Stress-induced Growth Research Articles

Genomic analysis of xCT-mediated regulatory network: Identification of novel targets against AIDS-associated lymphoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), a rapidly progressing malignancy mostly arising in HIV-infected patients. Even under conventional chemotherapy, PEL continues to portend nearly 100% mortality within several months, which urgently requires novel therapeutic strategies. We have previously demonstrated that targeting xCT, an amino acid transporter for cystine/glutamate exchange, induces significant PEL cell apoptosis through regulation of multiple host and viral factors. More importantly, one of xCT selective inhibitors, Sulfasalazine (SASP), effectively prevents PEL tumor progression in an immune-deficient xenograft model. In the current study, we use Illumina microarray to explore the profile of genes altered by SASP treatment within 3 KSHV(+) PEL cell-lines, and discover that many genes involved in oxidative stress/antioxidant defense system, apoptosis/anti-apoptosis/cell death, and cellular response to unfolded proteins/topologically incorrect proteins are potentially regulated by xCT. We further validate 2 downstream candidates, OSGIN1 (oxidative stress-induced growth inhibitor 1) and XRCC5 (X-ray repair cross-complementing protein 5), and evaluate their functional relationship with PEL cell survival/proliferation and chemoresistance, respectively. Together, our data indicate that targeting these novel xCT-regulated downstream genes may represent a promising new therapeutic strategy against PEL and/or other AIDS-related lymphoma.

A mechanism of grain growth-assisted intergranular fatigue fracture in electrodeposited nanocrystalline nickel–phosphorus alloy

Quantitative investigation of the grain growth and resultant change in grain boundary microstructure during high-cycle fatigue was performed to understand intergranular fatigue fracture in electrodeposited nanocrystalline Ni – 2.0mass% P alloys by using FE-SEM/EBSD technique. Pre-fatigued specimens had an average grain size of 45nm, a sharp {001} texture and a high fraction of low-angle boundaries and of twin, or Σ3 coincidence site lattice (CSL) boundaries. The considerable grain growth occurred due to the migration of low-angle boundaries induced by shear stress during cyclic deformation. The misorientation angle of those low-angle boundaries increased covering the whole surface of fatigue-fractured specimen. A certain fraction of low-angle boundaries was transformed into high-angle random boundaries resultant from grain growth during high-cycle fatigue. Those random boundaries which surrounded the grown {001}-grains were aligned along shear bands at almost 45° to the stress axis, and formed the diamond-shaped grain configuration, as reported in the literature on high temperature fatigue. The reported increase of the fatigue limit by nanocrystallization is likely reduced due to the cyclic stress-induced grain growth associated with the migration of low-angle boundaries composing nanograin cluster. Moreover, the random boundaries transformed from low-angle boundaries can be preferential sites for crack nucleation and propagation at the positions of initially formed shear bands during fatigue.

Root-applied brassinolide can alleviate the NaCl injuries on cotton

Brassinolide (BL) is a plant growth regulator. This study analyzes the effects of BL on cotton growth, Na+ accumulation, proline content, MDA content, antioxidant enzyme activities, and differentially expressed genes (DEGs) of cotton roots under NaCl stress. We grew two cotton cultivars, Sumian 12 (salt sensitive) and Sumian 22 (salt tolerant), in continuously aerated Hoagland’s nutrient solution supplemented with 200 mM NaCl. NaCl stress increased the Na+, proline, and MDA content and decreased root activity and protein content in the roots of Sumian 12 and 22, and the change rang of Sumian 12 was higher than that of Sumian 22. The application of BL counteracted the NaCl stress-induced growth inhibition in the two tested cotton cultivars. It reduced the accumulation of Na+, enhanced proline content, and resulted in an overall change in the activities of antioxidant enzymes causing a decrease in the MDA content of NaCl-stressed roots, and the influence of BL on salt-stressed Sumian 12 plants was more pronounced than that on Sumian 22. The digital gene expression analysis in Sumian 12 indicated that BL application significantly influenced the gene expression in NaCl-stressed roots. The majority of 7659 (3661 up-regulated/3998 down-regulated) DEGs of NaCl/CK in roots of Sumian 12 were regulated by BL, and the gene expression pattern as a result of the root-applied BL on NaCl-stressed cotton treatment (BL + NaCl) was similar to the control. Our results indicate that the root-applied brassinolide alleviates NaCl stress on cotton through improving root activity, physiology, and gene expression.

Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth.

Increased adrenergic signaling facilitates tumor progression, but the underlying mechanisms remain poorly understood. We examined factors responsible for stress-mediated effects on monocyte/macrophage recruitment into the tumor microenvironment, and the resultant effects on tumor growth. In vitro, MCP1 was significantly increased after catecholamine exposure, which was mediated by cAMP and PKA. Tumor samples from mice subjected to daily restraint stress had elevated MCP1 gene and protein levels, increased CD14+ cells, and increased infiltration of CD68+ cells. hMCP1 siRNA-DOPC nanoparticles significantly abrogated daily restraint stress-induced tumor growth and inhibited infiltration of CD68+ and F4/80+ cells. In ovarian cancer patients, elevated peripheral blood monocytes and tumoral macrophages were associated with worse overall survival. Collectively, we demonstrate that increased adrenergic signaling is associated with macrophage infiltration and mediated by tumor cell-derived MCP1 production.

Translating thyroid hormone effects into clinical practice: the relevance of thyroid hormone receptor α1 in cardiac repair.

Thyroid hormone (TH) appears to have a critical role in cardiac repair after injury beyond its role in development and metabolism homeostasis. This unique action is due to the fact that TH effect on the heart is shown to be differentiated depending on its administration on injured or healthy myocardium. Thus, TH can limit ischemia-reperfusion injury via a fine balance between pro-apoptotic and pro-survival signaling pathways. This response is thyroid hormone receptor (TRα1) dependent. Furthermore, an interaction between stress-induced growth kinase signaling and TRα1 is shown to occur and determine postischemic remodeling and cardiac recovery depending on the availability of TH. This new evidence is consistent with clinical observations showing the cardioprotective effect of TH treatment in cardiac surgery, transplantation and heart failure. TH and/or thyroid analogs may be novel agents in treating heart diseases.

Stress-induced growth of aluminum nanowires with a range of cross-sections

The use of aluminum (Al) as a plasmonic building block has drawn increasing attention of late, due to its natural abundance, and extended tunability into the ultraviolet range. However, a controllable way to grow Al nanowires (NWs) in a bottom-up manner has not been reported. Here a facile, stress-induced growth process for Al nanowires, influenced by the concentration of applied hydrofluoric acid, is reported. Physical characterizations show the nanowires to be polycrystalline fcc Al with ultrasmooth surfaces, with many possible cross-section geometries, making them potential candidates for Al plasmonic investigations and applications. Dark-field optical analysis of a crescent-shaped Al NW demonstrates its plasmonic nature. These results may stimulate new interest in the fabrication of unconventional, nearly one dimensional Al nanostructures.

An analytical model for stress-induced grain growth in the presence of both second-phase particles and solute segregation at grain boundaries

A theoretical framework that incorporates the influence of second-phase particles and solute segregation at grain boundaries (GBs) on stress-induced GB migration and grain rotation is formulated in the present paper. In our work, we modified the well-established Cahn–Taylor model to account for the drag stresses generated by second-phase particles and by solute atoms segregated at GBs. The theoretical framework is then implemented to rationalize GB migration and grain rotation using experimental data from a previously published study on stress-induced grain growth in the presence of both second-phase particles and solute segregation at GBs. The calculated grain growth results are generally consistent with the experimental data, providing support to the proposed theoretical model, despite the various assumptions involved. Moreover, the influence of second-phase particles and solute segregation at GBs on GB migration and grain rotation was also investigated using the model, and our results suggest that both second-phase particles and solute atoms segregated at GBs reduce the velocities of GB migration and grain rotation as compared to those in the case of high-purity Al.

