TRIM27 acts as an oncogene and regulates cell proliferation and metastasis in non-small cell lung cancer through SIX3-ß-catenin signaling.

The Wnt/ß-catenin pathway plays vital roles in diverse biological processes, including cell differentiation, proliferation, migration, and insulin sensitivity. A recent study reported that the DNA-binding transcriptional factor SIX3 is essential during embryonic development in vertebrates and capable of downregulating target genes of the Wnt/ß-catenin pathway in lung cancer, indicating negative regulation of Wnt/ß-catenin activation. However, regulation of the SIX3-Wnt/ß-catenin pathway axis remains unknown. We measured the expression of TRIM27 and SIX3 as well as investigated whether there was a correlation between them in lung cancer tissue samples. Herein, we found that the E3 ubiquitin ligase, TRIM27, ubiquitinates, and degrades SIX3. TRIM27 induces non-small cell lung cancer (NSCLC) cell proliferation and metastasis, and the expression of ß-catenin, S100P, TGFB3, and MMP-9 were significantly inhibited by SIX3. Furthermore, XAV939 is a selective ß-catenin-mediated transcription inhibitor that inhibited TRIM27- and SIX3-mediated NSCLC cell proliferation, migration, and invasion. Clinically, lung tissue samples of cancer patients showed increased TRIM27 expression and decreased SIX3 expression. Taken together, these data demonstrate that TRIM27 acts as an oncogene regulating cell proliferation and metastasis in NSCLC through SIX3-ß-catenin signaling.

Healing effect of andiroba-based emulsion in cutaneous wound healing via modulation of inflammation and transforming growth factor beta 31.

PURPOSE: To evaluate the effects and mechanisms of andiroba-based emulsion (ABE) topical treatment on full-thickness cutaneous wounds in rats. METHODS: The wounds were harvested on days 3, 7, 15, and 20 post-surgery. Wound contraction rate, quantitative immunohistochemistry [macrophages, myofibroblasts, capillaries, collagens (col) I and III, transforming growth factor ß3ß (TGFß3)], and tensile strength were assessed. RESULTS: Treated wounds were smaller, contracted earlier and had increased angiogenesis, fewer CD68+ and M2 macrophages on days 7 and 15, but higher on day 20. Myofibroblasts appeared on days 3 to 7 in untreated wounds and on days 7 to 15 in treated wounds. TGFß3 levels were higher in the treated wounds, less dense collagen fibers, lower col I/III ratios and a higher tensile strength. CONCLUSION: These results demonstrate the important anti-inflammatory role of treatment and the associated modulation of macrophages, myofibroblasts, and TGFß3 levels. Collagen fibers in the treated wounds were more organized and less dense, similar to unwounded skin, which likely contributed to the higher tensile strength.

Healing effect of andiroba-based emulsion in cutaneous wound healing via modulation of inflammation and transforming growth factor beta 3

Abstract Purpose: To evaluate the effects and mechanisms of andiroba-based emulsion (ABE) topical treatment on full-thickness cutaneous wounds in rats. Methods: The wounds were harvested on days 3, 7, 15, and 20 post-surgery. Wound contraction rate, quantitative immunohistochemistry [macrophages, myofibroblasts, capillaries, collagens (col) I and III, transforming growth factor β3β (TGFβ3)], and tensile strength were assessed. Results: Treated wounds were smaller, contracted earlier and had increased angiogenesis, fewer CD68+ and M2 macrophages on days 7 and 15, but higher on day 20. Myofibroblasts appeared on days 3 to 7 in untreated wounds and on days 7 to 15 in treated wounds. TGFβ3 levels were higher in the treated wounds, less dense collagen fibers, lower col I/III ratios and a higher tensile strength. Conclusion: These results demonstrate the important anti-inflammatory role of treatment and the associated modulation of macrophages, myofibroblasts, and TGFβ3 levels. Collagen fibers in the treated wounds were more organized and less dense, similar to unwounded skin, which likely contributed to the higher tensile strength.

[Effect of overdose fluoride on the expression of TGF-ß3 in rat incisor].

PURPOSE: To observe the effect of overdose fluoride on the expression of TGF-ß3 in rat incisor and to explore the possible mechanism of dental fluorosis． METHODS: Twenty Wistar rats were randomly divided into 2 groups. The animals were maintained in standard environmental conditions with free access to food and water (control group) or water added with 100mg/L F (experimental group). The rats were killed at the end of 8th week. The expression of TGF-ß3 was detected by immunohistochemical staining. Statistical analysis was performed using SPSS12.0 software package. RESULTS: The expression of TGF-ß3 in ameloblasts was significantly inhibited in the experimental of group II（P<0.01）. The gray value of the control group and the fluorine group were 85.89±7.90, 116.76±8.04, respectively. CONCLUSIONS: Fluoride might disturb the signal transduction between the epithelia and mesenchyma by inhibiting the expression of TGF-ß3 in ameloblasts, which in turn may inhibit the differentiation and function of the tooth-forming cells.

