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Thiazohalostatin is a new cytoprotective substance produced by Actinomadura sp. HQ24. Its structure was elucidated as shown in Fig. 1 by NMR spectral analyses and chemical modifications. Thiazohalostatin was found to possess a novel skeleton containing trichloropyrrole and thiazoline ring moieties.
Rumbrin has been isolated from a fungus, Auxarthron umbrinum, by a screening program designed to find microorganism-produced cytoprotective substances. It was purified by use of column chromatography on silica gel, reversed phase HPLC and then isolated as fine red needles. Rumbrin prevented cell death caused by calcium overload and exhibited a potent inhibitory activity against lipid peroxidation.
The structure of rumbrin (Fig. 1), a new cytoprotective substance, was elucidated by NMR spectral analysis. Rumbrin was found to possess a novel skeleton containing alpha-pyrone, tetraene and pyrrole moieties.
The experimental results demonstrate that TMZ displays the pharmacological characteristics of a "cytoprotective agent", since this drug exerts an anti-ischemic effect on myocardium totally independent of any hemodynamic changes.
The authors treated 10 patients with advanced (stage III-IV) ovarian cancer with a high-dose cyclophosphamide and cisplatin (CP) combined therapy in amifostine protection. Due to the effect of the cytoprotective agent the cycles of treatment were well tolerated and 7 of 10 patients achieved a complete remission. Nephrotoxicity, allergic reaction or minor complications did not occur. Starting of the next treatment cycle was to be delayed in only one case because of anaemia. The agent has an implicit place in the treatment of patients with ovarian cancer in order to achieve better results and improve the quality of life.
Cytoprotection in the stomach, consisting in the mucus secretion, mucous circulation intensification and bicarbonate secretion to the gastric lumen, is highly dependent on the products of arachidonic acid pathway and peroxidative-antioxidative balance. The aim of the paper was to examine the effects of selected inhibitors of arachidonic acid pathway on the natural protective system of the gastric mucosa exposed to 50% ethanol. The results show that leukotrienes, thromboxane and oxygen reactive forms significantly impair the protective function of the gastric mucosa while prostaglandins and antioxidant enzymes act protectively.
The atrial natriuretic peptide (ANP) was described as a peptide hormone synthesized and secreted by heart atria. It plays an important role in the regulation of volume homeostasis; however, the functions of ANP are not restricted to cardiovascular effects. The biological profile of ANP is much broader than originally thought. This article focuses on the immunomodulatory and anti-inflammatory functions of ANP addressing; for example, the influence of ANP on macrophage functions. Another important aspect of ANP reviewed here is its cytoprotective potential. The beneficial effect of ANP in preventing cell damage caused by ischemia and reperfusion warrants special attention. The therapeutic potential of ANP in organ preservation could be important for transplantation medicine.
Protease-activated receptor-2 (PAR-2), a G protein-coupled seven trans-membrane domain receptor, is distributed throughout the gastrointestinal tract, modulating various functions. In gastric mucosa, PAR-2 present in sensory neurons, upon activation, triggers mucus secretion by stimulating release of CGRP and tachykinins, resulting mucosal cytoprotection. PAR-2 activation also suppresses acid secretion and increase mucosal blood flow, contributing to the protective mechanisms. In contrast, PAR-2 is also present in chief cells, facilitating pepsinogen secretion. PAR-2 would thus appear to be primarily protective in gastric mucosa, but may also have an aggressive property in certain conditions. Finally, functions of PARs other than PAR-2 in gastric mucosa are also discussed.
To understand the bioavailability and mechanistic pathways of cytoprotection by IH636 grape seed proanthocyanidin extract (GSPE, commercially known as ActiVin) a series of in vitro and in vivo studies were conducted. Comparative protective abilities of GSPE, and vitamins C and E, singly and in combination, were assessed against smokeless tobacco extract (STE)-induced oxidative stress, DNA fragmentation and apoptotic cell death in a primary culture of normal human oral keratinocytes. GSPE protected against STE-induced oxidative stress, DNA damage and apoptotic cell death, and provided better protection as compared to vitamins C and E, singly and in combination. The bioavailability and protective ability of GSPE were examined against acetaminophen (AP)-induced hepato- and nephrotoxicity, amiodarone (AM)-induced lung toxicity, doxorubicin (DX)-induced cardiotoxicity and dimethylnitrosamine (DM)-induced spleenotoxicity in mice. GSPE-fed animals were compared with GSPE-untreated mice to evaluate the protective ability of GSPE against these structurally diverse drugs/chemicals. Serum chemistry changes, histopathology and DNA damage were evaluated. Results indicate that GSPE preexposure prior to the drugs/chemicals such as AP, AM, DX or DM treatment, provided near complete protection in terms of serum chemistry changes and inhibition of both forms of cell death, e.g., apoptosis and necrosis. DNA damage in various tissues triggered by these agents was significantly reduced in GSPE-fed animals. Histopathological examination of multiple target organs provided similar data. The results suggest that GSPE exposure is bioavailable and provides significant multiorgan protection against structurally diverse drug- and chemical-induced toxic assaults. Further, these studies exhibited a series of mechanistic information including free radical scavenging ability, anti-endonucleolytic activity, cytochrome P450 2E1 inhibitory activity, anti-necrotic, anti-apoptotic and anti-carcinogenic activities, modulatory effects on antioxidative and apoptotic regulatory genes such as Bcl2, c-myc and p53, which may be responsible for the novel chemoprotective properties exhibited by GSPE.
