Influence of daily oral prophylactic selenium treatment on the dibutyltin dichloride (DBTC)-induced pancreatitis in rats.

Dibutyltin dichloride (DBTC) is an organotin compound used as model for acute and chronic pancreatitis. Oxidative stress is one of the mechanisms of propagation of acinar cell injury in acute pancreatitis. Selenium is an essential cofactor in the antioxidant glutathione peroxidase pathway. Selenium levels are described to be subnormal in patients with acute and chronic pancreatitis. The aim of our studies was to determine the prophylactic effect of Na-selenite [5 mg kg-1 body weight (b.w.) per os (p.o.) 7 days] on the pathogenesis and course of DBTC- induced pancreatitis. Male inbred rats (LEW-1W Charles River) of 150 g body weight were used in this study. Experimental pancreatitis was induced by intravenous administration of 6 mg kg-1 b.w. DBTC in rats. Na-selenite was administered as daily oral dose of 5 mg kg-1 b.w. 7 days before induction of DBTC-pancreatitis. Malondialdehyde (MDA) was measured for monitoring levels of oxidative stress. Elimination of DBTC was reflected as tin concentration in bile and urine. Organ changes were indicated by serum parameters as well as histology. A prophylactic Na-selenite application significantly diminished MDA- and bilirubin concentration in serum, activities of lipase and transaminases as well as organ injuries compared to DBTC- treated rats in the absence of Na-selenite. The prophylactic oral treatment with Na-selenite in the scope of DBTC-induced pancreatitis points to a reduced oxidative stress characterized by diminished MDA serum levels and a milder course of pancreatitis suggesting prophylactic substitution with Na-selenite to probably elicit beneficial effect on the clinical outcome in patients with endoscopic retrograde cholangiopancreatography (ERCP).

Decisive role of cyclooxygenase-2 and lipocalin-type prostaglandin D synthase in chemotherapeutics-induced apoptosis of human cervical carcinoma cells.

The role of cyclooxygenase-2 (COX-2) in cancer remains controversial. Using cervical carcinoma cells (HeLa), the present study investigates the involvement of COX-2 in apoptosis elicited by the chemotherapeutics paclitaxel, cisplatin and 5-fluorouracil. Each compound led to a profound induction of COX-2 expression and prostaglandin (PG) synthesis, accompanied by a substantial decrease of viability and enhanced apoptosis. Cells were significantly less sensitive to apoptotic death when either COX-2 expression or its activity was suppressed by small-interfering RNA (siRNA) and by the selective COX-2 inhibitor NS-398, respectively. Experiments performed to clarify how COX-2 leads to apoptosis revealed a profound proapoptotic action of PGD2 and its dehydration product, 15-deoxy-Delta(12,14) PGJ2 (15d-PGJ2). In line with these findings, chemotherapeutics-induced apoptosis was prevented by siRNA targeting lipocalin-type PGD synthase (L-PGDS), which catalyses the isomerization of PGH(2) to PGD2. Moreover, apoptosis by chemotherapeutics, PGD2 and 15d-PGJ2 was suppressed by the peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist, GW-9662 or PPARgamma siRNA. Finally, a COX-2-dependent apoptotic mechanism of all investigated chemotherapeutics was confirmed in human lung cancer cells (A549) as well as in another cervical carcinoma cell line (C33A). Collectively, this study suggests COX-2 induction and synthesis of L-PGDS-derived, PPARgamma-activating PGs as a decisive target by which several chemotherapeutics induce apoptosis. COX-2 is therefore suspected to sensitize cancer cells to apoptotic death under certain circumstances, suggesting that COX-2 inhibition during cancer therapy could diminish its efficacy.

Upregulation of tissue inhibitor of matrix metalloproteinases-1 confers the anti-invasive action of cisplatin on human cancer cells.

Cancer cell invasion is one of the crucial events in local spreading, growth and metastasis of tumors. The present study investigates the mechanism underlying the anti-invasive action of the chemotherapeutic cisplatin. In human cervical carcinoma cells (HeLa), cisplatin caused a time- and concentration-dependent suppression of cell invasion through Matrigel. Inhibition of invasion was accompanied by upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), whereas levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and TIMP-2 remained unchanged. Cisplatin's effects on TIMP-1 expression and invasion were associated with phosphorylations of p38 and p42/44 mitogen-activated protein kinases and were abrogated by specific inhibitors of both pathways. The impact of TIMP-1 in the anti-invasive action of cisplatin was proven by transfecting cells with small interfering RNA targeting TIMP-1, which completely reversed suppression of invasion by cisplatin. A functional relevance of TIMP-1 upregulation was substantiated by findings showing a concentration-dependent inhibition of Matrigel invasion by recombinant TIMP-1. The essential role of TIMP-1 in the anti-invasive action of cisplatin was confirmed using another human cervical carcinoma cell line (C33A) and human lung carcinoma cells (A549). Altogether, our data demonstrate a hitherto unknown mechanism by which cisplatin exerts its antimetastatic properties on highly invasive cancer cells.

Design and realisation of star-geometry dual-mode bandpass filter.

A design of a planar dual-mode filter is proposed and developed for satellite and wireless communication systems. The novelty of the proposed structure consists of replacing simple diagonal design with a starlike one. This offers the ability of controlling the central frequency and the bandwidth. The filter was implemented on Rogers substrate with 10.8 dielectric constant. The proposed filter structure is 37% smaller in size in comparison with traditional dual mode filters.

