency and increased sleep efficiency, particularly slow-wave sleep. The effect of melatonin on sleep is the consequence of increasing sleep propensity (by augmenting the amplitude of circadian clock oscillation via MT1 receptors) and of synchronizing the circadian clock via MT2 receptors. Daily melatonin production decreases with age and in several pathologies, attaining its lowest values in Alzheimer's disease (AD) patients. About 45% of AD patients have disruptions in their sleep and "sundowning" agitation. Generally, melatonin treatment decreases sundowning in AD patients and reduced variability of sleep onset time. Both open and controlled studies have indicated a significant decrease of cognitive deterioration in AD patients treated with melatonin. The mechanisms accounting for the possible therapeutic effect of melatonin in AD patients may be manifold. On one hand, melatonin treatment promotes slow-wave sleep in the elderly and could be beneficial by augmenting the restorative phases of sleep. On the other hand, melatonin protects neurons against beta-amyloid toxicity. By its combined chronobiotic and cytoprotective properties melatonin provides an innovative neuroprotective strategy to reduce the cost of lifetime treatment of some neuropsychiatric disorders.

Aging↗
PubMed2005

Knock-down of the cytoprotective gene, clusterin, to enhance hormone and chemosensitivity in prostate and other cancers.

Discovery and targeting of genes mediating treatment resistance may lead to development of novel therapies that delay progression of recurrent and refractory cancers. Clusterin is a stress-associated cytoprotective chaperone expressed in many cancers that is upregulated in an adaptive cell survival manner by various apoptotic triggers and confers treatment resistance. Here, we review clusterin's functional role in regulating treatment-induced apoptosis and the use of a second generation antisense oligonucleotide to inhibit clusterin expression to enhance the cytotoxic effects of hormone- and chemotherapy in prostate and other xenograft models, as well as in recent human trials.

Animals↗
PubMed2005

Corticotropin-releasing factor is cytoprotective in Xenopus tadpole tail: coordination of ligand, receptor, and binding protein in tail muscle cell survival.

Upon metamorphosis, amphibian tadpoles lose their tails through programmed cell death induced by thyroid hormone (T3). Before transformation, the tail functions as an essential locomotory organ. The binding protein for the stress neuropeptide corticotropin-releasing factor (CRF; CRF-BP) is strongly up-regulated in the tail of Xenopus tadpoles during spontaneous or T3-induced metamorphosis. This finding led us to investigate physiological roles for CRF and CRF-BP in tadpole tail. We found CRF, CRF-BP, and functional CRF1 receptor in tail and CRF and functional CRF1 receptors, but not CRF-BP, in the tail muscle-derived cell line XLT-15. CRF, acting via the CRF1 receptor, slowed spontaneous tail regression in explant culture and caused a reduction in caspase 3/7 activity. CRF increased, but stable CRF-BP overexpression decreased, [3H]thymidine incorporation in XLT-15 cells. Overexpression of CRF-BP in vivo accelerated the loss of tail muscle cells during spontaneous metamorphosis. Lastly, exposure of tail explants to hypoxia increased CRF and urocortin 1 but strongly decreased CRF-BP mRNA expression. We show that CRF is expressed in tadpole tail, is up-regulated by environmental stressors, and is cytoprotective. The inhibitory binding protein for CRF is regulated by hormones or by environmental stressors and can modulate CRF bioactivity.

Animals↗
PubMed1997

Calcium ions and tyrosine phosphorylation interact coordinately with actin to regulate cytoprotective responses to stretching.

