Most segments of the gastrointestinal tract secrete HCO3−, but the molecular nature of the secretory mechanisms has not been identified. We had previously speculated that the regulator for intestinal electrogenic HCO3− secretion is the cystic fibrosis transmembrane regulator (CFTR) channel. To prove this hypothesis, we have now measured HCO3− secretion by pH‐stat titration, and recorded the electrical parameters of in vitro duodenum, jejunum and ileum of mice deficient in the gene for the CFTR protein (‘CF‐mice’) and their normal littermates. Basal HCO3− secretory rates were reduced in all small intestinal segments of CF mice. Forskolin, PGE2, 8‐bromo‐cAMP and VIP (cAMP‐dependent agonists), heat‐stable enterotoxin of Escherichia coli (STa), guanylin and 8‐bromo‐cGMP (cGMP‐dependent agonists) and carbachol (Ca2+ dependent) stimulated both the short‐circuit current (ISC) and the HCO3− secretory rate (JHCO3‐) in all intestinal segments in normal mice, whereas none of these agonists had any effect on JHCO3‐ in the intestine of CF mice. To investigate whether Cl−–HCO3− exchangers, which have been implicated in mediating the response to some of these agonists in the intestine, were similarly active in the small intestine of normal and CF mice, we studied CF gradient‐driven 36Cl− uptake into brush‐border membrane (BBM) vesicles isolated from normal and CF mouse small intestine. Both the time course and the peak value for 4,4’‐diisothiocyanostilbene‐2’,2‐disulphonic acid (DIDS)‐inhibited 36Cl− uptake was similar in normal and CF mice BBM vesicles. In summary, the results demonstrate that the presence of the CFTR channel is necessary for agonist‐induced stimulation of electrogenic HCO3− secretion in all segments of the small intestine, and all three intracellular signal transduction pathways stimulate HCO3− secretion exclusively via activation of the CFTR channel.

Macrophages are thought to represent a first line of defense in anti-tumor immunity. Despite infiltration by microglial cells, however, malignant gliomas are still highly aggressive tumors. We here identify monocyte chemoattractant protein-1 (MCP-1) as a critical chemoattractant for glioma-infiltrating microglial cells. MCP-1-transfected rat CNS-1 gliomas were massively infiltrated by microglial cells. Whereas MCP-1 did not promote the growth of CNS-1 cells in vitro, intracerebral CNS-1-transfected tumors grew more aggressively than control-transfected tumors. This provides the first functional evidence that MCP-1 recruits microglial cells to gliomas and promotes their growth in vivo. Microglial cells may support rather than suppress glioma growth.

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In contrast to the programmed nature of development, it is still a matter of debate whether aging is an adaptive and regulated process, or merely a consequence arising from a stochastic accumulation of harmful events that culminate in a global state of reduced fitness, risk for disease acquisition, and death. Similarly unanswered are the questions of whether aging is reversible and can be turned into rejuvenation as well as how aging is distinguishable from and influenced by cellular senescence. With the discovery of beneficial aspects of cellular senescence and evidence of senescence being not limited to replicative cellular states, a redefinition of our comprehension of aging and senescence appears scientifically overdue. Here, we provide a factor-based comparison of current knowledge on aging and senescence, which we converge on four suggested concepts, thereby implementing the newly emerging cellular and molecular aspects of geroconversion and amitosenescence, and the signatures of a genetic state termed genosenium. We also address the possibility of an aging-associated secretory phenotype in analogy to the well-characterized senescence-associated secretory phenotype and delineate the impact of epigenetic regulation in aging and senescence. Future advances will elucidate the biological and molecular fingerprints intrinsic to either process.

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Experimental studies in small rodents requiring high spatial resolution can be performed by using a clinical 3 T scanner with appropriate dedicated coils.