R(+)-methanandamide induces cyclooxygenase-2 expression in human neuroglioma cells via a non-cannabinoid receptor-mediated mechanism.

Cannabinoids affect prostaglandin (PG) formation in the central nervous system through as yet unidentified mechanisms. Using H4 human neuroglioma cells, the present study investigates the effect of R(+)-methanandamide (metabolically stable analogue of the endocannabinoid anandamide) on the expression of the cyclooxygenase-2 (COX-2) enzyme. Incubation of cells with R(+)-methanandamide was accompanied by concentration-dependent increases in COX-2 mRNA, COX-2 protein, and COX-2-dependent PGE(2) synthesis. Moreover, treatment of cells with R(+)-methanandamide in the presence of interleukin-1beta led to an overadditive induction of COX-2 expression. The stimulatory effect of R(+)-methanandamide on COX-2 expression was mimicked by the structurally unrelated cannabinoid Delta(9)-tetrahydrocannabinol. Stimulation of both COX-2 mRNA expression and subsequent PGE(2) synthesis by R(+)-methanandamide was not affected by the selective CB(1) receptor antagonist AM-251 or the G(i/o) protein inactivator pertussis toxin. Enhancement of COX-2 expression by R(+)-methanandamide was paralleled by time-dependent phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK. Consistent with the activation of both kinases, R(+)-methanandamide-induced COX-2 mRNA expression and PGE(2) formation were abrogated in the presence of specific inhibitors of p38 MAPK (SB203580) and p42/44 MAPK activation (PD98059). Together, our results demonstrate that R(+)-methanandamide induces COX-2 expression in human neuroglioma cells via a cannabinoid receptor-independent mechanism involving activation of the MAPK pathway. In conclusion, induction of COX-2 expression may represent a novel mechanism by which cannabinoids mediate PG-dependent effects within the central nervous system.

Up-regulation of cyclooxygenase-1 in neuroblastoma cell lines by retinoic acid and corticosteroids.

Cyclooxygenases-1 and -2 are both expressed in neuronal cells in vivo. In the neuroblastoma cell lines NG108 and N2a, however, only cyclooxygenase-1 was detectable. Differentiation of the cells with retinoic acid increased cyclooxygenase-1 mRNA and protein expression within 24 and 48 h, respectively. A further increase was observed when the cells were concomitantly treated with the glucocorticoid dexamethasone (a 2-3-fold increase compared with retinoic acid alone). In the absence of retinoic acid, dexamethasone only slightly up-regulated cyclooxygenase-1 expression. The inhibitor of protein synthesis cycloheximide abrogated the effect of dexamethasone, indicating the involvement of newly synthesised proteins. Retinoic acid increased the transcription of cyclooxygenase-1 mRNA, determined with a luciferase-coupled promoter construct. Dexamethasone only slightly augmented cyclooxygenase-1-promoter activity but increased cyclooxygenase-1 mRNA stability. Other corticosteroids, hydrocortisone and aldosterone, also up-regulated cyclooxygenase-1 whereas neurosteroids or oestrogen were ineffective. Up-regulation was mediated primarily by the glucocorticoid receptor, because the receptor antagonist RU486 strongly reduced the effects of all corticosteroids. This indicated that in NG108 cells, the mineralocorticoid aldosterone may bind to the glucocorticoid receptor. Treatment of NG108 or N2a cells with corticosteroids did not alter the morphological phenotype obtained during differentiation. We thus show that corticosteroids, which down-regulate cyclooxygenase expression in most cell types, up-regulate cyclooxygenase-1 during neuronal differentiation.

Hydrogen peroxide sterilization of hydrophilic contact lenses.

A new, simple, and effective procedure for the sterilization of soft contact lenses utilizes hydrogen peroxide, an inexpensive and readily availiable solution.

Ocular penetration of pilocarpine: the effect of pH on the ocular penetration of pilocarpine.

Under the conditions of this study, tritiated pilocarpine was topically applied to rabbits, and the activity in the aqueous humor was measured at selected times. It was found that higher pH affords greater pilocarpine penetration. At pH 7.5, for example, penetration into the aqueous was twice as great as at pH 4.

Teratogenicities of ophthalmic drugs. I. Antiviral ophthalmic drugs.

Nonradioactive idoxuridine (IDU,5-iodo-2'-deoxyuridine), while not teratogenic to rats, does produce fetal maliformations in rabbits when administered topically to the eye in doses similar to those used clinically, 0.1% four times a day for 12 days. These maliformations include exophthalmos and clubbing of the forelegs. By contrast, trifluorothymidine (F3TdR), another highly effective antiherpetic agent currently under investigation but not available for general use, was found not to be teratogenic to rabbits, even when given in concentrations tenfold greater than the doses used to produce idoxuridine teratogenicity.

Teratogenicities of ophthalmic drugs. II. Teratogenicities and tissue accumulation of thimerosal.

Under the conditions of this study, systemically or topically applied thimerosal was found to have no teratogenic effect even when given in concentrations approaching the 50% lethal dose of these compounds. A comparison of topical and subcutaneous administration of thimerosal to rabbits shows that a substantial concentration of mercury was present in blood and tissues of the treated animals and their offspring. Thimerosal was found to cross the blood-brain and placenta barriers.