ABSTRACT
Increased glutathione (GSH) level occurs early during liver regeneration and in many drug and/or radiation‐resistant tumors. Whether GSH level is elevated in liver cancer is unknown. GSH ...levels and expression of GSH synthetic enzymes were measured in hepatocellular carcinoma (HCC) and normal liver. GSH levels doubled in HCC. The mRNA levels of γ‐glutamylcysteine synthetase heavy subunit (GCS‐HS) and GSH synthetase (GS) doubled, whereas the expression of GCS light subunit was unchanged. Nuclear run‐on assay showed that the rate of gene transcription doubled for both GCS‐HS and GS. In HCC, there is increased binding to anti‐oxidant response, AP‐1 and NF‐ΚB, three cis‐acting elements in the 5'‐flanking region of the human GCS‐HS important for its transcriptional regulation. The role of GSH in cell growth was examined by using HepG2 cells. Cell GSH level was varied by treating cells with cystine (0 to 0.2 mM) with or without GSH ester or buthionine sulfoximine. Cell GSH level correlated directly with growth rate. Finally, preventing the increase in GSH after two‐thirds partial hepatectomy blunted liver regeneration. Thus, GSH level is increased during liver growth as a result of up‐regulation of GCS‐HS and GS. This increase, in turn, facilitates growth.
Methylation of promoter CpG islands in colorectal cancer (CRC) falls into two categories: age related and cancer specific. Most cancer-specific methylation at CpG islands occurs in a subset of cases ...that display the CpG island methylator phenotype (CIMP). The underlying cause of CIMP is not known. Using methylation-specific PCR, we studied 47 CRC patients for methylation at five loci to determine whether the methylation status of CpG islands is associated with family history of cancer. Four of the loci were differentially methylated between the CRC cases with a family history and those with no family history. Patients with methylation at all four loci were 14 times more likely to have a family history of cancer than patients with methylation at none of the four loci. These findings suggest that there may be a genetic component to CIMP in CRC.
Aims/hypothesis
Few data are available about intakes and food sources of
trans
-fatty acids (TFAs) or their associations with cardiometabolic outcomes in Asian people who consume a prudent diet but ...are experiencing rapid nutritional transitions. We aimed to investigate the relationships between TFA biomarkers and type 2 diabetes and cardiovascular risk factors in Chinese individuals.
Methods
Erythrocyte fatty acids were measured by gas chromatography among 3,107 men and women (50–70 years) recruited from urban and rural areas in Beijing and Shanghai, China.
Results
Total
trans
-18:1 and two
trans
-18:2 isomers were detected and accounted for 0.37% of the total fatty acids in the erythrocytes. Concentrations of TFAs were higher in women than men, and in urban than rural residents. Of the TFAs,
trans
-18:1, but not
trans
-18:2, showed a modest association with dairy consumption (β = 0.27), but not with other foods. After adjustment for BMI, social-demographic, lifestyle and dietary factors and other TFAs, erythrocyte
trans
-18:1 was shown to be associated with a lower risk of type 2 diabetes (OR comparing extreme first and fourth quartiles 0.68, 95% CI 0.48, 0.97,
p
trend
= 0.02), as well as 20–50% lower odds of central obesity, dyslipidaemia, hyperglycaemia, insulin resistance and chronic inflammation. In contrast,
trans
-18:2 fatty acids were positively associated with high triacylglycerol (
p
trend
< 0.001) and LDL-cholesterol (
p
trend
= 0.03) levels, but not with diabetes and other cardiometabolic risk factors.
Conclusions/interpretation
Among middle-aged and older Chinese individuals with overall low erythrocyte TFAs levels,
trans
-18:1 might serve as a marker of dairy intake. Higher
trans
-18:1 levels were associated with a lower risk of type 2 diabetes, whereas higher
trans
-18:2 levels were associated with dyslipidaemia.
After herbivore attack, many plants emit herbivore‐induced plant volatiles (HIPVs). HIPVs can attract carnivores and/or repel herbivores, thereby mediating tritrophic plant–herbivore–carnivore ...interactions. HIPVs act as chemical information between organisms; hence, their variability and stability are vital. In the present study, variations in the volatile emissions, from the tea plant Camellia sinensis (O. Ktze) damaged by the tea weevil Myllocerinus aurolineatus (Voss) (Coleoptera: Curculionidae), with weevil densities, photoperiod and infestation duration, were investigated. The volatiles induced by high‐density weevils were more abundant in composition and amount than those induced by low‐density weevils, whether at noon, night or after weevil removal. The induced volatile emissions were similar on the second and third day after infestation, and the emissions of the major induced compounds displayed diurnal cycles. Linalool, (E,E)‐α‐farnesene, and benzyl nitrile were emitted mainly at noon, whereas 1,3,8‐p‐menthatriene and (E)‐β‐ocimene were maximally emitted at night. Given the different emission dynamics, significant differences were found between noon‐ and night‐induced volatiles. In summary, tea plants damaged by different weevil densities emitted a relatively stable signal at a particular time. This stability could be attributed to the similarities under the two densities of the main induced volatile compounds, their relative ratios and the emission dynamics of the induced volatiles.