The actin-dependent sensory and response elements of stromal cells that are involved in mechanical signal transduction are poorly understood. To study mechanotransduction we have described previously a collagen-magnetic bead model in which application of well-defined forces to integrins induces an immediate (< 1 second) calcium influx. In this report we used the model to determine the role of calcium ions and tyrosine-phosphorylation in the regulation of force-mediated actin assembly and the resulting change in membrane rigidity. Collagen-beads were bound to cells through the focal adhesion-associated proteins talin, vinculin, alpha 2-integrin and beta-actin, indicating that force application was mediated through cytoskeletal elements. When force (2 N/m2) was applied to collagen beads, confocal microscopy showed a marked vertical extension of the cell which was counteracted by an actin-mediated retraction. Immunoblotting showed that force application induced F-actin accumulation at the bead-membrane complex but vinculin, talin and alpha 2-integrin remained unchanged. Atomic force microscopy showed that membrane rigidity increased 6-fold in the vicinity of beads which had been exposed to force. Force also induced tyrosine phosphorylation of several cytoplasmic proteins including paxillin. The force-induced actin accumulation was blocked in cells loaded with BAPTA/AM or in cells preincubated with genistein, an inhibitor of tyrosine phosphorylation. Repeated force application progressively inhibited the amplitude of force-induced calcium ion flux. As force-induced actin reorganization was dependent on calcium and tyrosine phosphorylation, and as progressive increases of filamentous actin in the submembrane cortex were correlated with increased membrane rigidity and dampened calcium influx, we suggest that cortical actin regulates stretch-activated cation permeable channel activity and provides a desensitization mechanism for cells exposed to repeated long-term mechanical stimuli. The actin response may be cytoprotective since it counteracts the initial force-mediated membrane extension and potentially strengthens cytoskeletal integrity at force-transfer points.

Actins↗
PubMed1995

Gastric cytoprotective activity of 2-cyclopenten-1-one and related compounds.

The cytoprotective activity of the isolated functional groups of several sesquiterpene lactones is reported. Among them the highest activity is shown by alpha-methylen-gamma-butyrolactone and 2-cyclopenten-1-one. The activity shown by those Michael acceptors with a beta carbon hindered by an alkyl substituent was always lower or almost null. A three-way mechanism of action is proposed: a) reduced glutathione synthesis, b) prostaglandin synthesis and c) mucosal glycoprotein synthesis.

Animals↗
PubMed1998

Gastric cytoprotective activity of dehydroleucodine in rats. Role of prostaglandins.

Previously, we reported that dehydroleucodine (DhL), a sesquiterpene lactone, protected the gastric mucosa of rats from absolute ethanol-induced lesions in a dose-dependent fashion. The mechanism is not mediated by an antiacid secretory action and DhL stimulated mucous production. In the present study, we report the effect of DhL on the mucosal production of prostaglandin E (PGE) and the mucosal release of PGE2 in rats stomach. DhL in acute treatment does not modify these values decreased by previous treatment with indomethacin or absolute ethanol. However, DhL in subchronic treatment significantly enhanced the mucosal production of PGE and the mucosal release of PGE2. Also, indomethacin pretreatment resulted in a significant reduction of the cytoprotective action of DhL. These results indicate the participation of endogenous prostaglandins in DhL protection against ethanol damage. Moreover, we suggest that the gastric protective activity of DhL against ethanol induced gastric mucosal damage is mediated, at least in part, through PGE and PGE2 in subchronic treatment.

Animals↗
PubMed2005

Comparison of the effects of cytoprotective drugs on human plasma adrenocorticotropic hormone and cortisol levels with continual stress exposure.

Cetraxate hydrochloride (cetraxate), ecabet sodium (ecabet), and sulpiride, which are cytoprotective drugs, have been used to treat peptic ulcers and acute or chronic gastritis. They are reported to improve mucosal blood flow in the stomach. One of the most important factors believed to cause gastric ulcers is mental and/or physiological stress. When people feel stress, the hypothalamo-pituitary-adrenal (HPA) axis is activated. Therefore, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol can be indicators of stress. We examined the effects of cetraxate, ecabet and sulpiride on the plasma levels of ACTH and cortisol under stress conditions by repetitive blood sampling. Venous blood samples were taken before and 20-240 min after a single administration of the drugs or a placebo. A single dose of ecabet caused significant suppression of increases in plasma ACTH-like immunoreactive substance (IS) levels at 90 to 120 min and cortisol levels at 240 min, compared with the response to placebo. Sulpiride only suppressed increases in plasma cortisol levels at 180 to 240 min, compared with the response to placebo. A single dose of cetraxate had no effect on plasma ACTH-IS and cortisol levels. Ecabet may have a modulatory effect on the HPA axis while sulpiride may have a partial modulatory effect on the HPA axis. These effects might be beneficial in stress-related disease.

