This first paragraph implies that cleaning up oxidative stress inhibits or reverses malignancy, diabetes, neurodegenerative diseases and aging.
It further shows that TNPIX is elevated in oxidative stress.
No stress low TNPIX.
Challenging stress low levels.
Overwhelming stress high levels.
TNPIX modulates ROS signaling AND has both pro oxidant and antioxidant effects dependent on level. (Interestingly melatonin has that same duality and may imply it shares TNPIX ROS modulation function.)
The article implicitly states that TNPIX declines with age.
It is firmly established that Melatonin declines with age.
High levels are associated with growth arrest and tumor suppression.
In diabetes formation TNPIX is elevated and beta cells decline (arrested.)
Challenging levels signal that "more antioxidant capacity" is needed.
Oxidative stress accelerates aging and reduces stem cells number and quality leading to stem cell exhaustion.
Does treating oxidative stress with hydrogen rich water, sulforaphane, melatonin, wheat germ spermidine reduce both aging and cancer?
Sepsis (and cardiac or respiratory failure ) is a major acute oxidative stressor. Antioxidant rescue of sepsis model animals that targets mitochondria increase survival and organ function survival acutely.
Does increasing net total antioxidant capacity protect against age related chronic oxidative stress including diabetes, neurodegenerative disease and malignancy?
TXNIP Maintains the Hematopoietic Cell Pool by Switching the Function of p53 under Oxidative Stress
Oxidative stress occurs mainly due to excessive accumulation of cellular reactive oxygen species (ROS) or deficiency of antioxidant defense system. Oxidative stress often leads to pathologic diseases such as diabetes, neurodegenerative diseases, and cancer (Hole et al., 2011, Sinha et al., 2013). There is growing evidence that balanced regulation of ROS is critical for hematopoiesis. Hematopoietic cells are vulnerable to oxidative stress, and malignancy of hematopoietic tissues is observed in the presence of chronic oxidative stress (Ghaffari, 2008). Homeostatic regulation of redox status in hematopoietic tissues is important for normal hematopoiesis.
Thioredoxin-interacting protein (TXNIP) is a 397 amino acid, 50 kDa protein that belongs to the arrestin family, and Txnip−/− mice show a high incidence of hepatocellular carcinoma (HCC) (Jeong et al., 2009, Kwon et al., 2011, Lee et al., 2005, Song et al., 2003). TXNIP expression is reduced in many types of tumors, and TXNIP overexpression inhibits tumor growth by blocking cell-cycle progression (Han et al., 2003). The numbers of natural killer (NK) cells in the bone marrow (BM) of Txnip−/− mice are reduced, and the long-term reconstituting HSC population shows an exhausted phenotype and is reduced in frequency (Jeong et al., 2009, Lee et al., 2005).
The tumor suppressor p53 plays a key role in restricting the expansion of abnormal cells through either growth arrest or apoptosis in response to genotoxic stresses (Olovnikov et al., 2009, Sablina et al., 2005). The p53 pathway is regulated by mouse double minute 2 (MDM2), an E3 ubiquitin ligase that targets the p53 protein for proteasomal degradation (Sasaki et al., 2011). p53 engages powerful prosurvival pathways by inducing the expression of antiapoptotic or antioxidant genes (Bensaad and Vousden, 2007, Jänicke et al., 2008). In addition, p53 is a critical regulator of HSC quiescence through its target genes (Liu et al., 2009). Previous reports imply that the protective or antiaging effects of TXNIP are important in maintaining hematopoietic cell pool (Jeong et al., 2009, Kim et al., 2007).
In this study, we demonstrate that Txnip−/− hematopoietic cells had defects in the regulation of ROS levels and were more sensitive than wild-type cells to oxidative stress. We also demonstrated that TXNIP exerted its antioxidant effects in hematopoietic cells by stabilizing p53 under oxidative stress. Our findings suggest that TXNIP plays a critical role in the antioxidant defense mechanisms of hematopoietic cells by activating the p53 pathway during oxidative stress.
To investigate the effects of TXNIP deficiency on hematopoiesis, we analyzed the frequency of hematopoietic stem cells (HSCs) and hematopoietic progenitors from young (12 weeks) and old (22–23 months) Txnip+/+ (wild-type [WT]) and Txnip−/− (KO) mice. Consistent with previous reports (Geiger and Van Zant, 2002, Sudo et al., 2000), old WT mice showed much higher frequencies of HSCs and hematopoietic progenitors, but old KO mice showed relatively decreased frequencies (Figure 1A). Next, we performed a competitive repopulation assay and a serial bone marrow transplantation (BMT) experiment (Figure 1B). We transplanted lineage−c-Kit+Sca-1+ (LKS) cells or WBM (whole bone marrow) cells from young (12 weeks) and old (22–23 months) mice (CD45.2+) with competitor WBM cells (CD45.1+) into congenic recipients (CD45.1+). Donor-derived cell populations of old WT LKS or WBM cell-transplanted recipients showed little change, but those of old KO LKS or WBM cell-transplanted recipients were markedly decreased (Figure 1C and Figure S1A available online). Also, WBM cells of recipients from young and old KO mice showed a greater reduction in donor-derived cell populations of HSCs and progenitors than those from WT mice (Figures 1D, S1B, and S1C), mostly due to the reduced frequency of HSCs and progenitors in donor WBM or LKS as shown in Figure 1A. Next, we performed a serial BMT experiment. Donor-derived CD45.2+ cells were dramatically decreased in the KO-derived recipient cells (Figures 1E and 1F).
The exhaustion of primitive HSCs is believed to result from increased ROS accumulation following serial transplants, which are a critical determinant of HSC pool maintenance (Abbas et al., 2010, Ito et al., 2006). We found dramatically increased ROS levels in old KO BM cells compared with those from WT littermates (Figure 2A). To assess the effects of the intrinsic increase in ROS on the maintenance of KO BM cells, we transplanted WBM cells (CD45.2+) into lethally irradiated WT congenic (CD45.1+) recipients. After 9 months, we confirmed higher levels of ROS in the KO-derived BM cells (Figure 2B). Our observations suggested that TXNIP plays a critical role in hematopoietic cell antioxidant defense through mechanisms other than its known prooxidant function as an inhibitor of thioredoxin (Trx) (Lee et al., 2005, Patwari et al., 2006, Schulze et al., 2002).
To examine the specificity of antioxidant defense by TXNIP in hematopoietic cells, we analyzed the levels of ROS in WT and KO mouse embryonic fibroblast (MEF) and lung fibroblast cells under oxidative stress. Interestingly, WT MEF and lung fibroblast cells showed the prooxidant function of TXNIP following oxidative stress (Figures S2A–S2D), indicating that TXNIP regulates ROS levels in a cell-type-specific manner. Next, to validate the antioxidant function of TXNIP in hematopoietic cells under oxidative stress, we intraperitoneally (i.p.) injected paraquat (PA), a strong oxidative stress inducer, into young mice. Consistent with our observations of old KO mice, young KO mice showed higher ROS levels and increased cell death in BM cells following PA challenge (Figures 2C and 2D). KO HSCs showed lower ROS levels than nonprimitive cells but also hypersensitivity under oxidative stress. KO HSCs entered into the cell cycle at an early time (0–12 hr) but showed decreased proliferating rates and frequencies at a late time (48–96 hr) following PA challenge (data not shown) (Macip et al., 2003). Taken together, the above data indicate that TXNIP shows cell-type-specific antioxidant function and plays an important role in the maintenance of both HSCs and nonprimitive hematopoietic cells by regulating ROS and cell death following oxidative stress.
Joseph Thomas (Tony) L
