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- Ahmed, Sultan, et al.
(författare)
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Arsenic-Associated Oxidative stress, Inflammation, and Immune Disruption in Human Placenta and Cord Blood
- 2011
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 119:2, s. 258-264
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Arsenic (As) exposure during pregnancy induces oxidative stress and increases the risk of fetal loss and low birth weight. OBJECTIVES: This study aimed to elucidate the effects of As exposure on immune markers in the placenta and cord blood, and the involvement of oxidative stress. METHODS: Pregnant women were enrolled around gestational week (GW) 8 in our longitudinal, population-based, mother-child cohort in Matlab, an area in rural Bangladesh with large variations in As concentrations in well water. Women (n=130) delivering at local clinics were included in the present study. We collected maternal urine twice during pregnancy (GW8 and 30) for measurements of As, and placenta and cord blood at delivery for assessment of immune and inflammatory markers. Placental markers were measured by immunohistochemistry and cord blood cytokines by multiplex cytokine assay. RESULTS: In multivariable adjusted models, maternal urinary As (U-As) exposure both at GW8 and 30 was significantly positively associated with placental markers of 8-oxoguanine (8-oxoG) and IL-1β, U-As at GW8 with TNF- α and IFN-γ, U-As at GW30 with leptin , and U-As at GW8 was inversely associated with CD3-T cells in the placenta. Cord blood cytokines (IL-1β, IL-8, IFN-γ, TNF-α) showed a U-shaped association with U-As at GW30. Placental 8-oxoG was significantly positively associated with placental pro-inflammatory cytokines. Multivariable adjusted analyses suggested that enhanced placental cytokine expression (TNF-α and IFN-γ) was primarily influenced by oxidative stress, while leptin expression appeared to be mostly mediated by As, and IL-1β appeared to be influenced by both oxidative stress and As. CONCLUSION: As exposure during pregnancy appeared to enhance placental inflammatory responses (in part by increasing oxidative stress), reduce placental T cells, and alter cord blood cytokines. These findings suggest that effects of As on immune function may contribute to impaired fetal and infant health.
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| 2. |
- Ahmed, Sultan, et al.
(författare)
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Arsenic Exposure Affects Plasma Insulin-Like Growth Factor 1 (IGF-1) in Children in Rural Bangladesh
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11, s. e81530-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Exposure to inorganic arsenic (As) through drinking water during pregnancy is associated with lower birth size and child growth. The aim of the study was to assess the effects of As exposure on child growth parameters to evaluate causal associations. Methodology/Findings: Children born in a longitudinal mother-child cohort in rural Bangladesh were studied at 4.5 years (n=640) as well as at birth (n=134). Exposure to arsenic was assessed by concurrent and prenatal (maternal) urinary concentrations of arsenic metabolites (U-As). Associations with plasma concentrations of insulin-like growth factor 1 (IGF-1), calcium (Ca), vitamin D (Vit-D), bone-specific alkaline phosphatase (B-ALP), intact parathyroid hormone (iPTH), and phosphate (PO4) were evaluated by linear regression analysis, adjusted for socioeconomic factor, parity and child sex. Child U-As (per 10 mu g/L) was significantly inversely associated with concurrent plasma IGF-1 (beta=-0.27; 95% confidence interval: -0.50, -0.0042) at 4.5 years. The effect was more obvious in girls (beta=-0.29; -0.59, 0.021) than in boys, and particularly in girls with adequate height (beta=-0.491; -0.97, -0.02) or weight (beta=-0.47; 0.97, 0.01). Maternal U-As was inversely associated with child IGF-1 at birth (r=-0.254, P=0.003), but not at 4.5 years. There was a tendency of positive association between U-As and plasma PO4 in stunted boys (beta=0.27; 0.089, 0.46). When stratified by % monomethylarsonic acid (MMA, arsenic metabolite) (median split at 9.7%), a much stronger inverse association between U-As and IGF-1 in the girls (beta=-0.41; -0.77, -0.03) was obtained above the median split. Conclusion: The results suggest that As-related growth impairment in children is mediated, at least partly, through suppressed IGF-1 levels.
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| 3. |
- Doi, Mariko, et al.
