| 1. |
- Basic, Vladimir T., 1982-, et al.
(författare)
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TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes
- 2014
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 34:1, s. 228-236
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Tidskriftsartikel (refereegranskat)abstract
- Decreased skeletal muscle capillarization is considered to significantly contribute to the development of pulmonary cachexia syndrome (PCS) and progressive muscle wasting in several chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). It is unclear to which extent the concurrent presence of systemic inflammation contributes to decreased skeletal muscle capillarization under these conditions. The present study was designed to examine in vitro the effects of the pro-inflammatory cytokine, tumor necrosis factor (TNF), on the regulation of hypoxia-angiogenesis signal transduction and capillarization in skeletal muscles. For this purpose, fully differentiated C2C12 skeletal muscle myocytes were stimulated with TNF and maintained under normoxic or hypoxic conditions. The expression levels of the putative elements of the hypoxia-angiogenesis signaling cascade were examined using qPCR, western blot analysis and immunofluorescence. Under normoxic conditinos, TNF stimulation increased the protein expression of anti-angiogenic von-Hippel Lindau (VHL), prolyl hydroxylase (PHD)2 and ubiquitin conjugating enzyme 2D1 (Ube2D1), as well as the total ubiquitin content in the skeletal muscle myocytes. By contrast, the expression levels of hypoxia-inducible factor 1‑α (HIF1-α) and those of its transcriptional targets, vascular endothelial growth factor (VEGF)A and glucose transporter 1 (Glut1), were markedly reduced. In addition, hypoxia increased the expression of the VHL transcript and further elevated the VHL protein expression levels in C2C12 myocytes following TNF stimulation. Consequently, an impaired angiogenic potential was observed in the TNF-stimulated myocytes during hypoxia. In conclusion, TNF increases VHL expression and disturbs hypoxia-angiogenesis signal transduction in skeletal muscle myocytes. The current findings provide a mechanism linking systemic inflammation and impaired angiogenesis in skeletal muscle. This is particularly relevant to further understanding the mechanisms mediating muscle wasting and cachexia in patients with chronic inflammatory diseases, such as COPD.
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| 2. |
- Bilbija, Dusan, et al.
(författare)
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Expression of retinoic acid target genes in coronary artery disease
- 2014
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Ingår i: International Journal of Molecular Medicine. - Athens, Greece : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 33:3, s. 677-86
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Tidskriftsartikel (refereegranskat)abstract
- Coronary atherosclerosis can lead to myocardial infarction, and secondarily to post-infarct remodelling and heart failure. Retinoic acid (RA) influences cell proliferation. We hypothesized that RA could influence gene expression and proliferation of cardiovascular cells. Left ventricular biopsies from patients with end-stage heart failure due to coronary artery disease (CAD) or dilated cardiomyopathy were investigated for the content of RA metabolites using liquid chromatography mass spectrometry (LC-MS/MS), and compared with healthy donors. All-trans retinoic acid (ATRA) was increased in the hearts of CAD patients. Gene expression (quantitative PCR) of RA target genes was not influenced in failing hearts, but was increased in the hearts of patients with CAD undergoing open heart surgery. The expression of RA target genes was increased in atherosclerotic lesions from carotid arteries compared to healthy arteries. Stimulation of cardiomyocytes, cardiofibroblasts, smooth muscle cells and endothelial cells with ATRA increased the gene expression of the key enzymes. Cardiofibroblast and smooth muscle cell proliferation were reduced by ATRA, which increased endothelial cell proliferation. Coronary artery disease leads to increased expression of RA target genes. ATRA accumulated in the failing human heart. All investigated cell types present in the heart had induced expression of RA target genes when stimulated with ATRA, which also influenced cell proliferation.
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| 3. |
- Du, Jian, et al.
(författare)
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Antiproliferative effect of alpinetin in BxPC-3 pancreatic cancer cells
- 2012
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 29:4, s. 607-612
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Tidskriftsartikel (refereegranskat)abstract
- Alpinetin is a novel plant flavonoid derived from Alpinia katsumadai Hayata, found to possess strong anticancer effects. However, the antitumor effect of alpinetin on pancreatic cancer cells and the detailed mechanism remain unclear. The aim of this study was to investigate alpinetin's beneficial effect on pancreatic cancer and the possible molecular mechanism involved. Pancreatic cancer cell lines were treated with alpinetin at various doses and for different times, and the effect of alpinetin on cell growth inhibition, apoptosis and the cell cycle was determined. The expression of Bcl-2, Bcl-xL, XIAP and Bax, the activity of caspases and the levels of cytochrome c released were measured. The results showed that alpinetin inhibited the viability of three pancreatic cancer cell lines and induced apoptosis of BxPC-3 cells in a dose- and time-dependent manner. This was accompanied by regulation of the expression of Bcl-2, Bcl-xL, Bax and XIAP. Furthermore, alpinetin treatment led to the release of cytochrome c and activation of caspases-3, -8 and -9 proteins. Taken together, our studies indicate that alpinetin inhibited the proliferation of pancreatic cancer cells possibly through the regulation of the Bcl-2 family and XIAP expression, release of cytochrome c and the activation of caspases. Alpinetin may serve as a potential agent for the development of pancreatic cancer cell therapies.