Cellular stressors such as UV irradiation, chemical irritants, or an immune system challenge in an otherwise healthy host induce the production and release of cytokines, such as tumor necrosis factor (TNF) alpha, which are powerful regulators of tissue homeostasis. TNFalpha, an important mediator of inflammation in the skin and mucosa, often represents the first physiological response to such noxious stimuli. TNFalpha not only acts systemically to promote inflammation, but also locally at the site of the stimulus to modulate cell growth and survival. It has been demonstrated previously that epithelial cells undergo growth arrest and differentiation in the presence of TNFalpha. However, the mechanism of this response is not well understood. Here we show that in primary cultures of human foreskin keratinocytes, TNFalpha mediates cellular growth arrest through activation of the transcription factor NF-kappaB. The cdk inhibitor p21(Cip1/Waf1) is activated through NF-kappaB and is an important mediator of this growth arrest response. In addition, TNFalpha-treated cell populations are markedly less susceptible to apoptosis by UV irradiation and this cytoprotective effect is at least in part mediated by p21(Cip1/Waf1) as well.
The effect of dilazep and dimethyl thiourea (DMTU) on the hydrogen peroxide-derived injury of culture pulmonary artery epithelial cells (CPAEC) was assessed by colorimetric assay of MTT formazan (MTT formazan assay). When CPAEC were treated with hydrogen peroxide, neither cell lysis nor detachment of the cells from surface of the well was observed. However, the MTT formazan formation was decreased in a time and dose dependent manner. The decrease in the formation was significantly suppressed in the presence of dilazep (0.1 to 10 microM) or DMTU (0.01 to 0.3 microM). CPAEC treated with hydrogen peroxide in the same way enhanced an activation of prothrombin, and this enhancement was significantly inhibited in the presence of dilazep (1 to 3 microM). These data indicate that dilazep exerts a cytoprotective effect against challenges of intracellular oxidant produced by hydrogen peroxide and suppresses augmented procoagulant activity of injured cells.
The authors report their experience in the use of ursodeoxycholic acid and silymarin in patients with active cirrhosis of different aetiology. Both drugs seemed safe and ameliorated the biochemical indices of cytolysis; however, the former did not appear to be effective when hepatic dysfunction was associated to hepatitis C infection. The residual functional liver mass, as assessed by quantitative liver function tests, was not affected by either cytoprotective agent.
A brief report is given on the possible role of oxygen-derived free radicals and cholecystokinin in the pathogenesis of experimentally induced acute pancreatitis. Furthermore, use of scavengers (superoxide dismutase, catalase), CCK-receptor antagonists and somatostatin are discussed in the therapy of acute pancreatitis induced in animal models. It is suggested that both the term of direct pancreatic cytoprotection of the above-mentioned agents and the validity of the animal models used for induction of acute pancreatitis have to be reconsidered.
Although the effects of prostaglandins on gastrointestinal secretion, blood flow, and motility are quite well characterized, the mechanism underlying the cytoprotective actions of this group of lipid mediators has yet to be clearly established. It seems likely that the ability of NSAIDs to inhibit gastric prostaglandin synthesis is an important contributing factor to the pathogenesis of this disorder; however, it is still not clear why depletion of gastric prostaglandins predisposes the mucosa to injury. The study of prostaglandin receptors in the gastrointestinal tract is still in its infancy. As we learn more about the distribution of these receptors and develop specific agonists, it may become possible to develop prostaglandin analogues that are highly selective in enhancing mucosal defense but without the untoward effects frequently associated with analogues currently used clinically in the treatment of NSAID-induced gastropathy.
