Abrogated Thioredoxin System Causes Increased Sensitivity to TNF-α-Induced Apoptosis via Enrichment of p-ERK 1/2 in the Nucleus

Thioredoxin (Trx) and thioredoxin reductase 1 (TR1) are among the major redox regulators in mammalian cells and have a wide variety of roles, including removal of intracellular reactive oxygen species (ROS) and prevention of cell death. Tumor necrosis factor-α (TNF-α) induces cancer cell death. Although ROS have been proposed to participate in this process, the role of the thioredoxin system in TNF-α stimulated cell death remains unclear. We investigated the possibility that the thioredoxin system protects against TNF-α-induced cancer cell death by examining whether TR1/Trx1 status controls TNF-α-induced apoptosis in EMT6 murine breast cancer cells. TR1-deficient cells were more sensitive to TNF-α than control cells. Increased sensitivity to TNF-α was most pronounced in Trx1-deficient cells. TNF-α-induced nuclear localization of phosphorylated ERK 1/2 (p-ERK 1/2) correlated with increased apoptosis in TR1- and Trx1-deficient cells, suggesting a pro-apoptotic role for nuclear p-ERK 1/2 in TNF-α-induced apoptosis. In addition, phosphoinositide 3-kinase (PI3K) inhibition dramatically reduced TNF-α-stimulated apoptosis and nuclear localization of p-ERK 1/2. In contrast, inhibition of ROS, MEK, JNK, or p38 did not significantly alter p-ERK 1/2 localization or apoptosis in TR1- and Trx1-deficient cells compared to control cells. Further, NF-κB p65 localization was not changed in TR1- and Trx1-deficient cells in response to TNF-α relative to control cells. Our data suggest that the thioredoxin system plays a critical role in protecting against TNF-α-induced apoptosis by regulating the levels of nuclear p-ERK 1/2 in a PI3K-dependent manner

Usefulness of Contralateral Indirect Decompression through Minimally Invasive Unilateral Transforaminal Lumbar Interbody Fusion

Study DesignRetrospective study.PurposeThis study aims to investigate the clinical and radiological results of contralateral indirect decompression through minimally invasive unilateral transforaminal lumbar interbody fusion (MI-TLIF).Overview of LiteratureSeveral studies have proposed that blood loss and operation time could be reduced through a unilateral approach, although many surgeons have forecast that satisfactory foraminal decompression is difficult to achieve through a unilateral approach.MethodsThe study included 30 subjects who had undergone single-level MI-TLIF. Visual analogue scale (VAS) and Oswestry disability index (ODI) were analyzed for clinical assessment. Disc height, segmental lordosis, and lumbar lordosis angle were examined for radiological assessment. The degree of contralateral indirect decompression was evaluated through a comparative analysis, with a magnetic resonance imaging (MRI) performed preoperatively and at one year postoperatively.ResultsIntraoperative blood loss volume was 308.75 mL in the unilateral approach group (UAP), and 575.00 mL in the bilateral approach group (BAP), showing a statistically significant difference. Operation time was 139.50 minutes in the UAP group, and 189.00 minutes in the BAP group, exhibiting a statistically significant difference (p0.05).ConclusionsSatisfactory results were acquired with MI-TLIF conducted through the unilateral approach of contralateral indirect decompression, in alignment with the bilateral approach. Therefore, contralateral indirect decompression is thought to be a useful procedure in reducing the operation time and volume of blood loss

Thioredoxin Reductase 1 Deficiency Reverses Tumor Phenotype and Tumorigenicity of Lung Carcinoma Cells

Dietary selenium has potent cancer prevention activity. Both low molecular weight selenocompounds and selenoproteins are implicated in this effect. Thioredoxin reductase 1 (TR1) is one of the major antioxidant and redox regulators in mammals that supports p53 function and other tumor suppressor activities. However, this selenium-containing oxidoreductase is also overexpressed in many malignant cells and has been proposed as a target for cancer therapy. To further assess the role of TR1 in the malignancy process, we used RNA interference technology to decrease its expression in mouse lung carcinoma (LLC1) cells. Stable transfection of LLC1 cells with a small interfering RNA construct that specifically targets TR1 removal manifested a reversal in the morphology and anchorage-independent growth properties of these cancer cells that made them similar to those of normal cells. The expression of at least two cancer-related protein mRNAs, Hgf and Opn1, were reduced dramatically in the TR1 knockdown cells. Mice injected with the TR1 knockdown showed a dramatic reduction in tumor progression and metastasis compared with those mice injected with the corresponding control vector. In addition, tumors that arose from injected TR1 knockdown cells lost the targeting construct, suggesting that TR1 is essential for tumor growth in mice. These observations provide direct evidence that the reduction of TR1 levels in malignant cells is antitumorigenic and suggest that the enzyme is a prime target for cancer therapy

Effects of Rhythmic Auditory Stimulation During Hemiplegic Arm Reaching in Individuals with Stroke: An Exploratory Study

SummaryObjective/BackgroundThis study investigated the effects of rhythmic auditory stimulation (RAS) on muscle activity and elbow motion during arm reaching with hemiplegic arm in participants with stroke.MethodsSixteen adults with stroke who resided in a community were recruited in this study. The RAS consisted of sound emitted from a digital metronome. While sitting upright in a chair, participants reached their arms towards a target (a switch on a table) both with and without RAS. The three-dimensional motion analysis system and surface electromyography system were used for measurements during the reaching tasks.ResultsWe found that RAS elicited better performance in reaching movements than those movements performed without RAS. RAS shortened the movement time (p = .002), reduced the change in acceleration (p = .001), increased the elbow extension range of motion (p = .001), increased muscle activation of the triceps brachii (p = .024), and reduced the co-contraction ratio (p = .015) of the affected arm.ConclusionRAS might be a useful technique to facilitate improvements in motor function of the affected arm in patients with stroke