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| 5. |
- Gabrielsson, Britt, 1957, et al.
(författare)
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Dietary herring improves plasma lipid profiles and reduces atherosclerosis in obese low-density lipoprotein receptor-deficient mice
- 2012
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 29:3, s. 331-37
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Tidskriftsartikel (refereegranskat)abstract
- Diet is a significant modifiable risk factor for cardiovascular disease and high fish intake has been associated with vascular health in population studies. However, intervention studies have been inconclusive. In this study, male low-density lipoprotein receptor-deficient mice were given 16-week high fat/high sucrose diets, supplemented with either minced herring fillets or minced beef. The diets were matched in total fat and cholesterol content; taurine content and fatty acid composition was analysed. Body weights were recorded throughout the study; plasma lipids were analysed at week 8 and 16. Body composition and adipocyte size were evaluated at study end. Atherosclerosis was evaluated at week 12 (ultrasound) and at termination (en face histology). Herring-fed mice had a higher proportion of long-chain n-3 polyunsaturated fatty acids in the hepatic triacylglycerides (TAG) and phospholipid fractions. The herring-fed mice had increased body weight (P=0.007), and reduced epididymal adipocyte size (P=0.009), despite similar food intake and body composition as the beef-fed mice. The herring-fed mice had lower plasma TAG and very-low-density lipoprotein (VLDL)-cholesterol concentrations throughout the study (TAG; P=0.0012 and 0.004, VLDL-cholesterol; P=0.006 and 0.041, week 8 and 16, respectively). At week 16, the herring-fed had higher plasma concentrations of HDL-cholesterol (P=0.004) and less atherosclerotic lesions in the aortic arch (P=0.007) compared with the beef-fed mice. In conclusion, dietary herring in comparison to beef markedly improved vascular health in this mouse model, suggesting that herring provides an added value beyond its content of macronutrients.
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| 7. |
- Guaran, Valeria, et al.
(författare)
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Association between idiopathic hearing loss and mitochondrial DNA mutations : a study on 169 hearing-impaired subjects
- 2013
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Ingår i: International Journal of Molecular Medicine. - Athen : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 32:4, s. 785-794
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in mitochondrial DNA (mtDNA) have been shown to be an important cause of sensorineural hearing loss (SNHL). In this study, we performed a clinical and genetic analysis of 169 hearing-impaired patients and some of their relatives suffering from idiopathic SNHL, both familial and sporadic. The analysis of four fragments of their mtDNA identified several polymorphisms, the well known pathogenic mutation, A1555G, and some novel mutations in different genes, implying changes in the aminoacidic sequence. A novel sporadic mutation in 12S rRNA (MT-RNR1), not previously reported in the literature, was found in a case of possible aminoglycoside-induced progressive deafness.
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| 10. |
- Hardell, Lennart, et al.
(författare)
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Exposure to wireless phone emissions and serum beta-trace protein.
- 2010
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Ingår i: International journal of molecular medicine. - : Spandidos Publications. - 1791-244X .- 1107-3756. ; 26:2, s. 301-306
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Tidskriftsartikel (refereegranskat)abstract
- The lipocalin type of prostaglandin D synthase or beta-trace protein is synthesized in the choroid plexus, lepto-meninges and oligodendrocytes of the central nervous system and is secreted into the cerebrospinal fluid. beta-trace protein is the key enzyme in the synthesis of prostaglandin D2, an endogenous sleep-promoting neurohormone in the brain. Electromagnetic fields (EMF) in the radio frequency (RF) range have in some studies been associated with disturbed sleep. We studied the concentration of beta-trace protein in blood in relation to emissions from wireless phones. This study included 62 persons aged 18-30 years. The concentration of beta-trace protein decreased with increasing number of years of use of a wireless phone yielding a negative beta coefficient = -0.32, 95% confidence interval -0.60 to -0.04. Also cumulative use in hours gave a negative beta coefficient, although not statistically significant. Of the 62 persons, 40 participated in an experimental study with 30 min exposure to an 890-MHz GSM signal. No statistically significant change of beta-trace protein was found. In a similar study of the remaining 22 participitants with no exposure, beta-trace protein increased significantly over time, probably due to a relaxed situation. EMF emissions may down-regulate the synthesis of beta-trace protein. This mechanism might be involved in sleep disturbances reported in persons exposed to RF fields. The results must be interpreted with caution since use of mobile and cordless phones were self-reported. Awareness of exposure condition in the experimental study may have influenced beta-trace protein concentrations.
