The endogenous cellular antioxidant defense system plays an important role in protecting cells from various external and internal stresses caused by xenobiotics and drugs (1), inflammation (2), and ionizing radiation (3). The perturbation of these cytoprotective regulations causes the accumulation of reactive oxygen species or electrophilic insults contributing to the pathogenesis of various diseases such as cancer, neurodegenerative disease, and atherosclerosis. Proper detoxification is mediated by the immediate expression of antioxidant proteins and phase 2 detoxifying enzymes through the activation of antioxidant-response element (ARE) 2 -binding transcription factors (4).The ARE was first identified as cis-element in the upstream regulatory region of the GSTA2 gene (5) and was found in the promoters of detoxifying enzyme genes such as glutathione S-transferases (6), NAD(P)H:quinone oxidoreductases (NQOs) (7,8), gastrointestinal glutathione peroxidase (9), and peroxiredoxin1 (10). The ARE is recognized by a subset of Cap'n'Collarcontaining basic leucine zipper proteins, nuclear factor erythroid 2-related factors (Nrfs), including Nrf1, Nrf2, and Nrf3. Among the three protein factors, Nrf2 is most potent transcription factor in regulation of basal and induced expression of antioxidant enzyme genes (11). Gene deletion studies also supported the important function of Nrf2 in cellular protection against oxidative stress and neoplasia (12).Under homeostatic conditions, Nrf2 resides predominantly within the cytoplasm of the cells by an interaction between Nrf2 and actin-bound cytosolic protein, INrf2 (inhibitor of Nrf2) or Keap1 (Kelch-like ECH-associated protein 1) (13-15). INrf2 functions as a substrate adaptor protein for a Cul3-dependent ubiquitin-protein isopeptide ligase complex to maintain the steady-state levels of Nrf2 (16). It is also believed that Nrf2 is rapidly degraded by INrf2-mediated ubiquitination because Nrf2 is barely detected in the cytoplasm. However, the exposure to oxidative stress leads to dissociation of Nrf2 from INrf2. Nrf2 is stabilized, translocates into the nucleus, and activates transcription of a battery of antioxidant genes. Recently, the mechanisms by which Nrf2 is released from INrf2 under stress have been actively investigated. One mechanism is that antioxidantinduced protein kinase C phosphorylation of serine 40 in Nrf2 leads to dissociation of Nrf2 from INrf2 (17,18). In addition, several protein kinases, including mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and PKR-like endoplasmic reticulum kinase have also been involved in post-translational modification of Nrf2 and activation of Nrf2 (11,19). On the other hand, cysteine thiol groups of INrf2 were shown to function as sensors for oxidative stress that are modified by the chemical inducers, causing formation of disulfide bonds between cysteines of two INrf2 peptides. This results in conformational change that renders INrf2 unable to bind to Nrf2 (20,21). The free Nrf2 translocates to the nucleus and acti...
Cachexia, defined as an involuntary weight loss ≥ 5%, is a serious and dose-limiting side effect of chemotherapy that decreases survival in cancer patients. Alterations in lipid metabolism are thought to cause the lipodystrophy commonly associated with cachexia. Ghrelin has been proposed to ameliorate the alterations in lipid metabolism due to its orexigenic and anabolic properties. However, the mechanisms of action through which ghrelin could potentially ameliorate chemotherapy-associated cachexia have not been elucidated. The objectives of this study were to identify mechanisms by which the chemotherapeutic agent cisplatin alters lipid metabolism and to establish the role of ghrelin in reversing cachexia. Cisplatin-induced weight and fat loss were prevented by ghrelin. Cisplatin increased markers of lipolysis in white adipose tissue (WAT) and of β-oxidation in liver and WAT and suppressed lipogenesis in liver, WAT, and muscle. Ghrelin prevented the imbalance between lipolysis, β-oxidation, and lipogenesis in WAT and muscle. Pair-feeding experiments demonstrated that the effects of cisplatin and ghrelin on lipogenesis, but not on lipolysis and β-oxidation, were due to a reduction in food intake. Thus, ghrelin prevents cisplatin-induced weight and fat loss by restoring adipose tissue functionality. An increase in caloric intake further enhances the anabolic effects of ghrelin.
CC patients have higher inflammation and lower testosterone, grip strength, functional status, erectile function, fat mass, and appendicular lean body mass. Inflammation, TT, and albumin are associated with heavier symptom burden in this population. Interventional trials are needed to determine whether testosterone replacement and/or antiinflammatory agents benefit cancer patients.
Aldehyde reductase reduces a wide variety of toxic and physiological aldehydes with a marked preference for negatively charged substrates such as glucuronate. Reduction of glucuronate to gulonate is a step in inositol catabolism, a process specific to the kidney cortex. Administration of the aldehyde reductase inhibitor AL-1576 to mice increases urinary output of glucuronate and decreases output of vitamin C. Aldehyde reductase mRNA with a 319-bp 5′-untranslated region is expressed ubiquitously in murine tissues. A new isoform with a short 64-bp 5′-untranslated region is found predominantly in the kidney, resulting in 10-fold higher enzymatic activity observed in this organ compared with other tissues. A moderate level of the new transcript is found in liver, intestine, and stomach, whereas brain, heart, lung, spleen, ovary, and testis have low to insignificant levels. The short transcript is absent during embryonic development and is first observed in the murine kidney on postnatal day 6. The abundance of the short transcript and enzyme activity increase sigmoidally with age; the sharpest increase occurs during the third week of life. As shown by immunohistochemistry, aldehyde reductase expression is limited to the proximal tubules and parietal epithelium of Bowman’s capsule. In the mouse, the intensity of staining in tubules increases with age, suggesting that induction of aldehyde reductase expression is part of renal tubular maturation. The human kidney also exhibits proximal tubular localization and the two mRNA transcripts of aldehyde reductase. Immunoreactive protein is present in the 9-wk-old fetal kidney, indicating that the induction of aldehyde reductase in humans occurs early in development.
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