Abietanes↗
PubMed1991

Preparation of glycyrrhetic acid glycosides having various beta(1----2)-linked disaccharides and their cytoprotective effects on carbon tetrachloride-induced hepatic injury.

Glycyrrhetic acid glycosides (1-7) having beta(1----2)-linked disaccharides such as 2-O-beta-D-glucopyranosyl-beta-D-galactopyranose, 2-O-beta-D-galactopyranosyl-beta-D-galactopyranose, 2-O-beta-D-glucuronopyranosyl-beta-D-galactopyranose, 2-O-beta-D-glucopyranosyl-beta-D-glucuronopyranose, 2-O-beta-D-galactopyranosyl-beta-D-glucuronopyranose, 2-O-beta-D-galactopyranosyl-beta-D-glucopyranose, 2-O-beta-D-glucuronopyranosyl-beta-D-glucopyranose, respectively, were synthesized by stepwise construction; from glycyrrhetic acid monoglycosides to the diglycosides. The cytoprotective activities of the glycosides 1-7 and 2-O-(beta-D-glucopyranosyl)-beta-D-glucopyranosyl-11-oxoolean-12-e n-30-oate (8) were compared with natural occurring glycyrrhizin (9). Among these glycosides 1-8, glycosides 3 and 7 having beta-D-glucuronopyranose (glcUA) as the only terminal sugar component were more effective materials against hepatic injury than glycyrrhizin 9.

Animals↗
PubMed1993

Preparation of glycyrrhetic acid beta-glycosides having beta (1-->2)-linked disaccharides by the use of 2-O-trichloroacetyl-beta-D-pyranosyl chlorides and their cytoprotective effects on hepatic injury in vivo.

Stepwise glycosidation was adopted for the construction of glycyrrhetic acid beta-glycosides (27-30) having beta (1-->2)-linked disaccharides such as 2-O-beta-D-glucuronopyranosyl-beta-D-glucopyranose, 2-O-beta-D-glucuronopyranosyl-beta-D-galactopyranose, 2-O-beta-D-glucopyranosyl-beta-D-glucuronopyranose and 2-O-beta-D-galactopyranosyl-beta-D-glucuronopyranose. In the first glycosidation, 2-O-trichloroacetyl-beta-D-payranosyl chlorides (9-11) were utilized as starting sugar derivatives to react with methyl glycyrrhetinate (5): Glycosidation of 5 with 9 and 10 gave beta- and alpha-monoglycosides (12) and (13), and (15) and (16), respectively. Treatment of the beta-glycosides 12 and 15 with ammonia-saturated ether gave products (14) and (17), respectively. The glycosidation of 5 with 11 followed by treatment with ammonia-saturated ether gave compounds (18) and (19), respectively. The second step glycosidations of 14 and 17 with methyl 2,3,4-tri-O-acetyl-alpha-D-glucuronatopyranosyl bromide (20) gave diglycoside derivatives (23) and (24), respectively, and that of 18 with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (21) and -alpha-D-galactopyranosyl bromide (22) gave diglycoside derivatives (25) and (26), respectively. The removal of the protecting groups of 23-26 gave diglycosides 27-30, respectively, having a beta-D-glucuronopyranose (beta-D-glcUA) as one of two sugar components in the molecules. The cytoprotective effects of the synthesized glycosides 27-30 on carbon tetrachloride (CCl4)-induced hepatotoxicity in vivo were compared with diglycosides 31-33 having only neutral sugar components and naturally occurring glycyrrhizin (34) having two acidic sugar components (beta-D-glcUA).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