Angiogenesis and expression of vascular endothelial growth factor, tumour necrosis factor-α and hypoxia inducible factor-1α in canine renal cell carcinoma

The aim of the present study was to determine the distribution and characteristics of microvessels in various histological types of canine renal cell carcinoma (RCC). The study compared microvessel density (MVD) and distribution of blood vessels according to histological type and evaluated the presence of angiogenesis-related proteins. Nine archival samples of canine RCC were studied. MVD was calculated as the mean number of blood vessels per mm(2). The diameter of blood vessels was calculated by determining either the length of the long axis of blood vessels (diameter(max)) or the mean distance from the centre of each blood vessel to the tunica adventia (diameter(mean)). A significant difference in MVD was evident between RCCs and normal kidneys (46.6 ± 28.0 versus 8.4 ± 2.2 microvessels/mm(2)). Diameter(max) in canine RCCs (34.1 ± 14.7 μm) was also significantly different from normal canine kidney (23.2 ± 3.4 μm). Vascular endothelial growth factor (VEGF) was expressed by tumour cells and vascular endothelial cells and tumour necrosis factor (TNF)-α expression was observed in vascular endothelial cells in both neoplastic and normal kidney. Although VEGF is involved in angiogenesis and correlates with tumour stage of development, no correlation was found between VEGF expression and MVD. Tumour-associated macrophages expressing TNF-α and hypoxia inducible factor 1α were identified in peritumoural tissue and may play an important role in angiogenesis.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Expression of hypoxia inducible factor-1α and basic fibroblast factor in the tissues of colorectal adenocarcinoma

Objective To observe expression of hypoxia inducible factor-1α(HIF-1α)and basic fibroblast growth factor(BFGF)in the tissues of colorectal adenoearcinoma and analyze the relationship between expression of the two factors and biological behavior of colorectal adenocarcinoma.Methods The samples of colorectal adenocarcinoma(n=60)and para-adenocarcinoma(n=60)were taken from surgical resection patients and normal colorectal tissues (n=20) from patients with irritable bowel syndrome.The expression of HIF-1α and BFGF were detected by immunohistochemical staining (SP method).Results Positive rates of HIF-1αand BFGF in colorectal adenocarcinoma tissues were 61.7% and 65.0%,and positive rates of HIF-1α and BFGF in para-adenocarcinoma tissues were 10.0%and 13.3%(P<0.05,respectively);HIF-1αand BFGF were not detected in normal intestinal mucosa.There was no significant correlation with HIF-1α and BFGF expression in colorectal adenocarcinoma tissues to the sexuality,age,tumor size,tumorposition and differentiation(P>0.05).A significant correlation between expression of the two factors and Dukes stage was observed (P<0.05).Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissuesof Dukes A and B stage were 47.2%and 52.7%,respectively.Positive rates of HIF-1α and BFGF in colorectal adenocarcinoma tissues of Dukes C and D stage were 83.3%and 83.3%.respectively.There was a positive correlation between expression of the two factors and carcinogenesis of colorectal adenocarcinoma(r=0.4276.P<0.001).Conclusion The results showed that the enhanced expression of HIF-1 α and BFGF incolorectal adenocarcinoma tissues may be associated with the prognosis of the patients with colorectal adenocarcinoma,and HIF-1α and BFGF may participate synergistically in the carcinogenesis of colorectal adenocarcinoma.     

Effects of interleukin-1β and tumor necrosis factor-α on osteoblastic expression of osteocalcin and mineralized extracellular matrix in vitro