Deficiency in the 15 kDa Selenoprotein Inhibits Human Colon Cancer Cell Growth

Selenium is an essential micronutrient for humans and animals, and is thought to provide protection against some forms of cancer. These protective effects appear to be mediated, at least in part, through selenium-containing proteins (selenoproteins). Recent studies in a mouse colon cancer cell line have shown that the 15 kDa selenoprotein (Sep15) may also play a role in promoting colon cancer. The current study investigated whether the effects of reversing the cancer phenotype observed when Sep15 was removed in mouse colon cancer cells, were recapitulated in HCT116 and HT29 human colorectal carcinoma cells. Targeted down-regulation of Sep15 using RNAi technology in these human colon cancer cell lines resulted in similarly decreased growth under anchorage-dependent and anchorage-independent conditions. However, the magnitude of reduction in cell growth was much less than in the mouse colon cancer cell line investigated previously. Furthermore, changes in cell cycle distribution were observed, indicating a delayed release of Sep15 deficient cells from the G0/G1 phase after synchronization. The potential mechanism by which human colon cancer cells lacking Sep15 revert their cancer phenotype will need to be explored further

Targeting Thioredoxin Reductase 1 Reduction in Cancer Cells Inhibits Self-Sufficient Growth and DNA Replication

Thioredoxin reductase 1 (TR1) is a major redox regulator in mammalian cells. As an important antioxidant selenoprotein, TR1 is thought to participate in cancer prevention, but is also known to be over-expressed in many cancer cells. Numerous cancer drugs inhibit TR1, and this protein has been proposed as a target for cancer therapy. We previously reported that reduction of TR1 levels in cancer cells reversed many malignant characteristics suggesting that deficiency in TR1 function is antitumorigenic. The molecular basis for TR1's role in cancer development, however, is not understood. Herein, we found that, among selenoproteins, TR1 is uniquely overexpressed in cancer cells and its knockdown in a mouse cancer cell line driven by oncogenic k-ras resulted in morphological changes characteristic of parental (normal) cells, without significant effect on cell growth under normal growth conditions. When grown in serum-deficient medium, TR1 deficient cancer cells lose self-sufficiency of growth, manifest a defective progression in their S phase and a decreased expression of DNA polymerase α, an enzyme important in DNA replication. These observations provide evidence that TR1 is critical for self-sufficiency in growth signals of malignant cells, that TR1 acts largely as a pro-cancer protein and it is indeed a primary target in cancer therapy

Selenoproteins regulate macrophage invasiveness and extracellular matrix-related gene expression

<p>Abstract</p> <p>Background</p> <p>Selenium, a micronutrient whose deficiency in diet causes immune dysfunction and inflammatory disorders, is thought to exert its physiological effects mostly in the form of selenium-containing proteins (selenoproteins). Incorporation of selenium into the amino acid selenocysteine (Sec), and subsequently into selenoproteins is mediated by Sec tRNA^[Ser]Sec.</p> <p>Results</p> <p>To define macrophage-specific selenoprotein functions, we generated mice with the Sec tRNA^[Ser]Secgene specifically deleted in myeloid cells. These mutant mice were devoid of the "selenoproteome" in macrophages, yet exhibited largely normal inflammatory responses. However, selenoprotein deficiency led to aberrant expression of extracellular matrix-related genes, and diminished migration of macrophages in a protein gel matrix.</p> <p>Conclusion</p> <p>Selenium status may affect immune defense and tissue homeostasis through its effect on selenoprotein expression and the trafficking of tissue macrophages.</p

Selenoproteins regulate macrophage invasiveness and extracellular matrix-related gene expression

Background: Selenium, a micronutrient whose deficiency in diet causes immune dysfunction and inflammatory disorders, is thought to exert its physiological effects mostly in the form of selenium-containing proteins (selenoproteins). Incorporation of selenium into the amino acid selenocysteine (Sec), and subsequently into selenoproteins is mediated by Sec tRNA[Ser]Sec. Results: To define macrophage-specific selenoprotein functions, we generated mice with the Sec tRNA[Ser]Sec gene specifically deleted in myeloid cells. These mutant mice were devoid of the selenoproteome in macrophages, yet exhibited largely normal inflammatory responses. However, selenoprotein deficiency led to aberrant expression of extracellular matrix-related genes, and diminished migration of macrophages in a protein gel matrix. Conclusion: Selenium status may affect immune defense and tissue homeostasis through its effect on selenoprotein expression and the trafficking of tissue macrophages

Long-Term Glycaemic Durability of Early Combination Therapy Strategy versus Metformin Monotherapy in Korean Patients with Newly Diagnosed Type 2 Diabetes Mellitus

We assessed the glycaemic durability with early combination (EC; vildagliptin+metformin [MET], n=22) versus MET monotherapy (n=17), among newly-diagnosed type 2 diabetes mellitus (T2DM) enrolled (between 2012 and 2014) in the VERIFY study from Korea (n=39). Primary endpoint was time to initial treatment failure (TF) (glycosylated hemoglobin [HbA1c]>= 7.0% at two consecutive scheduled visits after randomization [end of period 1]). Time to second TF was assessed when both groups were receiving and failing on the combination (end of period 2). With EC the risk of initial TF significantly reduced by 78% compared to MET (n=3 [15%] vs. n=10 [58.7%], P=0.0228). No secondary TF occurred in EC group versus five patients (29.4%) in MET. Patients receiving EC treatment achieved consistently lower HbA1c levels. Both treatment approaches were well tolerated with no hypoglycaemic events. In Korean patients with newly diagnosed T2DM, EC treatment significantly and consistently improved the long-term glycaemic durability as compared with MET.Peer reviewe