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| 17. |
- Nixon Tangi, Tebeng, et al.
(författare)
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Role of NLRP3 and CARD8 in the regulation of TNF-α induced IL-1β release in vascular smooth muscle cells
- 2012
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Ingår i: International Journal of Molecular Medicine. - Athens, Greece : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 30:3, s. 697-702
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin (IL)-1β is known to be activated by the inflammasome. Inflammasome activities depend on a plethora of moieties including NLRP3 and CARD8, which have been reported to be associated with several inflammatory diseases. Aortic smooth muscle cells (AOSMCs) were transfected with siRNA targeting the NLRP3 and CARD8 genes, followed by tumor necrosis factor-α (TNF-α) treatment. We found that TNF-α induces IL-1β, IL-1Ra and NLRP3 genes but not CARD8. Silencing of the NLRP3 gene significantly decreased IL-1β expression and release, the IL-1Ra expression showed a borderline non-significant increment, while CARD8 knockdown did not affect the IL-1β and IL-1Ra mRNA expression or IL-1β protein release. Our results suggest that mainly NLRP3 plays a role in the regulation of IL-1β expression and release in AOSMC and could be a potential future target for the treatment of atherosclerosis and other inflammatory diseases.
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| 18. |
- Obrosova, Irina G., et al.
(författare)
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Evaluation of the aldose reductase inhibitor fidarestat on ischemia-reperfusion injury in rat retina
- 2010
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1791-244X .- 1107-3756. ; 26:1, s. 135-142
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Tidskriftsartikel (refereegranskat)abstract
- This study evaluated the effects of retinal ischemia-reperfusion (IR) injury and pre-treatment with the potent and specific aldose reductase inhibitor fidarestat on apoptosis, aldose reductase and sorbitol dehydrogenase expression, sorbitol pathway intermediate concentrations, and oxidative-nitrosative stress. Female Wistar rats were pre-treated with either vehicle (N-methyl-D-elucamine) or fidarestat, 32 mg kg(-1)d(-1) for both, in the right jugular vein, for 3 consecutive days. A group of vehicle- and fidarestat-treated rats were subjected to 45-min retinal ischemia followed by 24-h reperfusion. Ischemia was induced 30 min after the last vehicle or fidarestat administration. Retinal IR resulted in a remarkable increase in retinal cell death. The number of TUNEL-positive nuclei increased 48-fold in the IR group compared with non-ischemic controls (p<0.01), and this increase was partially prevented by fidarestat. AR expression (Western blot analysis) increased by 19% in the IR group (p<0.05), and this increase was prevented by fidarestat. Sorbitol dehydrogenase and nitrated protein expressions were similar among all experimental groups. Retinal sorbitol concentrations tended to increase in the ER group but the difference with non-ischemic controls did not achieve statistical significance (p=0.08). Retinal fructose concentrations were 2.2-fold greater in the IR group than in the non-ischemic controls (p<0.05). Fidarestat pre-treatment of rats subjected to IR reduced retinal sorbitol concentration to the levels in non-ischemic controls. Retinal fructose concentrations were reduced by 41% in fidarestat-pre-treated IR group vs. untreated ischemic controls (p=0.0517), but remained 30% higher than in the non-ischemic control group. In conclusion, IR injury to rat retina is associated with a dramatic increase in cell death. elevated AR expression and sorbitol pathway intermediate accumulation. These changes were prevented or alleviated by the AR inhibitor fidarestat. The results identify AR as an important therapeutic target for diseases involving IR injury, and provide the rationale for development of fidarestat and other AR inhibitors.
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| 19. |
- Rafter, Ingalill, et al.
(författare)
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Isoform-specific alanine aminotransferase measurement candistinguish hepatic from extrahepatic injury in humans
- 2012
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 30, s. 1241-1249
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Tidskriftsartikel (refereegranskat)abstract
- Serum alanine aminotransferase (ALT) is used asa clinical marker to detect hepatic damage and hepatoxicity.Two isoforms of ALT have been identified, ALT1 and ALT2,which have identical enzymatic capacities and are detectedsimultaneously in human serum/plasma using classical clinicalchemical assays. Differences exist in the expression patterns ofthe ALT1 and ALT2 proteins in different organs which suggestthat changes in the proportion of ALT1 and ALT2 in plasmamay arise and reflect damage to different human organs.However, this has not been previously studied due to the lackof a selective methodology that can quantify both ALT1 andALT2 isoforms in the total ALT activity normally measuredin clinical samples. To the best of our knowledge, our currentstudy reveals for the first time, that under 3 different conditionsof liver damage (non-alcoholic fatty liver disease, hepatitis Cand during liver surgery) the leakage of ALT1 activity intoplasma greatly exceeds that of ALT2, and that the measurementof ALT1 during liver damage is equal to the measurement oftotal ALT activity. By contrast, during skeletal muscle injury,induced in volunteers by physical exertion, the leakage ofALT2 exceeds that of ALT1 and the proportion of circulatingALT isoforms changes accordingly. The ALT isoform changesoccurring in plasma reflect previously demonstrated relativecontents of ALT1 and ALT2 activities in human liver and skeletalmuscle. These data suggest that assessing the percentagecontribution of ALT1 and ALT2 activities to total ALT activityin plasma may distinguish hepatic from extrahepatic injuryusing the same standard analytical platform.
