Oxidant-induced cell injury has been implicated in the pathogenesis of several forms of acute renal failure. The present studies examined whether activation of poly(ADP-ribose)polymerase (PARP) by oxidant-induced DNA damage contributes to oxidant injury of renal epithelial cells. H2O2exposure resulted in an increase in PARP activity and decreases in cell ATP and NAD content. These changes were significantly inhibited by 10 mM 3-aminobenzamide (3-ABA), a PARP inhibitor. In contrast, H2O2-induced DNA damage was not prevented by 3-ABA. Exposure of LLC-PK1 cells to 1 mM H2O2for 2 h induced necrotic cell death as measured by increased lactate dehydrogenase (LDH) release. 3-ABA completely prevented the H2O2-induced LDH release. Live/dead fluorescent staining confirmed the protection by 3-ABA. These results are consistent with the view that oxidant-induced DNA damage activates PARP and that the subsequent ATP and NAD depletion contribute to necrotic cell death. Of note, although protected from necrosis, cells treated with H2O2and 3-ABA underwent apoptosis as evidenced by DNA fragmentation and bis-benzimide staining. In conclusion, activation of PARP contributes to oxidant-induced ATP depletion and necrosis in LLC-PK1 cells. However, PARP inhibition may target cells toward an apoptotic form of cell death.

Psoriasis is a common chronic inflammatory disease of the skin. Its pathogenesis has not been completely elucidated. Phosphoinositide-3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway has been identified as a key signaling pathway for important cellular functions. The data collected in this review suggest that overexpression of the PI3K/Akt/mTOR pathway may play an important role in the pathogenesis of psoriasis by mediating the immune-pathogenesis, the epidermal hyperplasia or/and the angiogenesis in the disease. Advances in understanding the pathogenesis of psoriasis has provided new insight into potential therapeutic targets, including the development of biological therapies, resulting in remarkable clinical responses in patients with severe psoriasis. More recently, small molecule oral preparations targeting intracellular signaling that may prove effective have been developed. Data suggest that PI3K/Akt/mTOR pathway may be a potential target for treatment of psoriasis.

An outwardly rectifying Cl- conductance was identified in primary isolated rat hepatocytes, and the whole cell patch-clamp technique was used to characterize its properties and mechanisms of activation. With symmetrical Cl(-)-containing solutions on both sides and adenosine 3',5'-cyclic monophosphate (cAMP; 100 microM) in the pipette solution, a large outwardly rectifying conductance (1,014 +/- 153 pS/pF, n = 20) developed in all cells within 3 min. This cAMP-activated conductance was highly anion selective and slowly inactivated at voltages > 80 mV. It was completely inhibited by the anion channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (200 microM, n = 6) and partially inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (150 microM, n = 7). It displayed a halide selectivity of I- > Br- > Cl-. In the absence of cAMP, a functionally similar conductance was activated by cell swelling. Reduction of bath osmolality from 300 to 250 mosmol/kg increased membrane conductance from 64 +/- 16.4 to 487 +/- 23 pS/pF (n = 4). This swelling-activated conductance was also highly anion selective and had identical halide selectivity and blocker sensitivity as the cAMP-activated conductance. Although cell swelling was not necessary for cAMP activation, cell shrinkage with hyperosmotic bath (350 mosmol/kg), either before or after exposure to cAMP, inhibited the cAMP-activated conductance. By the determination of conductance as a function of bath osmolality in the presence and absence of cAMP, it was observed that cAMP shifted the osmotic set point for conductance activation without changing either the maximum or minimum conductance. In conclusion, both cAMP and cell swelling activate a large outwardly rectifying Cl- conductance in rat hepatocytes. Its ionic selectivity and sensitivity to channel blockers are identical to those seen for swelling-activated Cl- conductances in many cell types. The conductive properties are not those of cystic fibrosis transmembrane conductance regulator-mediated Cl- conductance. cAMP appears to activate this conductance by altering the volume set point of a swelling-activated channel.

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Psoriasis is caused by a complex interplay among the immune system, genetic background, autoantigens, and environmental factors. Recent studies have demonstrated that patients with psoriasis have a significantly higher serum homocysteine (Hcy) level and a higher prevalence of hyperhomocysteinaemia (HHcy). Insufficiency of folic acid and vitamin B12 can be a cause of HHcy in psoriasis. Hcy may promote the immuno-inflammatory process in the pathogenesis of psoriasis by activating Th1 and Th17 cells and neutrophils, while suppressing regulatory T cells. Moreover, Hcy can drive the immuno-inflammatory process by enhancing the production of the pro-inflammatory cytokines in related to psoriasis. Hcy can induce nuclear factor kappa B activation, which is critical in the immunopathogenesis of psoriasis. There may be a link between the oxidative stress state in psoriasis and the effect of HHcy. Hydrogen sulfide (H2S) may play a protective role in the pathogenesis of psoriasis and the deficiency of H2S in psoriasis may be caused by HHcy. As the role of Hcy in the pathogenesis of psoriasis is most likely established, Hcy can be a potential therapeutic target for the treatment of psoriasis. Systemic folinate calcium, a folic acid derivative, and topical vitamin B12 have found to be effective in treating psoriasis.

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Endotoxin (LPS) can cause hepatocellular injury under several circumstances, and leukotrienes have been implicated as a contributing factor. Since ion channel activation has been associated with cytotoxicity, the aim of this study was to determine the circumstances under which LPS and/or leukotrienes activate ionic conductances in hepatocytes. LPS treatment of rats increased Cl

Oxidative stress contributes to renal epithelial cell injury in certain settings. Chloride influx has also been proposed as an important component of acute renal epithelial cell injury. The present studies examined the role of Cl(-) in H(2)O(2)-induced injury to LLC-PK(1) renal epithelial cells. Exposure of LLC-PK(1) cells to 1 mM H(2)O(2) resulted in the following: depletion of intracellular ATP content; DNA damage; lipid peroxidation; and a loss of membrane integrity to both small molecules, e.g., trypan blue, and macromolecules, e.g., lactate dehydrogenase (LDH), and cell death. Substitution of Cl(-) by isethionate or the inclusion of certain Cl(-) channel blockers, e.g., diphenylamine-2-carboxylate (DPC), 5-nitro-2-(3-phenylpropylamino). benzoate (NPPB), and niflumic acid, prevented the H(2)O(2)-induced loss of membrane integrity to LDH. In addition, the H(2)O(2)-induced loss of membrane integrity was prevented by raising the osmolality of the extracellular solutions, by depletion of cell ATP, and by inhibitors of volume-sensitive Cl(-) channels. However, these maneuvers did not prevent the H(2)O(2)-induced permeability to small molecules or H(2)O(2)-induced ATP depletion, DNA damage, lipid peroxidation, or cell death. These results support the view that volume-sensitive Cl(-) channels play a role in the progressive loss of cell membrane integrity during injury.