Liver regeneration after partial hepatectomy is a plastic process during which the mechanisms that coordinate liver mass restoration compensate one another through a complex regulatory network of cytokines, growth factors, and hormones. Vasopressin, an agonist that triggers highly organized Ca2+ signals in the liver, may be one of these factors, although little in vivo evidence is available in support of this hypothesis. We provide evidence that hypothalamic vasopressin secretion is stimulated early after partial hepatectomy. Although hepatocytes were fully responsive to vasopressin during the first hours of regeneration, they became desensitized and exhibited slow oscillating Ca2+ responses to vasopressin on the following days. On the first day, hepatocyte V1a receptor density decreased and its lobular gradient increased in hepatectomized rats. By antagonizing the V1a receptor in vivo, we demonstrated that vasopressin contributes to NF-kappaB and cyclin (D1 and A) activation, to hepatocyte progression in the cell cycle, and to liver mass restoration. Finally, vasopressin exerted a choleretic effect shortly after hepatectomy, both in the isolated perfused liver and in the intact rat. In conclusion, we provide compelling in vivo evidence that vasopressin contributes significantly to growth initiation and bile flow stimulation in the early stages of liver regeneration.

Extracellular ATP regulates many hepatic functions by stimulating purinergic receptors. Only the G protein‐coupled P2Y receptors have been studied in hepatocytes. We investigated the functional expression of P2X receptors, the ATP‐gated channels in rat hepatocytes. P2X4 and P2X7 transcripts and proteins were detected by RT‐PCR and by both Western blotting and immunocytochemistry. High concentrations of ATP, and 2′‐and 3′‐O‐(4‐benzoylbenzoyl)‐ATP the preferring agonist of P2X7, induced membrane blebbing and significant uptake of 4‐[(3‐methyl‐2(3H)‐benzoxazolylidene)methyl]‐1‐[3‐(triethylammonio)propyl]diiodide, both of which were inhibited by oxidised ATP, a blocker of P2X receptors. These results provide evidence that P2X4 and P2X7 receptors are expressed and functional on rat hepatocytes, possibly playing an important role in the purinergic signaling complex in these cells.

Arginine vasopressin elicits elaborate Ca 2+ signals in the liver (intercellular Ca 2+ waves), the functional implications of which are not understood. Waves propagate across hepatocyte plates following a lobular gradient in V1a vasopressin receptor density. Here, we report that changes in this receptor distribution control Ca 2+ wave propagation and bile flow. Although basal circulating vasopressin levels do not play a major role in the regulation of V1a receptor expression, increases in vasopressin concentration within physiological limits for 24 h can abolish the lobular gradient in V1a receptor, as assessed by spectrofluorimetry, videomicroscopy, binding studies, and RNase protection assays. In animals in which the V1a receptor gradient was abolished, intercellular Ca 2+ waves were impaired due to the equalization of Ca 2+ responses in the various zones of the lobule. In the isolated perfused liver, the early increase in vasopressininduced bile flow observed in control rats was much smaller if the V1a receptor density gradient was abolished. These findings suggest that V1a vasopressin receptor distribution controls intercellular Ca 2+ wave propagation and bile flow. The control of hormone receptor distribution in a tissue by an agonist may turn the signaling and function of this agonist on or off.Key words: intercellular signaling • cellular • heterogeneity • receptor • density • bile flow • vasopressin rginine vasopressin (AVP), in addition to having well-known antidiuretic effects, is involved in the regulation of many other functions, including liver processes such as ureogenesis, glycogenolysis, and neoglucogenesis (1-3). In the rat, the physiological impact of AVP stimulation in the liver is still a matter of debate, despite the fact that hepatocyte is one of the cell types richest in V1a AVP receptors (4). AVP, by activating the V1a receptor, induces increases in intracellular Ca 2+ concentration ([Ca 2+ ] i ), which may propagate among hepatocytes as intercellular waves, the complex mechanisms of which are beginning to be understood (5-7). In freshly isolated multicellular systems of hepatocytes and in the intact perfused liver, oriented Ca 2+ waves start in one cell and propagate towards the other cells on AVP stimulation (5,6,(8)(9)(10)(11)(12). We have recently suggested that this propagation follows a A gradient in sensitivity to the agonist. Each hepatocyte has its own density of hormone receptors, which results in a slight shift in phase of agonist-induced [Ca 2+ ] i increases with respect to neighboring cells. Intercellular calcium waves thus appear to be receptor-oriented in hepatocytes, a configuration comparable with cell-cell triggering in cardiac pacemaker cells (6, 7). This heterogeneity of Ca 2+ mobilization in adjacent hepatocytes results from an in situ gradient in the number of hormone receptors across the liver cell plate, as has been shown for the V1a vasopressin receptor, the density of which declines from the perivenous (PV) zone to the periportal (PP) area (6,9,13). The functional...