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| 20. |
- Sahlberg, Sara Haggblad, et al.
(författare)
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Radiation response in colorectal cancer cells
- 2012
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Ingår i: International Journal of Molecular Medicine. - 1107-3756 .- 1791-244X. ; 30:S1, s. S7-S7
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 23. |
- Svensson, Per-Arne, 1969, et al.
(författare)
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Gene expression in human brown adipose tissue.
- 2011
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Ingår i: International journal of molecular medicine. - : Spandidos Publications. - 1791-244X .- 1107-3756. ; 27:2, s. 227-32
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Tidskriftsartikel (refereegranskat)abstract
- Brown adipose tissue (BAT) has profound effects on body weight and metabolism in rodents. Recent reports show that human adults have significant amounts of BAT. Our aim was to study the gene expression profile of human BAT. Biopsies of adipose tissue with brown-red color and subcutaneous white adipose tissue (WAT) were obtained from 24 patients undergoing surgery in the thyroid region. Intrascapular BAT and epididymal WAT biopsies were obtained from 10 mice. Expression was analyzed by DNA microarray, real-time PCR and immunohistochemistry. Using the expression of the brown adipocyte-specific gene uncoupling protein 1 (UCP1) as a marker, approximately half of the human brown-red adipose tissue biopsies taken in the thyroid region contained BAT, and the presence of cells with brown adipocyte morphology was also verified by histology. Microarray analysis of 9 paired human BAT and WAT samples showed that 17 genes had at least a 4-fold higher expression in BAT compared to WAT and five of them (CKMT1, KCNK3, COBL, HMGCS2, TGM2) were verified using real-time PCR (P<0.05 for all). In addition, immunohistochemistry showed that the UCP1, KCNK3 and CKMT1 proteins are expressed in brown adipocytes. Except for UCP1 and KCNK3, the genes overexpressed in human BAT were not overexpressed in mouse BAT compared to mouse WAT. Our analysis identified genes that are differentially expressed in human BAT compared to WAT. The results also show that there are species-specific differences in BAT gene expression and this emphasizes the need for further molecular characterization of human BAT to clarify the mechanisms involved in regulated heat production in humans.
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| 26. |
- Wågsäter, Dick, et al.
(författare)
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MMP-2 and MMP-9 are prominent matrix metalloproteinases during atherosclerosis development in the LdlrApob100/100 mouse
- 2011
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 28:2, s. 247-253
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Tidskriftsartikel (refereegranskat)abstract
- Matrix-degrading proteases capable of degrading components of the extracellular matrix may play an important role in development and progression of atherosclerotic lesions. In the present study, we used the Ldlr(-/-)Apob(100/100) mouse model, which has a plasma lipoprotein profile similar to that of humans with atherosclerosis, to study the expression of matrix metalloproteinases (MMPs) during early stages of atherosclerosis development. We analyzed the expression of 11 proteases and three protease inhibitors in 5- to 40-week-old Ldlr(-/-)Apob(100/100) mice. Expression and activity of MMP-2 and MMP-9 was increased in advanced atherosclerotic lesions followed by macrophage infiltration as shown by real-time PCR, gel-based and in situ zymography and immunohistochemistry. Expression of other investigated MMPs did not increase during disease progression. However, the mRNA expression of MMP-8 and MMP-13 was down-regulated, which could explain the relatively high amount of collagen observed in the vessels in this model. In conclusion, low proteolytic expression at early stages of atherogenesis and a limited repertoire of proteolytic enzymes were associated with the progression of atherosclerosis in Ldlr(-/-)Apob(100/100) mice. The study suggests that MMP-2 and MMP-9 are the main proteases involved in atherogenesis in this mouse model.
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| 42. |
- Nordlind, K, et al.
(författare)
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Alcohol, psoriasis and pruritus
- 2012
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Ingår i: INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE. - 1107-3756. ; 30, s. S44-S44
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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