Levosimendan up-regulates transforming growth factor-beta and smad signaling in the aorta in the early stage of sepsis.

BACKGROUND: This prospective, controlled experimental study was planned to investigate the effects of levosimendan on transforming growth factor (TGF)-beta3 and Smad1, Smad2 and Smad3 expression in the early stages of sepsis. METHODS: Twenty-four rats were randomized into four groups: (1) sham-operated controls, (2) dobutamine group--subjected to abdominal hypertension and peritonitis-induced sepsis using cecal ligation and puncture (CLP), then treated with 10 microg x kg(-1) min(-1) intravenous (IV) dobutamine infusion, (3) levosimendan group--as in 2, then treated with levosimendan IV bolus 200 microg x kg(-1) followed by 200 microg x kq(-1) min(-1) IV infusion, and (4) a control group as in 2, with no treatment. All rats were killed 8 hours after CLP. Aorta tissue samples were analyzed by immunohistochemical staining. RESULTS: CLP caused mild interleukin (IL)-1 immunostaining in both control and dobutamine groups. Immunoreactivity of tumor necrosis factor (TNF)-alpha was mild in both sham and control groups. TGF-beta3 immunostaining was mildly increased in groups sham, control and dobutamine, whereas it was found moderate in group levosimendan. Smad1, Smad2 and Smad3 were found moderately increased only in group levosimendan. CONCLUSION: Beneficial effects of levosimendan on hemodynamics and global oxygen transport were reported in experimental and clinical trials. Besides its potency on C++ ion sensitivity, it should influence inflammatory cytokine production by diminishing TGF-beta3 and Smad1, Smad2 and Smad3 expression.

Molecular mechanism of teratogenic effects induced by the fungicide triadimefon: study of the expression of TGF-beta mRNA and TGF-beta and CRABPI proteins during rat in vitro development.

Azole derivatives are teratogenic in rats and mice in vitro and in vivo. The postulated mechanism for the dysmorphogenetic effects is the inhibition of retinoic acid (RA)-degrading enzyme CYP26. Azole-related abnormalities are confined to structures controlled by RA, especially the neural crest cells, hindbrain, cranial nerves, and craniofacial structures, through a complex signal cascade. The aim of this work is to study the expression of signal molecules activated by RA (TGF-betas) or involved in the modulation of cellular RA concentrations (CRABPI). E9.5 (9.5 day post coitum old embryos) rat embryos, exposed in vitro to triadimefon (FON) for 24 h, were examined or cultured in normal serum for extra 4, 16, and 24 h. RT-PCR was performed to quantify TGF-beta1, TGF-beta2, TGF-beta3, TGF-betaRI, TGF-betaRII, and TGF-betaRIII mRNA in the hindbrain after 24 h of culture. TGF-beta1, TGF-beta2, and TGF-betaRI were found significantly decreased by FON exposure, and consequently their protein expression was analyzed by Western blot and immunohistochemistry. In both controls and FON-exposed embryos, TGF-beta1 and TGF-betaRI were detected at 24 and 24+4 h; TGF-beta2 was present only at 24 h. Only TGF-beta1 was expressed at the level of hindbrain and branchial tissues. After quantization, TGF-beta1 was reduced in the FON group. The expression of CRABPI was observed at all developmental stages. However, in FON-exposed embryos, it was increased at 24 and 24+4 h. The hindbrain distribution of CRABPI-positive cells was abnormal in FON-exposed embryos. The results show that the two RA-related molecules (TGF-beta1 and CRABPI) are altered by FON exposure in vitro.

Avotermin: a novel antiscarring agent.

Published literature shows that both physicians and their patients are highly concerned about scarring, even relatively minor scars and those that can be concealed by clothing. Furthermore, both patients and their physicians value any opportunities to improve or minimize scarring. While a range of treatment paradigms have been evaluated, no single therapy has been adopted as a universally accepted standard of care and, currently, there are no marketed pharmaceuticals for the prophylactic reduction of scarring. Many of the available treatments are used empirically and most have not been evaluated in robust prospective, randomized, controlled clinical trials. To address this unmet medical need, translational research into the molecular mechanisms of scarring has led to the discovery and commercial development of a new class of prophylactic medicines that promote the regeneration of normal skin and improve scar appearance. Avotermin, the first agent identified in this class, is the clinical application of human recombinant transforming growth factor beta3 (TGFbeta3), a key protein involved in scar-free healing observed in embryos. Controlled, double-blind, randomized phase I/II clinical studies have shown that avotermin, administered as an intradermal injection at the time of surgery, leads to both short-term and longer-term (at >or=12 months) improvements in the appearance of scars compared with placebo and standard wound care.