| 1. |
- Al-Omari, Mariam, et al.
(author)
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Beneficial effects of alpha-1 antitrypsin therapy in a mouse model of colitis-associated colon cancer
- 2023
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In: BMC Cancer. - 1471-2407. ; 23:1
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Journal article (peer-reviewed)abstract
- Background: It is widely accepted that chronic inflammatory bowel diseases significantly higher a risk for colorectal cancer development. Among different types of treatments for patients with colon cancer, novel protein-based therapeutic strategies are considered. AIM: To explore the effect of human plasma alpha-1 antitrypsin (AAT) protein in the chemically induced mouse model of colorectal cancer. Methods: BALB/c mice with azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated colorectal cancer (CAC), we intraperitoneally treated with commercial preparation of human plasma AAT (4 mg per mouse). Effects of this therapy were evaluated histologically, and by immunohistochemical and gene expression assays. Results: When compared with non-treated controls, AOM/DSS mice receiving AAT therapy exhibited significantly longer colons, and less anal bleeding. Concurrently, AAT-treated mice had significantly fewer polyps, and lower numbers of large colon tumors. Immunohistochemical examinations of colon tissues showed significantly lower neutrophil counts, more granzyme B-positive but fewer MMP9 (gelatinase B)-positive cancer cells and lower numbers of apoptotic cells in mice receiving AAT therapy. The expression levels of IL4 were significantly higher while TNFA was slightly reduced in tumor tissues of AOM/DSS mice treated with AAT than in AOM/DSS mice. Conclusion: Human AAT is an acute phase protein with a broad-protease inhibitory and immunomodulatory activities used as a therapeutic for emphysema patients with inherited AAT deficiency. Our results are consistent with previous findings and support an idea that AAT alone and/or in combination with available anti-cancer therapies may represent a new personalized approach for patients with colitis-induced colon cancer.
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| 2. |
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| 3. |
- Aldonyte, Ruta, et al.
(author)
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Circulating monocytes from healthy individuals and COPD patients.
- 2003
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In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 4:1, s. 11-11
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Journal article (peer-reviewed)abstract
- Background: Chronic obstructive pulmonary disease (COPD) is characterized by incompletely reversible airflow obstruction associated with inflammation in which monocytes/macrophages are the predominant inflammatory cells. The only known genetic factor related to COPD is inherited PiZZ deficiency of alpha1-antitrypsin (AAT), an inhibitor of serine proteases. Methods: We investigated the basal and LPS-stimulated release of pro-inflammatory molecules from blood monocytes isolated from age and gender matched healthy (n = 30) and COPD (n = 20) individuals with and without AAT deficiency. Results: After 18 h of cell culture the basal release of MMP-9 was 2.5-fold, p < 0.02 greater, whereas IL-8 was 1.8-fold (p < 0.01) lower from COPD patient monocytes than from controls. LPS-stimulated release of IL-6 and MCP-1 was greater from COPD patient's monocytes relative to controls, while activation of control cells resulted in enhanced secretion of ICAM-1 and MMP-9 compared to COPD patients. Independent of disease status, monocytes from PiZZ AAT carriers released less TNFalpha (by 2.3-fold, p < 0.03). Conclusions: The basal and LPS-stimulated secretion of specific pro-inflammatory molecules from circulating monocytes differs between healthy and COPD subjects. These findings may be valuable for further studies on the mechanisms involved in recruitment and activation of inflammatory cells in COPD.
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| 4. |
- Aldonyte, Ruta, et al.
