In Schizosaccharomyces pombe, alcohol dehydrogenase 1 (Adh1) is an abundant zinc-requiring enzyme that catalyses the conversion of acetaldehyde to ethanol during fermentation. In a zinc-replete cell, adh1 is highly expressed. However, in zinc-limited cells, adh1 gene expression is repressed, and cells induce the expression of an alternative alcohol dehydrogenase encoded by the adh4 gene. In our studies examining this zinc-dependent switch in alcohol dehydrogenase gene expression, we isolated an adh1Δ strain containing a partial loss of function mutation that resulted in higher levels of adh4 transcripts in zinc-replete cells. This mutation also led to the aberrant expression of other genes that are typically regulated by zinc. Using linkage analysis, we have mapped the position of this mutation to a single gene called Loss Of Zinc sensing 1 (loz1). Loz1 is a 55-kDa protein that contains a double C 2 H 2 -type zinc finger domain. The mapped mutation that disrupts Loz1 function leads to an arginine to glycine substitution in the second zinc finger domain, suggesting that the double zinc finger domain is important for Loz1 function. We show that loz1Δ cells hyperaccumulate zinc and that Loz1 is required for gene repression in zinc-replete cells. We also have found that Loz1 negatively autoregulates its own expression. We propose that Loz1 is a unique metalloregulatory factor that plays a central role in zinc homeostasis in S. pombe. metallosensor | metallothionein | ncRNA | noncoding RNA
Acute kidney injury (AKI) is a severe complication of sepsis. High-mobility group box (HMGB)-1 was implicated as a late mediator of lethal systemic inflammation in sepsis. Since glutamine (GLN) was shown to have anti-inflammatory and antioxidant properties, we hypothesized that GLN administration may downregulate an HMGB-1-mediated pathway and thus ameliorate sepsis-induced AKI. Mice were randomly assigned to a normal group (NC), a septic saline group (SS), or a septic GLN group (SG). Sepsis was induced by cecal ligation and puncture (CLP). The SS group was injected with saline, and the SG group was given 0.75 g GLN/kg body wt once via a tail vein 1 h after CLP. Mice were killed 2, 6, and 24 h after CLP, and blood and kidneys of the animals were harvested for further analysis. The results showed that sepsis resulted in higher mRNA and/or protein expressions of kidney HMGB-1, toll-like receptor (TLR) 4, myeloid differentiation primary-response protein (MyD) 88, and receptor of advanced glycation end products (RAGE) compared with normal mice. Septic mice with GLN administration exhibited decreased HMGB-1, TLR4, RAGE, and phosphorylated NF-κB p65 protein expressions and reduced nitrotyrosine levels in kidney tissues. The histological findings showed that damage to the kidneys was less severe, and survival improved in the SG group. These results indicated that a single dose of GLN administered after the initiation of sepsis plays a prophylactic role in downregulating the expressions of HMGB-1-related mediators and decreasing oxidative stress in the kidneys, which may consequently have ameliorated AKI induced by sepsis.
These findings suggest that a single dose of GLN administration in either the early or late phase during sepsis promotes a more balanced immune regulation and reduced systemic and kidney inflammatory responses in mice.
This study investigated the effects of glutamine (GLN) administration on regulating lung γδ T cells in polymicrobial sepsis. Mice were randomly assigned to normal group (NC), septic saline group (SS), and septic GLN group (SG). All mice were fed with chow diet. Sepsis was induced by cecal ligation and puncture (CLP). The SS and SG groups were, respectively, injected with saline and 0.75 g GLN/kg body weight once via tail vein 1 h after CLP. Mice were killed 12 and 24 h after CLP. Their lungs were collected for further analysis. The results showed that, compared with normal mice, sepsis resulted in higher lung γδ T cell and neutrophil percentages and higher cytokine expressed by γδ T cells. Histopathologic findings showed that the extent of inflammatory lesions of the lung alveolar was less severe in the SG group than the SS group after CLP. The SG group had a higher γδ T cell percentage and lower γδ T cell apoptotic rates as well as lower neutrophil numbers in the lungs. Also, interleukin 17A (IL-17A), interferon γ, and IL-10 expressed by γδ T cells and CXC receptor 2 expressed by neutrophils decreased in the SG group. Moreover, GLN reduced IL-17A, IL-1β, and IL-23 concentrations and myeloperoxidase activity in lung tissues. Our results suggest that GLN administration after initiation of sepsis affects lung γδ T cell percentage and cytokine secretion and prevented apoptosis of γδ T cells and neutrophil infiltration to the lungs, which may partly be responsible for ameliorating acute lung injury induced by sepsis.