(författare)
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Association between calcium in cord blood and newborn size in Bangladesh
- 2011
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Ingår i: British Journal of Nutrition. - 0007-1145 .- 1475-2662. ; 106:9, s. 1398-1407
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Tidskriftsartikel (refereegranskat)abstract
- Ca status in the uterus during pregnancy has been suggested to affect fetal growth and size at birth. In Bangladesh, low Ca levels in pregnant women and low birth weight in infants are common. The present study explored the association between Ca levels in cord blood and newborn size at birth (birth weight and birth length) in Bangladesh. Samples and data included 223 women with live-born singleton deliveries in rural Bangladesh. Newborn weight and length were measured at birth. From cord blood obtained at delivery, Ca, 25-hydroxy vitamin D, bone-specific alkaline phosphatase and intact parathyroid hormone levels were determined. An association between size at birth and Ca levels in cord blood was found (birth weight, P = 0·022; birth length, P = 0·001). Associations between Ca and newborn size were further analysed using multivariate regression analyses. After adjusting for several covariates of characteristics in mothers and newborns (gestational weeks at birth, sex of newborn, socio-economic status, maternal height, BMI, age and season at birth), birth length still exhibited a significant relationship with Ca levels in cord blood (birth length, P = 0·030). The present study indicates that Ca status in cord blood might be associated with the birth length of newborns. Ca levels during gestation may affect fetal growth.
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| 4. |
- Muvva, Jagadeeswara Rao, et al.
(författare)
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Immunomodulatory Agents Combat Multidrug-Resistant Tuberculosis by Improving Antimicrobial Immunity
- 2021
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 224:2, s. 332-344
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Tidskriftsartikel (refereegranskat)abstract
- Background. Multidrug-resistant (MDR) tuberculosis has low treatment success rates, and new treatment strategies are needed. We explored whether treatment with active vitamin D-3 (vitD) and phenylbutyrate (PBA) could improve conventional chemotherapy by enhancing immune-mediated eradication of Mycobacterium tuberculosis. Methods. A clinically relevant model was used consisting of human macrophages infected with M. tuberculosis isolates (n = 15) with different antibiotic resistance profiles. The antimicrobial effect of vitD+PBA, was tested together with rifampicin or isoniazid. Methods included colony-forming units (intracellular bacterial growth), messenger RNA expression analyses (LL-37, beta-defensin, nitric oxide synthase, and dual oxidase 2), RNA interference (LL-37-silencing in primary macrophages), and Western blot analysis and confocal microscopy (LL-37 and LC3 protein expression). Results. VitD+PBA inhibited growth of clinical MDR tuberculosis strains in human macrophages and strengthened intracellular growth inhibition of rifampicin and isoniazid via induction of the antimicrobial peptide LL-37 and I,C3-dependent autophagy. Gene silencing of LL-37 expression enhanced MDR tuberculosis growth in vitD+PBA-treated macrophages. Me combination of vitD+PBA and isoniazid were as effective in reducing intracellular MDR tuberculosis growth as a >125-fold higher dose of isoniazid alone, suggesting potent additive effects of vitD+PBA with isoniazid. Conclusions. Immunomodulatory agents that trigger multiple immune pathways can strengthen standard MDR tuberculosis treatment and contribute to next-generation individualized treatment options for patients with difficult-to-treat pulmonary tuberculosis.
