BCL‐XL exerts a protective role against anemia caused by radiation‐induced kidney damage

Studies of gene‐targeted mice identified the roles of the different pro‐survival BCL‐2 proteins during embryogenesis. However, little is known about the role(s) of these proteins in adults in response to cytotoxic stresses, such as treatment with anti‐cancer agents. We investigated the role of BCL‐XL in adult mice using a strategy where prior bone marrow transplantation allowed for loss of BCL‐XL exclusively in non‐hematopoietic tissues to prevent anemia caused by BCL‐XL deficiency in erythroid cells. Unexpectedly, the combination of total body γ‐irradiation (TBI) and genetic loss of Bcl‐x caused secondary anemia resulting from chronic renal failure due to apoptosis of renal tubular epithelium with secondary obstructive nephropathy. These findings identify a critical protective role of BCL‐XL in the adult kidney and inform on the use of BCL‐XL inhibitors in combination with DNA damage‐inducing drugs for cancer therapy. Encouragingly, the combination of DNA damage‐inducing anti‐cancer therapy plus a BCL‐XL inhibitor could be tolerated in mice, at least when applied sequentially.     

Quantitation and localization of acinar cell-specific mucin in submandibular glands of mice during postnatal development

Summary In this study, antiserum to acinar cell-specific mucin was utilized to determine whether mucin could be detected in the mouse submandibular gland prior to cytodifferentiation of acinar cells. Results from radioimmunoassay indicated that mucin occurs in submandibular glands from newborn mice, i.e., before the appearance of mature acinar cells. Additionally, mucin quantitated in various stages of development was found to be antigenically identical to adult mucin. After sections of glands were treated with immunohistochemical reagents, we observed that the mature acinar cell-specific mucin was present in secretory terminal-tubule cells and in proacinar cells of newborn animals. The present findings suggest that in young animals, the proacinar cells are an immediate precursor of acinar cells and that the secretory terminal-tubule cells may represent an earlier stage in development of acinar cells. In adult female glands, mucin was also detected in the granular intercalating-duct cells. This latter observation is consistent with the hypothesis that these cells are an intermediate in the acinar cell replacement process.     

Epigallocatechin gallate protects BEAS-2B cells from lipopolysaccharide-induced apoptosis through upregulation of gastrin-releasing peptide

Gastrin-releasing peptide (GRP) plays a major role in the development and maintenance of lung epithelial cells by promoting cell division, whereas its suppression causes growth arrest and apoptosis. The present study shows that human bronchial epithelial BEAS-2B cells challenged with lipopolysaccharide (LPS), an endotoxin from gram-negative bacteria, downregulated GRP expression and induced apoptosis via upregulation of p53 and active caspase-3, signifying the importance of GRP in lung epithelial cell survival. However, in the presence of epigallocatechin-3-gallate (EGCG), a polyphenol in green tea, BEAS-2B cells resisted LPS-induced apoptosis and restored the expression of GRP and its downstream effectors such as epidermal growth factor receptor and NF-κB, as analysed by immunoblotting and qPCR. Based on our findings, we objectify that cytoprotective functions of EGCG, via upregulation of GRP in cells challenged with LPS, are novel and can be further explored in a therapeutic point of view for diseases such as septic shock.     

Radiosensitization of mammalian cells in vitro by nitroacridines

The nitroacridine nitracrine (1-NC) is a DNA intercalator and a hypoxia-selective, electron-affinic radiosensitizer. Sensitization of Chinese hamster fibroblast cultures at 0 degrees C by the nitro positional isomers of 1-NC has now been compared to help establish structure-activity relationships. The des-nitro analog (E(1) at pH 7 = -899 mV) did not sensitize, suggesting that an electron-affinic chromophore is required. All the nitroacridines (E(1) range -376 to -257 mV) sensitized hypoxic cells with a maximum sensitizer enhancement ratio of about 1.7, but with a 200-fold range in potency. When mean intracellular drug concentrations were compared, 2-, 3-, and 4-NC had potencies which were similar, independent of E(1), and no greater than predicted for non-DNA binding nitroheterocycles. Sensitization by these three isomers occurred at intracellular concentrations likely to saturate the potential intercalation sites on DNA. A large fraction of the radical sites sensitized by O2 are apparently inaccessible to these drugs. It is suggested that sensitization results from electron transfer from migrating transient charge carriers of low reduction potential to immobile bound intercalators. An additional sensitizing mechanism may be available to 1-NC, which was 20 times more potent, a potency not accounted for by E(1), cell uptake, or DNA binding affinity. The dissociation kinetics of the DNA-drug complex was faster for 1-NC than for the other isomers. The higher potency of 1-NC may reflect a short mean residence time (less than 1 ms) in its intercalation site, allowing significant mobility on the DNA within the lifetime of relatively stable radiation-induced target radicals.