Launaea taraxacifolia is a leafy vegetable of the family of Asteraceae (Compositae) found in several countries in West Africa including Ghana, Benin and Nigeria. The plant leaves are eaten either fresh as salad or cooked as sauces. They are also consumed as infusion to fight against several diseases including non-communicable diseases such as diabetes and hypertension. Several studies have been conducted in Ghana, Nigeria on the nutritional and medicinal values of this plant but no study has yet been conducted in Benin on the virtues of this plant. In this work we have achieved the phytochemical characterization and evaluated the cytotoxicity as well as hypolipidemic and antioxidant effects of the ethanol-aqueous extracts of Launaea taraxacifolia leaves. Cytotoxicity and hypolipidemic activities have been performed on HepG2 cells; the antioxidant effect has been performed on the PLB985 cells. The results showed that the ethanol-aqueous extracts of Launaea taraxacifolia leaves contained the following metabolites: catechic tannin, flavonoids, phenolic acids, mucilage and leucoanthocyanins. Only very high concentrations (>20 mg/ml) of leaves extracts are toxic for HepG2 cells. Launaea taraxacifolia leaves have significant antioxidant and hypolipidemic activities.

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The role of second messengers in the diversion of cellular processes by pathogens remains poorly studied despite their importance. Among these, Ca virtually regulates all known cell processes, including cytoskeletal reorganization, inflammation, or cell death pathways. Under physiological conditions, cytosolic Ca increases are transient and oscillatory, defining the so-called Ca code that links cell responses to specific Ca oscillatory patterns. During cell invasion, induces atypical local and global Ca signals. Here, we show that by hydrolyzing phosphatidylinositol-(4,5)bisphosphate, the type III effector IpgD dampens inositol-(1,4,5)trisphosphate (InsP) levels. By modifying InsP dynamics and diffusion, IpgD favors the elicitation of long-lasting local Ca signals at invasion sites and converts-induced global oscillatory responses into erratic responses with atypical dynamics and amplitude. Furthermore, IpgD eventually inhibits InsP-dependent responses during prolonged infection kinetics. IpgD thus acts as a pathogen regulator of the Ca code implicated in a versatility of cell functions. Consistent with this function, IpgD prevents the Ca-dependent activation of calpain, thereby preserving the integrity of cell adhesion structures during the early stages of infection.

Increases in both Ca2؉ and nitric oxide levels are vital for a variety of cellular processes; however, the interaction between these two crucial messengers is not fully understood. Here, we demonstrate that expression of inducible nitric-oxide synthase in hepatocytes, in response to inflammatory mediators, dramatically attenuates Ca 2؉ signaling by the inositol 1,4,5-trisphosphateforming hormone, vasopressin. The inhibitory effects of induction were reversed by nitric oxide inhibitors and mimicked by prolonged cyclic GMP elevation. Induction was without effect on Ca 2؉ signals in response to AlF 4 ؊ or inositol 1,4,5-trisphosphate, indicating that phospholipase C activation and release of Ca 2؉ from inositol 1,4,5-trisphosphate-sensitive Ca 2؉ stores were not targets for nitric oxide inhibition. Vasopressin receptor levels, however, were dramatically reduced in induced cultures. Our data provide a possible mechanism for hepatocyte dysfunction during chronic inflammation.