Malaria is estimated to cause 0.7 to 2.7 million deaths per year, but the actual figures could be substantially higher owing to under-reporting and difficulties in diagnosis. If no new control measures are developed, the malaria death toll is projected to double in the next 20 years. Efforts to control the disease are hampered by drug resistance in the Plasmodium parasites, insecticide resistance in mosquitoes, and the lack of an effective vaccine. Because mosquitoes are obligatory vectors for malaria transmission, the spread of malaria could be curtailed by rendering them incapable of transmitting parasites. Many of the tools required for the genetic manipulation of mosquito competence for malaria transmission have been developed. Foreign genes can now be introduced into the germ line of both culicine and anopheline mosquitoes, and these transgenes can be expressed in a tissue-specific manner. Here we report on the use of such tools to generate transgenic mosquitoes that express antiparasitic genes in their midgut epithelium, thus rendering them inefficient vectors for the disease. These findings have significant implications for the development of new strategies for malaria control.

The proliferation of hepatic stellate cells (HSCs) is a critical step in hepatic fibrogenesis. Platelet‐derived growth factor (PDGF) is the most potent mitogen for HSCs. We investigated the role of nonphagocytic NAD(P)H oxidase–derived reactive oxygen species (ROS) in PDGF‐induced HSC proliferation. The human HSC line, LI‐90 cells, murine primary‐cultured HSCs, and PDGF‐BB were used in this study. We examined the mechanism of PDGF‐BB‐induced HSC proliferation in relation to the role of a ROS scavenger and diphenylene iodonium, an inhibitor of NAD(P)H oxidase. We also measured ROS production with the aid of chemiluminescence. We showed that PDGF‐BB induced proliferation of HSCs through the intracellular production of ROS. We also demonstrated that HSCs expressed key components of nonphagocytic NAD(P)H oxidase (p22phox, gp91phox, p47phox, and p67phox) at both the messenger RNA and protein levels. Diphenylene iodonium suppressed PDGF‐BB–induced ROS production and HSC proliferation. Coincubation of H2O2 and PDGF‐BB restored the proliferation of HSCs that was inhibited by diphenylene iodonium pretreatment. Phosphorylation of the mitogen‐activated protein kinase (MAPK) family constitutes a signal transduction pathway of cell proliferation. Our data demonstrate that NAD(P)H oxidase–derived ROS induce HSC proliferation mainly through the phosphorylation of p38 MAPK. Moreover, an in vivo hepatic fibrosis model also supported the critical role of NAD(P)H oxidase in the activation and proliferation of HSCs. In conclusion, NAD(P)H oxidase is expressed in HSCs and produces ROS via activation of NAD(P)H oxidase in response to PDGF‐BB. ROS further induce HSC proliferation through the phosphorylation of p38 MAPK. (HEPATOLOGY 2005;41:1272–1281.)

No abstract

No abstract