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| 5. |
- Rekha, Rokeya Sultana
(författare)
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Role of antimicrobial peptides in tuberculosis and respiratory tract infections : clinical and mechanistic studies
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antimicrobial peptides (AMPs) are effector molecules of the innate immune system in multicellular organisms. They are mainly expressed in epithelial cells and immune cells, providing the first line of defense against a wide range of pathogens. AMPs are able to kill pathogens and show additional important functions such as chemotaxis, angiogenesis, and wound healing. These peptides are constitutively expressed; however, their expression can also be induced or suppressed by different stimuli in a cell and tissue specific manner. The overall aim of the present thesis was to elucidate the role of AMPs in tuberculosis and respiratory tract infections by clinical and mechanistic studies. Vitamin D3 (vitD3) is known as a potent inducer of AMPs. Low levels of serum vitD3 are associated with an increased risk of respiratory tract infections (RTIs). One of our objectives was to elucidate whether supplementation with vitD3 could reduce infectious symptoms and antibiotic consumption in patients with antibody deficiency or frequent RTIs. Patients (n=140) were included with symptoms of respiratory tract infections for more than 42 days over a 12-month period. They were randomized and received either vitD3 (4000 IU) or placebo daily for one year. The primary endpoint was an infectious score based on five parameters: symptoms from the respiratory tract, sinuses, and ears, malaise, and antibiotic consumption. Secondary endpoints were serum 25-hydroxyvitamin D3 [25(OH)D3] levels, microbiological outcomes, and the levels of the antimicrobial peptides LL-37 and Human Neutrophil Peptides (HNP) 1-3 in nasal fluids. We observed that vitD3 supplementation reduced infectious score, antibiotic consumption, and increased serum 25(OH)D3 concentrations in the patients compared to placebo control group. However, no major changes were observed for LL-37 and HNP 1-3. To control the global spread of tuberculosis (TB) and multi-drug resistance TB, development of new anti-tuberculosis drugs and alternative treatment strategies are urgently required. PBA is a potent inducer of AMPs, and together with 1,25-dihydroxyvitamin D3, it synergistically induces the expression of LL-37 in lung epithelial cell line. Thus, we aimed to estimate a therapeutic dose of PBA alone, or in combination with vitD3 for the induction of LL-37 expression in immune cells, and enhanced antimycobacterial activity in monocyte-derived macrophages (MDMs). Healthy volunteers were enrolled in an 8-days open trial (n=15). The expression of the CAMP (cathelicidin antimicrobial peptide) gene encoding LL-37 was measured in immune cells both in mRNA and peptide levels. MDM-mediated killing of Mycobacterium tuberculosis (Mtb) (H37Rv) was performed. From this trial, we demonstrated that 500 mg PBA twice daily with 5000 IU vitD3 once daily was the optimal dose for the induction of LL-37 in MDMs and lymphocytes, and the enhancement of intracellular killing of Mtb by MDMs. Using these findings, we further investigated if oral adjunctive therapy with 5000 IU vitD3 and/or 2x500 mg PBA along with standard anti-TB therapy would lead to an enhanced recovery in sputum smear-positive pulmonary TB patients. Adult TB patients (n=288) were enrolled in a randomized, double-blind, placebo-controlled trial. Primary endpoints were the proportion of patients with a negative sputum culture at week 4, and the reduction in clinical symptoms at week 8. Secondary endpoints included sputum smear conversion time, radiological findings, concentrations of 25(OH)D3 in plasma, expression of the antimicrobial peptide LL-37 in immune cells and intracellular killing of Mtb by MDMs. We found that the adjunct therapy with PBA and vitD3 treatment significantly reduced the sputum culture conversion time together with better clinical recovery in pulmonary tuberculosis patients. Additionally we observed that PBA and vitD3 treatment enhanced the expression of LL-37 in immune cells and increased intracellular killing of Mtb by MDMs. Next, we explored the potential mechanisms of PBA and LL-37-induced intracellular killing of Mtb in macrophages by autophagy. We observed that Mtb infection of MDMs downregulated the expression of LL-37 and certain autophagy-related genes (Beclin1 and ATG5) at both mRNA and protein levels. We also found that PBA and/or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] were able to overcome the Mtb-induced suppression of LL-37 expression. In addition, autophagy process was activated by stimulation of MDMs with PBA and promoted co-localization of LL-37 and LC3-II (a marker of autophagy) in autophagosomes. When LL-37 expression was silenced, PBA treatment failed to induce autophagy in Mtb-infected THP-1 cells. On the other hand, when LL-37 knockdown cells were supplemented with synthetic LL-37, autophagy was restored. Additionally, we found that LL-37-induced autophagy was mediated via the P2RX7 receptor and intracellular free Ca2+, the AMPK and the PI3K pathways. These results suggest that PBA induces autophagy in LL-37-dependent manner and promotes intracellular killing of Mtb in human MDMs. In summary, vitD3 supplementation could beneficial for the patients with antibody deficiency or frequent RTIs. PBA and vitD3 supplementation improves the clinical outcomes through the increased expression of LL-37, indicating that this supplementation might be an alternative strategy to treat pulmonary TB patients. The enhanced expression of LL-37 activates the cellular host defense mechanism autophagy, and subsequent killing of Mtb in human macrophages.
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