Recent radiobiological analysis of the radiotherapy results for prostate cancer revealed that prostate carcinoma behaves as a late responding tissue, sharing an alpha/beta ratio lower than 2Gy. These findings suggest that hypofractionation may be more effective. Reduction of the overall treatment time could further increase response by abrogating the effect of rapid tumor repopulation. In the present study we report a conformal technique applied (to pelvis and prostate) for the treatment of high-risk prostate cancer, using hypofractionated and accelerated radiotherapy (3.4Gy x 15 consecutive fractions) supported with high-dose daily amifostine (1000mg subcutaneously) to protect normal tissues against early and late effects. The biological dose delivered to the prostate cancer by this HypoARC (hypofractionated accelerated radiotherapy with cytoprotection) technique is estimated to be 71.4Gy (alpha/beta= 1.5 Gy). The time-adjusted biological dose is estimated to 77-94 Gy. Amifostine tolerance was excellent. All seven patients recruited up to now have accomplished their treatment with grade 0-1 cystitis or diarrhoea (5/7 grade 0). The study is ongoing to assess efficacy and late effects of HypoARC.
The duodenal mucosa is normally challenged by intermittent exposure to acid because of periodic gastric emptying. We studied the mechanisms of duodenal adaptation to acid in anesthetized rats. A polyvinyl chloride tube passing through a ligated pylorus was used for duodenal pulse instillations of 1 mL of saline or acid (100 or 400 mumols HCl) at 30-minute intervals. Duodenal lesions were blindly assessed using a combined macroscopic and histological score. Mucosal damage after exposure to saline or 100 mumols HCl was negligible in intact, vagotomized, and indomethacin-pretreated rats, whereas 400 mumols induced noticeable macroscopic and microscopic lesions. Interestingly, in intact and vagotomized rats, previous exposure to a 100-mumols HCl bolus significantly prevented mucosal damage by a subsequent 400-mumols bolus. This effect was not observed in indomethacin-pretreated rats. In these rats, however, intraduodenal instillation of exogenous 16,16-dimethyl prostaglandin E2 (16,16-dm-PGE2) prevented the damage induced by 400 mumols of HCl. A second protocol investigated the luminal release of bicarbonate and PGE2 in response to intraduodenal perfusion with 100 mumols of HCl. Duodenal bicarbonate release was stimulated by acid in all groups, whereas the release of PGE2 increased in intact and vagotomized rats but not in the indomethacin-pretreated group. In summary, these data suggest that adaptive cytoprotection plays a significant role in protecting the duodenal mucosa from acid. Vagal innervation and bicarbonate release do not appear to be as critical as cyclo-oxygenase activity for this mechanism.
Studies in vitro and in vivo show that hydrophobic bile acids tend to accumulate in the liver tissue in chronic liver disease, thus damaging hepatocyte membranes. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid which counteracts hepatotoxicity of more hydrophobic bile acids by partially replacing the pool of bile acids in the liver and/or by inhibiting the intestinal absorption of toxic bile acids. UDCA seems safe and effective in the early stages of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and possibly in other severe cholestatic syndromes of infancy. Moreover, there is increasing evidence that UDCA improves the common indices of liver function in chronic non-cholestatic hepatic disorders including active cirrhosis, though maintaining the residual functional liver mass. This article reviews the cytoprotective effect of UDCA in chronic cholestatic and non-cholestatic liver disease based on the results of major clinical trials on this topic.
Calcitriol is originally known to decrease proliferation rates of several carcinoma cells, partly via induction of apoptosis. On the other hand, the secosteroid is revealed to protect some cell types like thyrocytes, HL-60 cells and melanocytes against programmed cell death. Here we report that calcitriol despite its strong antiproliferative effect on human dermal fibroblasts did not induce apoptosis in these cells. In contrast, calcitriol possessed an antiapoptotic action in dermal fibroblasts. Thus, the ability of the apoptotic stimuli TNFalpha/actinomycin and C2-ceramides (C2-Cer) to induce programmed cell death was drastically diminished in the presence of calcitriol. Moreover, we identified sphingosine 1-phosphate (S1P) as a downstream mediator of calcitriol for its cytoprotective property. Thus, the secosteroid could not protect fibroblasts from apoptosis in the presence of N,N-dimethylsphingosine (DMS), which inhibits sphingosine kinase, the crucial enzyme to form S1P. Like calcitriol, S1P in different concentrations did not induce fibroblast apoptosis and moreover drastically decreased the rates of apoptotic cells after treatment with TNFalpha1/actinomycin. As S1P has been identified to modify the Bcl-2/ Bax ratio in epithelial cells and keratinocytes, we also measured the expression of these proteins in dermal fibroblasts revealing an increased Bcl-2 level after stimulation with S1P while the Bax protein expression was not modified. In conclusion, calcitriol H was revealed to protect human fibroblasts from apoptosis by formation of S1P resulting in a changed Bcl-2/Bax ratio.