Erratum to: Stress-Induced Grain Growth in an Ultra-Fine Grained Al Alloy

This paper reports on a study of the stress-induced grain growth phenomenon in the presence of second-phase particles and solutes segregated at grain boundaries (GBs) during high-temperature deformation of an ultra-fine grained (UFG) Al alloy synthesized via the consolidation of mechanically milled powders. Our results show that grain growth was essentially inhibited during annealing at 673 K (400 °C) in the absence of an externally applied stress, whereas in contrast, grain growth was enhanced by a factor of approximately 2.7 during extrusion at 673 K (400 °C). These results suggest that significant grain growth during hot extrusion was attributable to the externally applied stresses stemming from the state of stress imposed during extrusion and that the externally applied stresses can overcome the resistance forces generated by second-phase particles and solutes segregated at GBs. The mechanisms underlying stress-induced grain growth were identified as GB migration and grain rotation, which were accompanied by dynamic recovery and possible geometric dynamic recrystallization, while discontinuous dynamic recrystallization did not appear to be operative.

Reduction of the chronic stress response by inhalation of hiba (Thujopsis dolabrata) essential oil in rats.

To verify the effects of hiba essential oil in restrained stressed rats, we analyzed physiological variables and psychophysiological behavior. Stressed-HEO rats inhaled hiba essential oil aroma after restraint period. The quantities of food and water intake and the excretion amount of stressed rats were smaller than those of non-stressed control rats. Body weights of stressed rats decreased compared with those of control rats. These physiological variables of stress-HEO rats significantly recovered compared with those of stressed rats (P < 0.001). Stress-related anxiety was assessed using the elevated plus-maze test. Entry times into the open arms of stressed rats were less than those of control rats (P < 0.05). In contrast, the suppression of entry times into the open arms of stressed rats was restored by the inhalation of hiba oil. The results suggest that hiba essential oil inhalation reduced stress-induced growth inhibition and stress-related anxiety.

Salt stress-induced seedling growth inhibition coincides with differential distribution of serotonin and melatonin in sunflower seedling roots and cotyledons.

Indoleamines regulate a variety of physiological functions during the growth, morphogenesis and stress-induced responses in plants. Present investigations report the effect of NaCl stress on endogenous serotonin and melatonin accumulation and their differential spatial distribution in sunflower (Helianthus annuus) seedling roots and cotyledons using HPLC and immunohistochemical techniques, respectively. Exogenous serotonin and melatonin treatments lead to variable effect on hypocotyl elongation and root growth under NaCl stress. NaCl stress for 48 h increases endogenous serotonin and melatonin content in roots and cotyledons, thus indicating their involvement in salt-induced long distance signaling from roots to cotyledons. Salt stress-induced accumulation of serotonin and melatonin exhibits differential distribution in the vascular bundles and cortex in the differentiating zones of the primary roots, suggesting their compartmentalization in the growing region of roots. Serotonin and melatonin accumulation in oil body rich cells of salt-treated seedling cotyledons correlates with longer retention of oil bodies in the cotyledons. Present investigations indicate the possible role of serotonin and melatonin in regulating root growth during salt stress in sunflower. Effect of exogenous serotonin and melatonin treatments (15 μM) on sunflower seedlings grown in the absence or presence of 120 mM NaCl substantiates their role on seedling growth. Auxin and serotonin biosynthesis are coupled to the common precursor tryptophan. Salt stress-induced root growth inhibition, thus pertains to partial impairment of auxin functions caused by increased serotonin biosynthesis. In seedling cotyledons, NaCl stress modulates the activity of N-acetylserotonin O-methyltransferase (HIOMT; EC 2.1.1.4), the enzyme responsible for melatonin biosynthesis from N-acetylserotonin.