Zinc is an essential trace element that is required for the function of a large number of proteins. As these zinc-binding proteins are found within the cytosol and organelles, all eukaryotes require mechanisms to ensure that zinc is delivered to organelles, even under conditions of zinc deficiency. Although many zinc transporters belonging to the Cation Diffusion Facilitator (CDF) families have well characterized roles in transporting zinc into the lumens of intracellular compartments, relatively little is known about the mechanisms that maintain organelle zinc homeostasis. The fission yeast Schizosaccharomyces pombe is a useful model system to study organelle zinc homeostasis as it expresses three CDF family members that transport zinc out of the cytosol into intracellular compartments: Zhf1, Cis4, and Zrg17. Zhf1 transports zinc into the endoplasmic reticulum, and Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. Here we have used the high and low affinity ZapCY zinc-responsive FRET sensors to examine cytosolic zinc levels in yeast mutants that lack each of these CDF proteins. We find that deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency, whereas deletion of zhf1 results in zinc accumulating in the cytosol when zinc is not limiting. We also show that the expression of cis4, zrg17, and zhf1 is independent of cellular zinc status. Taken together our results suggest that the Cis4/Zrg17 complex is necessary for zinc transport out of the cytosol under conditions of zinc-deficiency, while Zhf1 plays the dominant role in removing zinc from the cytosol when labile zinc is present. We propose that the properties and/or activities of individual CDF family members are fine-tuned to enable cells to control the flux of zinc out of the cytosol over a broad range of environmental zinc stress.
This study investigated the effect of glutamine (GLN) on intestinal intraepithelial lymphocyte (IEL) γδT-cell cytokines and immune regulatory factor gene expressions in a mouse model of polymicrobial sepsis. Mice were randomly assigned to a normal group, a sepsis with saline (SS) group, or a sepsis with GLN (SG) group. All mice were fed a chow diet. Sepsis was induced by cecal ligation and puncture (CLP). The SS group was injected with saline, and the SG group was given 0.75 g GLN/kg body weight once via a tail vein 1 h after CLP. Septic mice were killed 12 h after CLP, and IEL γδT cells of the animals were isolated for further analysis. Results showed that compared with normal mice, sepsis resulted in lower IEL γδT-cell percentage and higher messenger RNA expressions of interferon γ, tumor necrosis factor α, interleukin 4 (IL-4), IL-13, IL-17, retinoid acid receptor-related orphan receptor γt, and complement 5a receptor by IEL γδT cells. These immunomodulatory mediator genes exhibited decreases, whereas IL-7 receptor expression increased in IEL γδT cells in septic mice with GLN administration. Annexin V/7-amino-actinomycin D stain revealed significantly lower rates of apoptosis, and IEL γδT-cell percentage was higher in the SG group. The histological findings also showed that damage to intestinal epithelial cells was less severe in the SG group. These results indicated that a single dose of GLN administered as treatment after the initiation of sepsis prevented apoptosis of IEL γδT cells and downregulated γδT cell-expressed inflammatory mediators that may consequently ameliorate the severity of sepsis-induced intestinal epithelial injury.
The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients’ progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.
Acute lung injury (ALI) is a critical syndrome associated with respiratory dysfunction, and neutrophils are considered to be central to the pathogenesis of ALI. This study investigated the effects of glutamine (Gln) on neutrophil recruitment in a model of lipopolysaccharide (LPS)-induced ALI. C57BL/6 mice were fed a standard diet either with casein as the nitrogen source or with 25% of total nitrogen replaced by Gln. After 10 days, intratracheal instillation of LPS was used to induce ALI. Mice were killed at 0, 6, 12, and 24 h after LPS administration (n = 10/group). Bronchoalveolar lavage fluid and lung tissues were collected for further analysis. The results showed that, compared with the control group, lipid peroxide levels in the lungs were higher at 12 and 24 h after LPS administration in the Gln group. CXC chemokines as well as tumor necrosis factor-alpha were significantly elevated and reached peaks at 6 h in the Gln group, which was earlier than in the control group. Histopathological findings showed that the thickening of alveolar septal space was extensive in the Gln group 24 h and 2 wk after LPS. Also, greater amounts of collagen had accumulated in lung tissue in the Gln group. This study indicates that dietary Gln administration resulted in higher inflammatory cytokine production, with more neutrophils recruited at the early stage of ALI. These results were consistent with the histopathological findings that Gln supplementation causes more severe interstitial inflammation and fibrosis in a model of ALI induced by LPS.
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