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Cross talk between NF-[kappa]B and c-Jun N-terminal kinases (JNKs) has been implicated in the cell life and death decision under various stresses. Functional suppression of JNK activation by NF-[kappa]B has recently been proposed as a key cellular survival mechanism and contributes to cancer cells escaping from apoptosis. We provide a novel scenario of the proapoptotic role of I[kappa]B kinase [beta] (IKK[beta])-NF-[kappa]B, which can act as the activator of the JNK pathway through the induction of GADD45[alpha] for triggering MKK4/JNK activation, in response to the stimulation of arsenite, a cancer therapeutic reagent. This effect of IKK[beta]NF-[kappa]B is dependent on p50 but not the p65/relA NF-[kappa]B subunit, which can increase the stability of GADD45[alpha] protein through suppressing its ubiquitination and proteasome-dependent degradation. IKK[beta]-NF-[kappa]B can therefore either activate or suppress the JNK cascade and consequently mediate pro- or antiapoptotic effects, depending on the manner of its induction. Furthermore, the NF-[kappa]B p50 subunit can exert a novel regulatory function on protein modification independent of the classical NF-[kappa]B transcriptional activity.

We aimed to determine whether nitroparacetamol (NO-paracetamol) and paracetamol exhibit cardioprotective effects. Myocardial infarction (MI) was induced in rats, and drug treatment was started 1 wk before surgery. Mortality rate and infarct size at 2 days after MI were compared. Treatment groups included vehicle (saline), paracetamol (5 mg * [kg.sup.-1] * [day.sup.-1]) and NO-paracetamol (15 mg * [kg.sup.-1] * [day.sup.-1]). Mortality rates for vehicle (n = 80), paracetamol (n = 79), and NOparacetamol (n = 76) groups were 37.5%, 21.5%, and 26.3%, respectively. Infarct size for the vehicle group was 44.8% ([+ or -] 6.1%) of the left ventricle (LV). For the paracetamol and NO-paracetamol groups, infarct size was 31.3% ([+ or -]5.6%) and 30.7% ([+ or -] 8.1%) of the LV, respectively. Both paracetamol- and NO-paracetamol-treated groups showed increased activities of catalase and SOD compared with the vehicle group. They could attenuate endothelial, inducible, and neuronal nitric oxide synthase and cyclooxygenase-1 and -2 gene expression after MI. The observation indicates the potential clinical significance of the cardioprotective effects of these drugs. infarct size; cardioprotection

Aim: Numerous studies have shown that H2S serves as an acute oxygen sensor in a variety of cells. We hypothesize that H2S also serves in extended oxygen sensing. Methods: Here, we compare the effects of extended exposure (24‐48 hours) to varying O2 tensions on H2S and polysulphide metabolism in human embryonic kidney (HEK 293), human adenocarcinomic alveolar basal epithelial (A549), human colon cancer (HTC116), bovine pulmonary artery smooth muscle, human umbilical‐derived mesenchymal stromal (stem) cells and porcine tracheal epithelium (PTE) using sulphur‐specific fluorophores and fluorometry or confocal microscopy. Results: All cells continuously produced H2S in 21% O2 and H2S production was increased at lower O2 tensions. Decreasing O2 from 21% to 10%, 5% and 1% O2 progressively increased H2S production in HEK293 cells and this was partially inhibited by a combination of inhibitors of H2S biosynthesis, aminooxyacetate, propargyl glycine and compound 3. Mitochondria appeared to be the source of much of this increase in HEK 293 cells. H2S production in all other cells and PTE increased when O2 was lowered from 21% to 5% except for HTC116 cells where 1% O2 was necessary to increase H2S, presumably reflecting the hypoxic environment in vivo. Polysulphides (H2Sn, where n = 2‐7), the key signalling metabolite of H2S also appeared to increase in many cells although this was often masked by high endogenous polysulphide concentrations. Conclusion: These results show that cellular H2S is increased during extended hypoxia and they suggest this is a continuously active O2‐sensing mechanism in a variety of cells. [ABSTRACT FROM AUTHOR]