Influence of the magnitude and direction of applied elastic stress on the transport properties of (La0.4Pr0.6)0.67Ca0.33MnO3 thin films

We measured the electrical transport properties of single crystalline (La0.4Pr0.6)0.67Ca0.33MnO3 films grown on NdGaO3 (110) substrates as functions of temperature and applied stress. The metal-to-insulator transition (MIT) shifts to higher temperature with compressive stress and lower temperature with tensile stress. The resistance of the film in the metallic phase was strongly dependent upon the sign and direction of applied stress. We observed anisotropy in the responses of the MIT and resistance in the sample plane with current. The observed anisotropic response of the resistance to the bending stress can be explained by stress-induced rotation and growth of stripe ferromagnetic (metallic) domains.

Structural, electronic transport and magnetoresistance of a 142nm lead telluride nanowire synthesized using stress-induced growth

In this study, structurally uniform single crystalline PbTe nanowires (NWs) were synthesized using a stress-induced growth. Selected-area electron diffraction patterns show that the PbTe NWs were grown along the [100] direction. The electrical conductivity σ of a NW with 142 nm in diameter exhibited a semiconducting behavior at 50–300 K. An enhancement of electrical conductivity σ up to 2383 S m−1 at 300 K is much higher than σ [0.44–1526 S m−1, Chen et al., Appl. Phys. Lett. 103, p023115, (2013)] in previous studies. The room temperature magnetoresistance of the 142 nm NW was ∼0.8% at B = 2 T, which is considerably higher than that [0.2% at B = 2 T, Ovsyannikov et al., Sol. State Comm. 126, 373, (2003)] of the PbTe bulk reported.

Hierarchical Functional Specificity of Cytosolic Heat Shock Protein 70 (Hsp70) Nucleotide Exchange Factors in Yeast

Heat shock protein 70 (Hsp70) molecular chaperones play critical roles in protein homeostasis. In the budding yeast Saccharomyces cerevisiae, cytosolic Hsp70 interacts with up to three types of nucleotide exchange factors (NEFs) homologous to human counterparts: Sse1/Sse2 (Heat shock protein 110 (Hsp110)), Fes1 (HspBP1), and Snl1 (Bag-1). All three NEFs stimulate ADP release; however, it is unclear why multiple distinct families have been maintained throughout eukaryotic evolution. In this study we investigate NEF roles in Hsp70 cell biology using an isogenic combinatorial collection of NEF deletion mutants. Utilizing well characterized model substrates, we find that Sse1 participates in most Hsp70-mediated processes and is of particular importance in protein biogenesis and degradation, whereas Fes1 contributes to a minimal extent. Surprisingly, disaggregation and resolubilization of thermally denatured firefly luciferase occurred independently of NEF activity. Simultaneous deletion of SSE1 and FES1 resulted in constitutive activation of heat shock protein expression mediated by the transcription factor Hsf1, suggesting that these two factors are important for modulating stress response. Fes1 was found to interact in vivo preferentially with the Ssa family of cytosolic Hsp70 and not the co-translational Ssb homolog, consistent with the lack of cold sensitivity and protein biogenesis phenotypes for fes1Δ cells. No significant consequence could be attributed to deletion of the minor Hsp110 SSE2 or the Bag homolog SNL1. Together, these lines of investigation provide a comparative analysis of NEF function in yeast that implies Hsp110 is the principal NEF for cytosolic Hsp70, making it an ideal candidate for therapeutic intervention in human protein folding disorders.

Stress-Induced Grain Growth in an Ultra-Fine Grained Al Alloy

This paper reports on a study of the stress-induced grain growth phenomenon in the presence of second-phase particles and solutes segregated at grain boundaries (GBs) during high-temperature deformation of an ultra-fine grained (UFG) Al alloy synthesized via the consolidation of mechanically milled powders. Our results show that grain growth was essentially inhibited during annealing at 673 K (400 °C) in the absence of an externally applied stress, whereas in contrast, grain growth was enhanced by a factor of approximately 2.7 during extrusion at 673 K (400 °C). These results suggest that significant grain growth during hot extrusion was attributable to the externally applied stresses stemming from the state of stress imposed during extrusion and that the externally applied stresses can overcome the resistance forces generated by second-phase particles and solutes segregated at GBs. The mechanisms underlying stress-induced grain growth were identified as GB migration and grain rotation, which were accompanied by dynamic recovery and possible geometric dynamic recrystallization, while discontinuous dynamic recrystallization did not appear to be operative.