(author)
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Concentration-dependent effects of native and polymerised alpha 1-antitrypsin on primary human monocytes, in vitro
- 2004
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In: BMC Cell Biology. - : Springer Science and Business Media LLC. - 1471-2121. ; 5
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Journal article (peer-reviewed)abstract
- Background: alpha1-antitrypsin (AAT) is one of the major serine proteinase inhibitors controlling proteinases in many biological pathways. There is increasing evidence that AAT is able to exert other than antiproteolytic effects. To further examine this question we compared how various doses of the native (inhibitory) and the polymerised (non- inhibitory) molecular form of AAT affect pro-inflammatory responses in human monocytes, in vitro. Human monocytes isolated from different donors were exposed to the native or polymerised form of AAT at concentrations of 0.01, 0.02, 0.05, 0.1, 0.5 and 1 mg/ml for 18 h, and analysed to determine the release of cytokines and to detect the activity of NF-kappaB. Results: We found that native and polymerised AAT at lower concentrations, such as 0.1 mg/ml, enhance expression of TNFalpha (10.9- and 4.8-fold, p < 0.001), IL-6 (22.8- and 23.4-fold, p < 0.001), IL-8 (2.4- and 5.5-fold, p < 0.001) and MCP-1 (8.3- and 7.7-fold, p < 0.001), respectively, compared to buffer exposed cells or cells treated with higher doses of AAT ( 0.5 and 1 mg/ml). In parallel to increased cytokine levels, low concentrations of either conformation of AAT (0.02-0.1 mg/ml) induced NF-kappaB p50 activation, while 1 mg/ml of either conformation of AAT suppressed the activity of NF-kappaB, compared to controls. Conclusions: The observations reported here provide further support for a central role of AAT in inflammation, both as a regulator of proteinase activity, and as a signalling molecule for the expression of pro-inflammatory molecules. This latter role is dependent on the concentration of AAT, rather than on its proteinase inhibitory activity.
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| 5. |
- Baker, Crystal, et al.
(author)
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Effects of Alzheimer's peptide and alpha 1-antichymotrypsin on astrocyte gene expression
- 2007
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In: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 28:1, s. 51-61
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Journal article (peer-reviewed)abstract
- We employed gene array technology to investigate the effects of alpha 1-antichymotrypsin (ACT), soluble or fibrillar Alzheimer's peptide (A beta(1-42)) alone and the combination of ACT/A beta(1-42) on human astrocytes. Using a 1.2-fold change as significance threshold, 398 astrocyte genes showed altered expression in response to these treatments compared to controls. Of the 276 genes affected by the ACT/soluble A beta(1-42) combination, 195 (70.6%) were suppressed. The ACT/fibrillar A beta(1-42) combination affected expression of 64 genes of which 58 (90.5%) were up-regulated. The most prominent gene expression changes in response to the ACT/soluble A beta(1-42), were the down-regulation of at least 60 genes involved in transcription, signal transduction, apoptosis and neurogenesis. The ACT/fibril A beta(1-42) increased the expression of genes involved in transcription regulation and signal transduction. Surprisingly, gene expression of astrocytes exposed to soluble or fibrillar A beta(1-42) alone was largely unaffected. Thus, the molecular forms generated by the combination of ACT/A beta(1-42) alter expression of astrocyte genes more profoundly in breadth and magnitude than soluble or fibrillar A beta(1-42) alone, suggesting that pathogenic effects of A beta(1-42) may occur as a consequence of its association with other proteins. (c) 2005 Elsevier Inc. All rights reserved.
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| 6. |
- Blanco Blanco, Ignacio, et al.
(author)
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Intravenous Infusions of Purified Alpha-1 Antitripsyn Effectively Controls Symptoms and Reverts Muscle Biopsy Changes in an MZ Alpha-1 Antitripsyn Deficiency and Fibromyalgia Syndrome Patient
- 2010
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In: Journal of Musculoskeletal Pain. - : Informa UK Limited. - 1540-7012 .- 1058-2452. ; 18:2, s. 167-172
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Journal article (peer-reviewed)abstract
- Background: An MZ phenotype alpha-1 antitrypsin [AAT] deficiency and fibromyalgia syndrome [FMS] patient participated in a trial with AAT-intravenous augmentationtherapy [AAT-IV-AT] after failure of conventional therapeutic measures. Three quadricep biopsies were performed at different stages. The first one showed large aggregates of AAT and ubiquitin in myocytes and blood vessels, and moderate muscle atrophy, before AAT-IV-AT. The two remaining biopsies were performed while receiving AAT-IV-AT. Findings: Remarkably good clinical response and histological improvement in the follow-up biopsies. Conclusions: The clinical and histopathological efficacy of AAT-IV-AT evidenced in this patient should open new perspectives of research and management of AAT deficiency and FMS patients.