The role of hydrogen sulfide (H2S) in myocardial infarction (MI) has not been previously studied. We therefore investigated the effect of H2S in a rat model of MI in vivo. Animals were randomly divided into three groups (n = 80) and received either vehicle, 14 μmol/kg of sodium hydrosulfide (NaHS), or 50 mg/kg propargylglycine (PAG) everyday for 1 wk before surgery, and the treatment was continued for a further 2 days after MI when the animals were killed. The mortality was 35% in vehicle-treated, 40% in PAG-treated, and 27.5% in NaHS-treated (P < 0.05 vs. vehicle) groups. Infarct size was 52.9 ± 3.5% in vehicle-treated, 62.9 ± 7.6% in PAG-treated, and 43.4 ± 2.8% in NaHS-treated (P < 0.05 vs. vehicle) groups. Plasma H2S concentration was significantly increased after MI (59.2 ± 7.16 μM) compared with the baseline concentration (i.e., 38.2 ± 2.07 μM before MI; P < 0.05). Elevated plasma H2S after MI was abolished by treatment of animals with PAG (39.2 ± 5.02 μM). We further showed for the first time cystathionine-gamma-lyase protein localization in the myocardium of the infarct area by using immunohistochemical staining. In the hypoxic vascular smooth muscle cells, we found that cell death was increased under the stimuli of hypoxia but that the increased cell death was attenuated by the pretreatment of NaHS (71 ± 1.2% cell viability in hypoxic vehicle vs. 95 ± 2.3% in nonhypoxic control; P < 0.05). In conclusion, endogenous H2S was cardioprotective in the rat model of MI. PAG reduced endogenous H2S production after M1 by inhibiting cystathionine-gamma-lyase. The results suggest that H2S might provide a novel approach to the treatment of MI. [ABSTRACT FROM AUTHOR]

We aimed to determine whether nitroparacetamol (NO-paracetamol) and paracetamol exhibit cardioprotective effects. Myocardial infarction (MI) was induced in rats, and drug treatment was started 1 wk before surgery. Mortality rate and infarct size at 2 days after MI were compared. Treatment groups included vehicle (saline), paracetamol (5 mg∙kg-1 day-1)and NO-paracetamol (15 mg∙kg-1 day-1). Mortality rates for vehicle (n = 80), paracetamol (n = 79), and NO- paracetamol (n = 76) groups were 37.5%, 21.5%, and 26.3%, respectively. Infarct size for the vehicle group was 44.8% (±6.1%) of the left ventricle (LV). For the paracetamol and NO-paracetamol groups, infarct size was 31.3% (±5.6%) and 30.7% (±8.1%) of the LV, respectively. Both paracetamol- and NO-paracetamol-treated groups showed increased activities of catalase and SOD compared with the vehicle group. They could attenuate endothelial, inducible, and neuronal nitric oxide synthase and cyclooxygenase-1 and -2 gene expression after MI. The observation indicates the potential clinical significance of the cardioprotective effects of these drugs. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (HS) has been shown to have a potential protective role in a number of disease states including diabetes and various kidney disorders; however, the mechanisms involved are still unclear. The aim of this study was to investigate if HS effects the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in human kidney cells. Human mesangial cells and human podocytes were cultured at normal physiological glucose concentration (5.5 mM) and then treated with different HS donors for a 24-h period. Protein was then extracted from the cells, and the expression levels of HO-1 determined by Western blotting. There was a significant increase in HO-1 expression after treatment with the HS donors in both mesangial and podocyte cells. These results suggest that HS has a role in the regulation of HO-1 expression, and the ability to upregulate this antioxidant enzyme maybe a potential mechanism by which HS exerts its protective effects. [ABSTRACT FROM AUTHOR]