[Studying the influence of Candesartan cilexetil on the lung fibrosis in rats exposed to silica].

OBJECTIVE: To explore the effects of Candesartan cilexetil on the rats exposed to silica. METHOD: Ninety-six wistar rats were randomly divided into model-group, intervention-group and control-group (32 rats a group). The intervention-group, model-group and control group were orally exposed to Candesartan cilexetil (10 mg/kg) and normal solution for a week, respectively. Then the model and intervention groups were exposed to silica by intratracheal infusion of silica dust suspension (50 mg/ml), the control group was exposed to 0.5 ml normal solution for 2 days. On the 3rd, 7th, 14th and 28th days after exposure to silica, 8 rats of each group were sacrificed, respectively. The samples of lung tissues were collected. The lung/body coefficients were detected. The pathological examinations were performed by HE and Masson staining. The levels of ACE in the lung tissues were observed by immunochemistry staining. The levels of TGF-ß1 and Ang II in the BALF were examined by ELISA. RESULTS: On the 3rd, 7th, 14th and 28th days after exposure, the levels of alveolitis and pulmonary fibrosis in the intervention group were significantly alleviated as compared with model group, and the lung/body coefficients in the intervention group, which were significantly lower than those in model group respectively (P < 0.01). As compared with control group, the levels of TGF-ß1 and Ang II of the BALF in the model and intervention groups significantly enhanced (P < 0.01). As compared with model group, the levels of TGF-ß1 and Ang II of the BALF in the intervention group significantly decreased (P < 0.01). As compared with control group, the levels of ACE of the lung tissues in the model and intervention groups significantly increased (P < 0.01). But the level of ACE of the lung tissues in the intervention group was significantly lower than that in the model group (P < 0.01). CONCLUSION: The early Candesartan cilexetil intervention could significantly decrease the levels of alveolitis and lung fibrosis, declined the levels of TGF-ß(1) and Ang II of BALF and downregulated the expression level of ACE in lung tissues in rats exposed to silica.

Severe folate restriction results in depletion of and alteration in the composition of the intracellular folate pool, moderate sensitization to methotrexate and trimetrexate, upregulation of endogenous DHFR activity, and overexpression of metallothionein II and folate receptor alpha that, upon folate repletion, confer drug resistance to CHL cells.

DC-3F/FA3 cells (FA3) were derived from antifolate-sensitive CHL cells by selection for growth in folate-free media containing 15 pM [6S]-5CHOFH4. These cells undergo a 30-fold decrease in intracellular folates, overexpress folate receptor alpha (FR alpha) and metallothionein II, and display increased sensitivity to the dihydrofolate reductase (DHFR) targeted anti-folates methotrexate (MTX) and trimetrexate (TMTX), which can be attributed primarily to the folate pool status. Upon folate repletion by growth in 15 nM [6S]-5CHOFH4, they display a 5- and 10-fold increase in resistance to both drugs, respectively, even though folate pools are restored by only 43%. Enforced overexpression of FR alpha in transfectants cultured in nanomolar folate did not confer resistance to MTX but did support a modest 2-fold increase in resistance to TMTX. Enforced overexpression of MTII had a similar effect, but when both were overexpressed together no increase in resistance beyond that conferred by each one separately was noted, suggesting that both confer resistance to TMTX through a common downstream mechanism. Analysis of three independent low folate selected clones, FA3, FA7, and FA14, showed that each had a 5- to 6-fold increase in DHFR activity accompanied by a similar increase in DHFR protein level. However, no differences were detected in the DHFR gene copy number or in the steady-state amount of DHFR mRNA, suggesting that a posttranscriptional mechanism was responsible for the increase in DHFR expression.

Computational analysis of alternative splicing using EST tissue information.

Expressed sequence tags (ESTs) from normal and tumor tissues have been deposited in public databases. These ESTs and all mRNA sequences were aligned with the human genome sequence using LEADS, Compugen's alternative splicing modeling platform. We developed a novel computational approach to analyze tissue information of aligned ESTs in order to identify cancer-specific alternative splicing and gene segments highly expressed in particular cancers. Several genes, including one encoding a possible pre-mRNA splicing factor, displayed cancer-specific alternative splicing. In addition, multiple candidate gene segments highly expressed in colon cancers were identified.