Stress-Induced Grain Growth in an Ultra-Fine Grained Al Alloy

This paper reports on a study of the stress-induced grain growth phenomenon in the presence of second-phase particles and solutes segregated at grain boundaries (GBs) during high-temperature deformation of an ultra-fine grained (UFG) Al alloy synthesized via the consolidation of mechanically milled powders. Our results show that grain growth was essentially inhibited during annealing at 673 K (400 °C) in the absence of an externally applied stress, whereas in contrast, grain growth was enhanced by a factor of approximately 2.7 during extrusion at 673 K (400 °C). These results suggest that significant grain growth during hot extrusion was attributable to the externally applied stresses stemming from the state of stress imposed during extrusion and that the externally applied stresses can overcome the resistance forces generated by second-phase particles and solutes segregated at GBs. The mechanisms underlying stress-induced grain growth were identified as GB migration and grain rotation, which were accompanied by dynamic recovery and possible geometric dynamic recrystallization, while discontinuous dynamic recrystallization did not appear to be operative.

Calcineurin inhibitors suppress the high-temperature stress sensitivity of the yeast ubiquitin ligase Rsp5 mutant: a new method of screening for calcineurin inhibitors.

The ubiquitin/proteasome system plays significant and important roles in the regulation of metabolism of various proteins. The dysfunction of this system is involved in several diseases, for example, cancer, neurogenic diseases and chronic inflammation. Therefore, the compounds, which regulate the ubiquitin/proteasome system, might be candidates for the development use as clinical drugs. The Saccharomyces cerevisiae mutant (rsp5(A401E)) has a single amino acid change, Ala401Glu, in the RSP5 gene, which encodes an essential E3 ubiquitin ligase, is hypersensitive to high-temperature stress. Here, we found that the immunosuppressants FK506 and cyclosporin A, both known as calcineurin inhibitors, complemented the high-temperature stress-induced growth defect of rsp5(A401E) strain. The defect of calcineurin pathway by disrupting the CNB1 and CRZ1 gene also partially complemented the high-temperature stress sensitivity of rsp5(A401E) cells. Thus, these results suggest that inhibition of the calcineurin pathway confers the tolerance to high-temperature stress on rsp5(A401E) cells. Furthermore, some diterpenoid compounds, which restore the growth of rsp5(A401E) cells, showed the activities of calcineurin inhibition and protein phosphatase 2C activation. These results indicate that calcineurin inhibitors suppress the high-temperature stress sensitivity of rsp5(A401E) cells and that analysis of their physiological function is effective for the screening of calcineurin inhibitors in yeast cells.

Stress-induced grain growth during high-temperature deformation of nanostructured Al containing nanoscale oxide particles

In this study we analyze the phenomenon of stress-induced grain growth in nanostructured Al containing a high volume fraction of nanoscale oxide particles during high-temperature extrusion. Our results show that in the absence of an externally applied stress, grain growth was essentially inhibited during annealing at 600°C. In contrast, when the same material was extruded at 400°C, the grains increased in size by a factor of 2.2 relative to the initial microstructure. The experimental results were analyzed on the basis of the mechanisms that govern grain growth. We discuss the role of grain boundary (GB) migration, grain rotation, discontinuous dynamic recrystallization and geometric dynamic recrystallization on stress-induced grain growth. Finally, the influence of nanoscale oxide particles on GB migration and grain rotation was rationalized on the basis of a theoretical model.