S-adenosylmethionine (AdoMet) is an essential compound in cellular transmethylation reactions and a precursor of polyamine and glutathione synthesis in the liver. In liver injury, the synthesis of ...AdoMet is impaired and its availability limited. AdoMet administration attenuates experimental liver damage, improves survival of alcoholic patients with cirrhosis, and prevents experimental hepatocarcinogenesis. Apoptosis contributes to different liver injuries, many of which are protected by AdoMet. The mechanism of AdoMet's hepatoprotective and chemopreventive effects are largely unknown. The effect of AdoMet on okadaic acid (OA)-induced apoptosis was evaluated using primary cultures of rat hepatocytes and human hepatoma cell lines. AdoMet protected rat hepatocytes from OA-induced apoptosis dose dependently. It attenuated mitochondrial cytochrome c release, caspase 3 activation, and poly(ADP-ribose) polymerase cleavage. These effects were independent from AdoMet-dependent glutathione synthesis, and mimicked by 5'-methylthioadenosine (MTA), which is derived from AdoMet. Interestingly, AdoMet and MTA did not protect HuH7 cells from OA-induced apoptosis; conversely both compounds behaved as proapoptotic agents. AdoMet's proapoptotic effect was dose dependent and observed also in HepG2 cells. In conclusion, AdoMet exerts opposing effects on apoptosis in normal versus transformed hepatocytes that could be mediated through its conversion to MTA. These effects may participate in the hepatoprotective and chemopreventive properties of this safe and well-tolerated drug. (HEPATOLOGY .)
Our previous studies and the others have strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in ischemic brain injury. Here we reported that Tat-JNK binding ...domain (JBD) of JNK-interacting protein-1 (JIP-1), a smaller 11-mer peptide corresponding to residues 153–163 of murine JIP-1 conjugated to Tat peptide, perturbed the assembly of JIP-1–JNK3 complexes, thus inhibiting the activation of JNK3 induced by ischemia/reperfusion in the vulnerable hippocampal CA1 subregion. As a result, Tat-JBD diminished the increased phosphorylation of c-Jun (a nuclear substrate of JNK) and the increased expression of Fas ligand induced by ischemia/reperfusion in the vulnerable hippocampal CA1 subregion. At the same time, through inhibiting phosphorylation of Bcl-2 (a cytosolic target of JNK) and the release of Bax from Bcl-2/Bax dimers, Tat-JBD attenuated Bax translocation to mitochondria and the release of cytochrome c induced by ischemia/reperfusion. Furthermore, the activation of caspase3 and hydrolyzation of poly-ADP-ribose-polymerase induced by brain ischemia/reperfusion were also significantly suppressed by preinfusion of the peptide Tat-JBD. Importantly, Tat-JBD showed neuroprotective effects on ischemic brain damage
in vivo, and administration of the peptide after ischemia also achieved the same effects as preinfusion of the peptide did. Thus, our findings imply that Tat-JBD induced neuroprotection against ischemia/reperfusion in rat hippocampal CA1 region via inhibiting nuclear and non-nuclear pathways of JNK signaling. Taken together, these results indicate that Tat-JBD peptide provides a promising therapeutic approach for ischemic brain injury.
The crystal structures of two group III alpha-like toxins from the scorpion Buthus martensii Karsch, BmK M1 and BmK M4, were determined at 1.7 A and 1.3 A resolution and refined to R factors of 0.169 ...and 0.166, respectively. The first high-resolution structures of the alpha-like scorpion toxin show some striking features compared with structures of the "classical" alpha-toxin. Firstly, a non-proline cis peptide bond between residues 9 and 10 unusually occurs in the five-member reverse turn 8-12. Secondly, the cis peptide 9-10 mediates the spatial relationship between the turn 8-12 and the C-terminal stretch 58-64 through a pair of main-chain hydrogen bonds between residues 10 and 64 to form a unique tertiary arrangement which features the special orientation of the terminal residues 62-64. Finally, in consequence of the peculiar orientation of the C-terminal residues, the functional groups of Arg58, which are crucial for the toxin-receptor interaction, are exposed and accessible in BmK M1 and M4 rather than buried as in the classical alpha-toxins. Sequence alignment and characteristics analysis suggested that the above structural features observed in BmK M1 and M4 occur in all group III alpha-like toxins. Recently, some group III alpha-like toxins were demonstrated to occupy a receptor site different from the classical alpha-toxin. Therefore, the distinct structural features of BmK M1 and M4 presented here may provide the structural basis for the newly recognized toxin-receptor binding site selectivity. Besides, the non-proline cis peptide bonds found in these two structures play a role in the formation of the structural characteristics and in keeping accurate positions of the functionally crucial residues. This manifested a way to achieve high levels of molecular specificity and atomic precision through the strained backbone geometry.
Female athletes are two to eight times more likely to suffer a knee or ankle ligament injury than male athletes, and sex hormones have been considered to play an important role in the injury. Because ...ligaments are always under mechanical loading during sports, mechanical force is also a critical factor in ligament injuries. In this study, the effects of estrogen and mechanical loading on the gene expression of three major components of ligament—collagen type I, type III, and biglycan—in primary cultured porcine anterior cruciate ligament (ACL) fibroblasts were investigated individually and collectively using reverse transcript-polymerase chain reaction (RT-PCR). The results revealed that cyclic tensile loading alone increased the messenger RNA expression of collagen I but did not affect that of collagen III and biglycan, and estrogen alone increased the gene expression of collagen I and III but not of biglycan. However, combined administration of estrogen and cyclic loading inhibited the mRNA expression of all the three genes. These results suggested that the inhibition of the gene expression of major extracellular matrix component molecules caused by the combined effects of estrogen and mechanical loading, unique to females, might be responsible for the increased incidence of ligaments injury in female athletes.
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