Association between Organochlorine Pesticide Levels in Breast Milk and Their Effects on Female Reproduction in a Taiwanese Population.

Only few studies have focused on organochlorine pesticides (OCPs) in breast milk and the related health risks for women in Taiwan. Our goal is to examine breast milk OCPs and their associations with female reproductive function (infertility, gynecological diseases, and menstruation characteristics) as well as their correlation with sociodemographic parameters (age, pre-pregnant body mass index (BMI), annual incomes, population, birth year, and parity) and dietary habit. The breast milk samples were collected in southern Taiwan (n = 68) from 2013 to 2016 and the OCP residues were analyzed using high resolution gas chromatography with low resolution mass spectrometry (HRGC/LRMS). The results show that the most abundant OCP residues in the breast milk was ΣDDT with the geometric mean ± standard deviation of 9.81 ± 7.52 ng−1 lipid−1 followed by ΣHCH (0.539 ± 0.557 ng−1·lipid−1). In the principal component analysis, cis-chlordane (cis-CHL) and γ-HCH were found to be related to participants who received medical treatment for infertility, and 4,4′-DDT was associated with those who received gynecological surgery. The logistic regression showed that the odds ratio (OR) of log γ-hexachlorocyclohexane (γ-HCH) was higher for mothers who had received medical treatment for infertility than for the normal group (OR = 25.6, p = 0.035) after adjustments for age, pre-pregnant BMI, annual income, population (i.e., native-born Taiwanese), birth year, and parity. Cow milk and beef consumption as well as menstruation characteristics such as average menstrual period (>5 days), shortest menstrual period (<3 days), and women who had taken hormonal drugs were significantly associated to several OCP residues in the breast milk. In addition, ΣHCH including β-HCH and γ-HCH was correlated with annual family income and gravidity as well as cow milk and beef consumptions. Overall, γ-HCH exhibited a probable association with the infertility diseases of Taiwanese women, and dietary habit might play an important role in the female Taiwanese exposure to OCPs.

Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol alleviates elastase-induced emphysema in a mouse model.

Chronic obstructive pulmonary disease (COPD) is a sustained blockage of the airways due to lung inflammation occurring with chronic bronchitis and/or emphysema. Progression of emphysema may be slowed by vascular endothelial growth factor A (VEGFA), which reduces apoptotic tissue depletion. Previously, authors of the present report demonstrated that cis-resveratrol (c-RSV)-induced heat-shock protein 70 (HSP70) promoter-regulated VEGFA expression promoted neovascularization of genetically modified mesenchymal stem cells (HSP-VEGFA-MSC) in a mouse model of ischemic disease. Here, this same stem cell line was evaluated for its protective capacity to alleviate elastase-induced pulmonary emphysema in mice. Results of this study showed that c-RSV-treatment of HSP-VEGFA-MSC exhibited synergy between HSP70 transcription activity and induced expression of anti-oxidant-related genes when challenged by cigarette smoke extracts. Eight weeks after jugular vein injection of HSP-VEGFA-MSC into mice with elastase-induced pulmonary emphysema followed by c-RSV treatment to induce transgene expression, significant improvement was observed in respiratory functions. Expression of VEGFA, endogenous nuclear factor erythroid 2-related factor (Nrf 2), and manganese superoxide dismutase (MnSOD) was significantly increased in the lung tissues of the c-RSV-treated mice. Histopathologic examination of treated mice revealed gradual but significant abatement of emphysema and restoration of airspace volume. In conclusion, the present investigation demonstrates that c-RSV-regulated VEGFA expression in HSP-VEGFA-MSC significantly improved the therapeutic effects on the treatment of COPD in the mouse, possibly avoiding side effects associated with constitutive VEGFA expression.

Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis is a progressive diffuse parenchymal lung disorder of unknown etiology. Mesenchymal stem cell (MSC)-based therapy is a novel approach with great therapeutic potential for the treatment of lung diseases. Despite demonstration of MSC grafting, the populations of engrafted MSCs have been shown to decrease dramatically 24 hours post-transplantation due to exposure to harsh microenvironments. Hypoxia is known to induce expression of cytoprotective genes and also secretion of anti-inflammatory, anti-apoptotic and anti-fibrotic factors. Hypoxic preconditioning is thought to enhance the therapeutic potency and duration of survival of engrafted MSCs. In this work, we aimed to prolong the duration of survival of engrafted MSCs and to enhance the effectiveness of idiopathic pulmonary fibrosis transplantation therapy by the use of hypoxia-preconditioned MSCs. METHODS: Hypoxic preconditioning was achieved in MSCs under an optimal hypoxic environment. The expression levels of cytoprotective factors and their biological effects on damaged alveolar epithelial cells or transforming growth factor-beta 1-treated fibroblast cells were studied in co-culture experiments in vitro. Furthermore, hypoxia-preconditioned MSCs (HP-MSCs) were intratracheally instilled into bleomycin-induced pulmonary fibrosis mice at day 3, and lung functions, cellular, molecular and pathological changes were assessed at 7 and 21 days after bleomycin administration. RESULTS: The expression of genes for pro-survival, anti-apoptotic, anti-oxidant and growth factors was upregulated in MSCs under hypoxic conditions. In transforming growth factor-beta 1-treated MRC-5 fibroblast cells, hypoxia-preconditioned MSCs attenuated extracellular matrix production through paracrine effects. The pulmonary respiratory functions significantly improved for up to 18 days of hypoxia-preconditioned MSC treatment. Expression of inflammatory factors and fibrotic factor were all downregulated in the lung tissues of the hypoxia-preconditioned MSC-treated mice. Histopathologic examination observed a significant amelioration of the lung fibrosis. Several LacZ-labeled MSCs were observed within the lungs in the hypoxia-preconditioned MSC treatment groups at day 21, but no signals were detected in the normoxic MSC group. Our data further demonstrated that upregulation of hepatocyte growth factor possibly played an important role in mediating the therapeutic effects of transplanted hypoxia-preconditioned MSCs. CONCLUSION: Transplantation of hypoxia-preconditioned MSCs exerted better therapeutic effects in bleomycin-induced pulmonary fibrotic mice and enhanced the survival rate of engrafted MSCs, partially due to the upregulation of hepatocyte growth factor.

Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol promotes angiogenesis in a mouse model.

Several studies of stem cell-based gene therapy have indicated that long-lasting regeneration following vessel ischemia may be stimulated through VEGFA gene therapy and/or MSC transplantation for reduction of ischemic injury in limb ischemia and heart failure. The therapeutic potential of MSC transplantation can be further improved by genetically modifying MSCs with genes which enhance angiogenesis following ischemic injury. In the present study, we aimed to develop an approach in MSC-based therapy for repair and mitigation of ischemic injury and regeneration of damaged tissues in ischemic disease. HSP70 promoter-driven VEGFA expression was induced by resveratrol (RSV) in MSCs, and in combination with known RSV biological functions, the protective effects of our approach were investigated by using ex vivo aortic ring coculture system and a 3D scaffolds in vivo model. Results of this investigation demonstrated that HSP promoter-driven VEGFA expression in MSC increased approximately 2-fold over the background VEGFA levels upon HSP70 promoter induction by RSV. Exposure of HUVEC cells to medium containing MSC in which VEGFA had been induced by cis-RSV enhanced tube formation in the treated HUVEC cells. RSV-treated MSC cells differentiated into endothelial-like phenotypes, exhibiting markedly elevated expression of endothelial cell markers. These MSCs also induced aortic ring sprouting, characteristic of neovascular formation from pre-existing vessels, and additionally promoted neovascularization at the MSC transplantation site in a mouse model. These observations support a hypothesis that VEGFA expression induced by cis-RSV acting on the HSP70 promoter in transplanted MSC augments the angiogenic effects of stem cell gene therapy. The use of an inducible system also vastly reduces possible clinical risks associated with constitutive VEGFA expression.

cis-Resveratrol produces anti-inflammatory effects by inhibiting canonical and non-canonical inflammasomes in macrophages.

Resveratrol, a natural phenolic compound found in red grapes and wine, exists as cis and trans isomers. Recent studies have shown that trans-resveratrol possesses anti-inflammatory, anti-oxidant, anti-carcinogenic, anti-tumor and immunomodulatory properties. However, it remains unclear whether cis-resveratrol may exhibit similar activities. The objective of the present study was to examine the effects of cis- and trans-resveratrol on the production of pro-inflammatory cytokines and mediators in human macrophages. We examined the possibility that cis- and trans-resveratrol may affect cytokine secretion by modulating inflammasomes, intracellular multi-protein complexes, the assembly of which leads to caspase-1 activation and secretion of active IL-1ß by macrophages. Our results show that pre-treatment of macrophages with cis-resveratrol not only reduces pro-IL-1ß production and IL-1ß secretion, but also suppresses ATP-induced transcription and activation of caspase-1 and caspase-4. Notably, cis-resveratrol inhibits the expression of the purinergic receptor, P2X(7)R, and the endoplasmic reticulum stress marker, Glc-regulated protein 78, but also reduces reactive oxygen species production. Moreover, cis-resveratrol attenuates cyclooxygenase-2 expression and prostaglandin E2 production. cis-Resveratrol also decreases the phosphorylation of p38 MAPK and expression of the c-Jun protein. These results indicate that cis-resveratrol produces anti-inflammatory effects by inhibiting both the canonical and non-canonical inflammasomes, and associated pathways in human macrophages.