Allele-Specific Imbalance of Oxidative Stress-Induced Growth Inhibitor 1 Associates With Progression of Hepatocellular Carcinoma

Although there are a few highly penetrant mutations that are linked directly to cancer initiation, more less-penetrant susceptibility alleles have been associated with cancer risk and progression. We used RNA sequence analysis to search for genetic variations associated with pathogenesis of hepatocellular carcinoma (HCC). We analyzed 400 paired HCC and adjacent nontumor tissues, along with clinical information, from patients who underwent surgery at Sun Yat-Sen University in Guangzhou, China. Total RNA was extracted from tissues and sequenced, and variations with allele imbalance were identified. Effects of variants on cell functions were investigated in HCC cell lines and tumor xenografts in mice. Variants were associated with patient outcomes. We found a high proportion of allele imbalance in genes related to cellular stress. A nucleotide variation in the Oxidative Stress-Induced Growth Inhibitor 1 (OSGIN1) gene (nt 1494: G-A) resulted in an amino acid substitution (codon 438: Arg-His). The variant form of OSGIN1 was specifically retained in the tumor tissues. Functional assays showed that the common form of OSGIN1 functioned as a tumor suppressor, sensitizing HCC cells to chemotherapeutic agents by inducing apoptosis. However, the variant form of OSGIN1 was less effective. It appeared to affect the translocation of OSGIN1 from the nucleus to mitochondria, which is important for its apoptotic function. The expression pattern and localization of OSGIN1 was altered in HCC specimens, compared with adjacent liver tissue. Levels of OSGIN1 messenger RNA were reduced in 24.7% of HCC specimens, and down-regulation was associated with shorter overall and disease-free survival times of patients. Patients with the OSGIN1 1494A variant had the shortest mean survival time (32.68 mo) among patient subgroups, and their tumor samples had the lowest apoptotic index. We identified OSGIN1 as a tumor suppressor that is down-regulated or altered in human HCCs. Variants of OSGIN1 detected in HCC samples reduce apoptosis and are associated with shorter survival times of patients.

Does Our “Flight and Fight” Response Have a Link With Cancer?

Does Our “Flight and Fight” Response Have a Link With Cancer?

Changes in translation rate modulate stress-induced damage of diverse proteins

Proteostasis is the maintenance of the proper function of cellular proteins. Hypertonic stress disrupts proteostasis and causes rapid and widespread protein aggregation and misfolding in the nematode Caenorhabditis elegans. Optimal survival in hypertonic environments requires degradation of damaged proteins. Inhibition of protein synthesis occurs in response to diverse environmental stressors and may function in part to minimize stress-induced protein damage. We recently tested this idea directly and demonstrated that translation inhibition by acute exposure to cycloheximide suppresses hypertonicity-induced aggregation of polyglutamine::YFP (Q35::YFP) in body wall muscle cells. In this article, we further characterized the relationship between protein synthesis and hypertonic stress-induced protein damage. We demonstrate that inhibition of translation reduces hypertonic stress-induced formation and growth of Q35::YFP, Q44::YFP, and α-synuclein aggregates; misfolding of paramyosin and ras GTPase; and aggregation of multiple endogenous proteins expressed in diverse cell types. Activation of general control nonderepressible-2 (GCN-2) kinase signaling during hypertonic stress inhibits protein synthesis via phosphorylation of eukaryotic initiation factor-2α (eIF-2α). Inhibition of GCN-2 activation prevents the reduction in translation rate and greatly exacerbates the formation and growth of Q35::YFP aggregates and the aggregation of endogenous proteins. The current studies together with our previous work provide the first direct demonstration that hypertonic stress-induced reduction in protein synthesis minimizes protein aggregation and misfolding. Reduction in translation rate also serves as a signal that activates osmoprotective gene expression. The cellular proteostasis network thus plays a critical role in minimizing hypertonic stress-induced protein damage, in degrading stress-damaged proteins, and in cellular osmosensing and signaling.