Osteoblasts play a pivotal role during the bioresponse of bone to agents that stimulate bone resorption and/or inhibit bone formation including hormones, polypeptide growth factors, and cytokines. We examined the cytokines interleukin-1-beta (IL-1) and tumor necrosis factor-alpha (TNF-) for their effects on osteoblastic proliferation and development and expression of alkaline phosphatase and the osteoblast-specific protein osteocalcin in a mineralizing environment. Primary rat osteoblast-like cells (ROB) and osteoblastic cell lines derived from rat (ROS 17/2.8) and human (MG-63) osteosarcomas were studied. IL-1 and TNF- were chosen because of their critical importance during the host response to local inflammatory stimuli. Qualitatively similar two- to threefold inhibition of osteocalcin synthesis by IL-1 and TNF- were observed in all three postconfluent bone-forming model systems. Because of the readily measurable concentrations of osteocalcin produced in our culture protocol, it was not necessary to enhance osteoblastic synthesis of osteocalcin by supplementation with 1,25(OH)₂-vitamin D₃, a treatment which exerts pleiotropic effects on osteoblasts. Under the constraints of our protocol, where alkaline phosphatase and mineralization were already elevated at the 14-day onset of treatment, neither of these phenotypic properties was sensitive to a three-day cytokine exposure. Differences were noted in proliferation, where only TNF- stimulated DNA synthesis in ROB cells, while both cytokines stimulated MG-63 cells. IL-1 and TNF- failed to alter ROS 17/2.8 DNA synthesis except at the highest doses (25 pM IL-1 and l nM TNF-) where inhibition was observed. These results further support the view that cytokine-mediated osteoblastic regulation can be relatively selective.     

Effects of propofol on P2X7 receptors and the secretion of tumor necrosis factor-α in cultured astrocytes

Upon CNS injury, adenosine-5′-triphosphate is released and acts on P2X7 receptors, which might influence many cytokines secretion from glial cells and, in turn, affects the survival of neurons. Propofol, an intravenous anesthetic, has been shown to provide neuroprotective effect. However, the effect of propofol on astrocyte-associated processes remains to be clarified. In this study, we investigated the effects of propofol on P2X7 activity in astrocytes and tumor necrosis factor-α (TNF-α) secretion from these cells and thereby to infer the possible role(s) of glial P2X7 receptors in propofol neural protective effects. Whole-cell patch clamp results showed that in clinically relevant concentrations (3.3, 10 or 33 μM), propofol increased the P2X7 current amplitudes significantly and propofol in 10 μM extended the inactivation times of P2X7 receptors. Enzyme-linked immunosorbent assay showed that propofol increased the secretion of TNF-α from astrocytes in high concentration (300 μM), while inhibited in clinically relevant concentration (10 μM). Both of these effects were not influenced by Brilliant blue G. These results suggest that in clinically relevant concentrations, propofol increases the activity of P2X7 receptors in activated astrocytes, but this does not contribute to the downregulation of the secretion of TNF-α.     

Follicular dendritic cell tumor of the mediastinum: expression of fractalkine and SDF-1α as mast cell chemoattractants

Follicular dendritic cell tumor (FDCT) is a rare tumor mainly located in laterocervical lymph nodes. We report one case of mediastinal FDCT associated with a history of bullous skin disease and clinically obvious immunosuppression. This tumor was characterized by heavy mast cell infiltration. Mast cells were in close relationship with tumor cells as demonstrated by ultrastructural examination and their presence are probably related with the strong expression of mast cell chemoattractants as fraktalkine and stromal cell-derived factor-1α by tumor cells. The long follow-up period of more than 17 years allowed to us assess the relatively indolent evolution of this tumor characterized by three slowly growing local recurrences without metastasis.     

Effects of clofazimine analogues and tumor necrosis factor-α individually and in combination on human polymorphonuclear leukocyte functions in vitro

In the present study the individual and interactive effects of clofazimine, or three analogues of this agent (selected on the basis of similar or superior pro-oxidative properties: B669, B746 and B4021) and human recombinant TNF-α on the generation of antimicrobial oxidants by human polymorphonuclear leukocytes (PMNL), as well as release of granule enzymes from these cells, were investigated in vitro. All four riminophenazines at the concentrations tested (0.5 and 1.0 μg/ml) significantly increased myeloperoxidase (MPO)-mediated iodination, superoxide (0₂·⁻) generation, oxygen (0₂) consumption and chemiluminescence (CL), as well as the release of both primary and secondary granule contents (measured as the release of MPO, lysozyme and vitamin B₁₂-binding protein) by stimulated PMNL. Similar, but less impressive effects were observed with TNF-α (0.4–50.0 ng/ml). When PMNL were preincubated with both TNF-α and clofazimine or its analogues, the observed stimulation of cellular oxidative metabolism and granule enzyme release was at least additive in many assays. These data demonstrate that the spectrum of effects of clofazimine and its analogues on PMNL closely resemble those of TNF-α. Furthermore, TNF-α potentiates the pro-oxidative effects of clofazimine and its analogues on PMNL. Among the riminophenazines tested, clofazimine and B669 appear to be the most potent pro-oxidative agents for PMNL.     