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| 7. |
- Blanco, Ignacio, et al.
(author)
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Estimates of the prevalence and number of Fibromyalgia syndrome patients and their alpha-1 antitrypsin phenotypic distribution in ten countries
- 2007
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In: Journal of Musculoskeletal Pain. - 1540-7012. ; 15:4, s. 41540-41540
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Research review (peer-reviewed)abstract
- Objectives: During the last few years, clinical, epidemiological, and pathological evidence has suggested that inherited alpha-1 antitrypsin [AAT] deficiency might play a role in the development of the fibromyalgia syndrome [FMS], probably because of the loss of AAT anti-inflammatory efficacy. The objective of this study was to estimate the prevalence and number of FMS patients, and their AAT phenotypic distribution worldwide. Methods: A critical review selecting reliable studies on the subject. Results: Studies on AAT gene frequencies and FMS prevalence were retrieved for ten countries worldwide, namely Canada, the United States of America [USA], Denmark, Finland, Germany, Italy, the Netherlands, Spain, Sweden, and Pakistan. The severe deficiency Z allele was found in all these countries, with very high frequencies in Denmark and Sweden [23 and 27 per 1,000, respectively], high frequencies in Italy and Spain [16 and 17], intermediate frequencies in Germany, the Netherlands, Canada, and the USA [10 to 14], and a low frequency in Pakistan [nine per 1,000]. The calculated prevalence of AAT deficiency and the number of FMS patients with AAT deficiency were 1/10 and 25,408 in Canada, 1/11 and 478,681 in the US, 1/9 and 3,124 in Denmark, 1/36 and 726 in Finland, 1/16 and 48,523 in Germany, 1/13 and 84,876 in Italy, 1115 and 9,639 in the Netherlands, 1/4 and 114,359 in Spain, 1/11 and 9,065 in Sweden, and 1/25 and 85.965 in Pakistan. Our calculations predict that AAT deficiency would remain undetected in around nine percent of FMS patients, with about eight percent of them carrying moderate deficiency phenotypes [MS, SS, and MZ], and less than one percent with severe deficiency phenotypes [SZ and ZZ]. Conclusions: Therefore, AAT phenotype characterization should be recommended in FMS patients and the possible efficacy of AAT replacement therapy in severe deficiency FMS patients should warrant further Studies.
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| 8. |
- Blanco, Ignacio, et al.
(author)
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Low plasma levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF alpha), and vascular endothelial growth factor (VEGF) in patients with alpha1-antitrypsin deficiency-related fibromyalgia
- 2010
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In: Clinical Rheumatology. - : Springer Science and Business Media LLC. - 1434-9949 .- 0770-3198. ; 29:2, s. 189-197
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Journal article (peer-reviewed)abstract
- Abnormalities in blood inflammatory markers have been associated with clinical manifestations and the pathogenesis of the fibromyalgia syndrome (FMS); a relationship between inherited alpha1-antitrypsin deficiency (AATD) and FMS has also been recently raised. In this study, plasma levels of inflammatory markers in FMS patients with and without AATD have been investigated. Blood samples from 138 age-matched females (79 FMS) and 59 general population (GP), with normal MM [n = 82 (59.4%)] and with MS, MZ, SZ, and ZZ AATD genotypes [n = 56 (40.6%)], were analyzed by ELISA for monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF alpha), soluble TNF alpha receptors I and II, interleukin-8, and vascular endothelial growth factor (VEGF). Plasma levels of MCP-1, VEGF, and TNF alpha were significantly lower in FMS and GP subjects with AATD compared with those with normal MM-AAT genotypes. Moreover, plasma levels of MCP-1, VEGF, and TNF alpha were lower in AATD subjects with FMS than in those without FMS (P = 0.000, 0.000, and 0.046, respectively). No statistical differences were found for the other substances measured. Furthermore, a logistic regression model based on plasma MCP-1 cutoff value of a parts per thousand currency sign130 pg/ml allowed us to discriminate between FMS and GP subjects with a sensitivity of about 93% and a specificity of 79%. Low plasma levels of MCP-1, VEGF, and TNF alpha are related to AATD, although more markedly in FMS patients. Thus, hypotheses considering FMS as an inflammatory condition related to high plasma levels of inflammatory biomarkers cannot be supported.