Microgravity inhibition of lipopolysaccharide-induced tumor necrosis factor-α expression in macrophage cells

Objective and design

Microgravity environments in space can cause major abnormalities in human physiology, including decreased immunity. The underlying mechanisms of microgravity-induced inflammatory defects in macrophages are unclear.

Material or subjects

RAW264.7 cells and primary mouse macrophages were used in the present study. Lipopolysaccharide (LPS)-induced cytokine expression in mouse macrophages was detected under either simulated microgravity or 1g control.

Methods

Freshly isolated primary mouse macrophages and RAW264.7 cells were cultured in a standard simulated microgravity situation using a rotary cell culture system (RCCS-1) and 1g control conditions. The cytokine expression was determined by real-time PCR and ELISA assays. Western blots were used to investigate the related intracellular signals.

Results

LPS-induced tumor necrosis factor-α (TNF-α) expression, but not interleukin-1β expression, in mouse macrophages was significantly suppressed under simulated microgravity. The molecular mechanism studies showed that LPS-induced intracellular signal transduction including phosphorylation of IKK and JNK and nuclear translocation of NF-κB in macrophages was identical under normal gravity and simulated microgravity. Furthermore, TNF-α mRNA stability did not decrease under simulated microgravity. Finally, we found that heat shock factor-1 (HSF1), a known repressor of TNF-α promoter, was markedly activated under simulated microgravity.

Conclusions

Short-term treatment with microgravity caused significantly decreased TNF-α production. Microgravity-activated HSF1 may contribute to the decreased TNF-α expression in macrophages directly caused by microgravity, while the LPS-induced NF-κB pathway is resistant to microgravity.     

Hypoxia inducible factor 1α in hepatocellular carcinoma with cirrhosis: Association with prognosis

Background

Hypoxia inducible factor 1α (HIF-1α) is a protein related with carcinogenesis and metastasis in many tumors. However, little is known about the prognostic value of HIF-1α in hepatocellular carcinoma (HCC) patients with cirrhosis.

Role of tumor necrosis factor-α in the regulation of keratinocyte cell cycle and DNA repair after ultraviolet-B radiation

Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine produced in the skin in response to ultraviolet B radiation (UVB). TNF-α facilitates UVB-induced apoptosis and probably contributes to removal of damaged cells. Surprisingly, murine TNF-α-knockout models have demonstrated that TNF-α is necessary for the early stages of skin carcinogenesis and development of squamous cell carcinoma. In the present PhD thesis, we examined the effects of TNF-α on DNA repair and cell cycle regulation in UVB-irradiated keratinocytes. In the model of premalignant keratinocytes (HaCaT), TNF-α abolished the UVB-induced G2/M checkpoint and diminished the DNA repair despite induction of apoptosis. TNF-α activated the protein kinase B/Akt and regulation of its downstream targets, mTOR, Bad and FoxO3a. This effect was dependent on atypical protein kinase C species (aPKC) since a specific peptide blocking the activity of the PKCξ and ι/λ abrogated the activation of Akt by TNF-α. The aPKC-Akt axis was likely to be responsible for the TNF-α-induced decrease in DNA repair since blocking of Akt activity restored DNA repair. Since anti-TNF-α approaches are increasingly used in the therapy of autoimmune diseases and one of the safety concerns is the potential enhancement of skin carcinogenesis, we investigated the effect of the chimeric monoclonal anti-TNF-α antibody infliximab on UVB-irradiated HaCaT cells. Cells treated with infliximab had significantly increased levels of DNA damage despite enhanced G2/M checkpoint arrest, increased apoptosis and inhibition of Akt. In conclusion, we identified a possible novel mechanism by which TNF-α promotes UVB-induced skin carcinogenesis. This depends on aPKC-Akt activation and inhibition of DNA repair. TNF-α-treated cells are prone to escape checkpoint control and are possibly more likely to accumulate mutations, which may constitute a relevant mechanism enhancing tumor development. The effect of anti-TNF-α therapy on skin carcinogenesis warrants further investigation as our study indicates that, in contrast to what had been expected, infliximab may impair DNA repair.