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| 9. |
- Buchhave, Peder, et al.
(author)
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Elevated plasma levels of soluble CD40 in incipient Alzheimer's disease.
- 2009
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In: Neuroscience letters. - : Elsevier BV. - 0304-3940. ; 450:1, s. 56-9
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Journal article (peer-reviewed)abstract
- CD40 is a member of the tumor necrosis factor receptor super-family and has been suggested to play a role in the metabolism of beta-amyloid (Abeta) in Alzheimer's disease (AD). However, the role of CD40-signalling in incipient AD has not yet been studied. We investigated the plasma levels of soluble CD40 (sCD40) and the soluble CD40 ligand (sCD40L) at baseline in 136 subjects with mild cognitive impairment (MCI) and 30 age-matched controls. Sixty of the 136 MCI cases converted to AD (MCI-AD) during a clinical follow-up period of 4-7 years. The baseline levels of sCD40, but not sCD40L, were elevated in MCI-AD cases when compared to age-matched controls (Mann-Whitney U-test, p=0.02). However, MCI patients who were cognitively stable or developed vascular dementia during follow-up did not have significantly increased levels of sCD40 or sCD40L when compared to controls. The levels of sCD40 correlated to decreased baseline performance on mini-mental state examination (MMSE) in both controls (r(s)=-0.37, p<0.05) and MCI-AD cases (r(s)=-0.29, p<0.05). Finally, the plasma levels of sCD40 correlated with the levels of soluble amyloid precursor protein-alpha (sAPP-alpha) (r(s)=0.28, p<0.01) and sAPP-beta (r(s)=0.23, p<0.05) in cerebrospinal fluid. In conclusion, CD40-signalling might play a role in the pathogenesis of early AD.
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| 10. |
- Buchhave, Peder, et al.
(author)
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Soluble TNF receptors are associated with Abeta metabolism and conversion to dementia in subjects with mild cognitive impairment.
- 2010
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In: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 31:11, s. 1877-1884
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Journal article (peer-reviewed)abstract
- OBJECTIVE: There is evidence supporting that tumor necrosis factor receptor (TNFR)-signaling can induce production of beta-amyloid (Abeta) in the brain. Moreover, amyloid-induced toxicity has been shown to be dependent on TNFR-signaling. However, it is still unclear whether TNFRs are involved in the early stages of dementia. METHODS: We analyzed soluble TNFR1 and TNFR2 levels in plasma and cerebrospinal fluid (CSF) at baseline in 137 patients with mild cognitive impairment (MCI) and 30 age-matched controls. The MCI patients were followed for 4-6 years with an incidence of Alzheimer's disease (AD) or vascular dementia (VaD) of 15% per year. RESULTS: The patients with MCI who subsequently developed these forms of dementias had higher levels of sTNFR1 and sTNFR2 in both CSF and plasma already at baseline when compared to age-matched controls (p<0.05). In the CSF of MCI subjects and controls the levels of both sTNFR1 and sTNFR2 correlated strongly with beta-site APP-cleaving enzyme 1 (BACE1) activity (r(s)=0.53-0.68, p<0.01) and Abeta 40 levels (r(s)=0.59-0.71, p<0.001). Similarly, both sTNFRs were associated with Abeta 40 (r(s)=0.39-0.46, p<0.05) in plasma. Finally, the levels of both sTNFRs correlated with the axonal damage marker tau in the CSF of MCI subjects and controls (r(s)=0.57-0.83, p<0.001). CONCLUSION: TNFR-signaling might be involved in the early pathogenesis of AD and VaD, and could be associated with beta-amyloid metabolism.
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