ROS release by PPARβ/δ-null fibroblasts reduces tumor load through epithelial antioxidant response.

Tumor stroma has an active role in the initiation, growth, and propagation of many tumor types by secreting growth factors and modulating redox status of the microenvironment. Although PPARβ/δ in fibroblasts was shown to modulate oxidative stress in the wound microenvironment, there has been no evidence of a similar effect in the tumor stroma. Here, we present evidence of oxidative stress modulation by intestinal stromal PPARβ/δ, using a FSPCre-Pparb/d <sup>-/-</sup> mouse model and validated it with immortalized cell lines. The FSPCre-Pparb/d <sup>-/-</sup> mice developed fewer intestinal polyps and survived longer when compared with Pparb/d <sup>fl/fl</sup> mice. The pre-treatment of FSPCre-Pparb/d <sup>-/-</sup> and Pparb/d <sup>fl/fl</sup> with antioxidant N-acetyl-cysteine prior DSS-induced tumorigenesis resulted in lower tumor load. Gene expression analyses implicated an altered oxidative stress processes. Indeed, the FSPCre-Pparb/d <sup>-/-</sup> intestinal tumors have reduced oxidative stress than Pparb/d <sup>fl/fl</sup> tumors. Similarly, the colorectal cancer cells and human colon epithelial cells also experienced lower oxidative stress when co-cultured with fibroblasts depleted of PPARβ/δ expression. Therefore, our results establish a role for fibroblast PPARβ/δ in epithelial-mesenchymal communication for ROS homeostasis

The role of peroxisome proliferator-activated receptor β/δ in colorectal cancer

Peroxisome proliferator–activated receptor β/δ (PPAR β/δ) is overexpressed in human colon cancer, but its contribution to colonic tumorigenesis is controversial. We generated a mouse model in which PPARβ/δ was genetically disrupted in the fibroblasts (FSPCre-Pparb/d-/-). FSPCre-Pparb/d-/- mice were less susceptible to DSS-induced colitis, developed fewer intestinal polyps and survived longer when compared with Pparb/dfl/fl mice. Comparative gene expression analysis of epithelial and mucosal layers revealed enhanced NRF2-mediated stress responses in intestinal epithelium owing to the deletion of fibroblast PPARβ/δ. The pre-treatment of FSPCre-Pparb/d−/− and Pparb/dfl/fl with antioxidant N-acetyl-cysteine prior DSS-induced tumorigenesis resulted in lower tumor load.​Doctor of Philosophy (SBS

Angiopoietin-like 4 Increases Pulmonary Tissue Leakiness and Damage during Influenza Pneumonia

Excessive host inflammatory responses negatively impact disease outcomes in respiratory infection. Host-pathogen interactions during the infective phase of influenza are well studied, but little is known about the host’s response during the repair stage. Here, we show that influenza infection stimulated the expression of angiopoietin-like 4 (ANGPTL4) via a direct IL6-STAT3-mediated mechanism. ANGPTL4 enhanced pulmonary tissue leakiness and exacerbated inflammation-induced lung damage. Treatment of infected mice with neutralizing anti-ANGPTL4 antibodies significantly accelerated lung recovery and improved lung tissue integrity. ANGPTL4-deficient mice also showed reduced lung damage and recovered faster from influenza infection when compared to their wild-type counterparts. Retrospective examination of human lung biopsy specimens from infection-induced pneumonia with tissue damage showed elevated expression of ANGPTL4 when compared to normal lung samples. These observations underscore the important role that ANGPTL4 plays in lung infection and damage and may facilitate future therapeutic strategies for the treatment of influenza pneumonia

Angiopoietin-like 4 Mediates Colonic Inflammation by Regulating Chemokine Transcript Stability via Tristetraprolin

Many gastrointestinal diseases exhibit a protracted and aggravated inflammatory response that can lead to hypercytokinaemia, culminating in extensive tissue damage. Recently, angiopoietin-like 4 (ANGPTL4) has been implicated in many inflammation-associated diseases. However, how ANGPTL4 regulates colonic inflammation remains unclear. Herein, we show that ANGPTL4 deficiency in mice (ANGPTL4−/−) exacerbated colonic inflammation induced by dextran sulfate sodium (DSS) or stearic acid. Microbiota was similar between the two genotypes prior DSS challenge. A microarray gene expression profile of the colon from DSS-treated ANGPTL4−/− mice was enriched for genes involved in leukocyte migration and infiltration, and showed a close association to inflamed ulcerative colitis (UC), whereas the profile from ANGPTL4+/+ littermates resembled that of non-inflamed UC biopsies. Bone marrow transplantation demonstrates the intrinsic role of colonic ANGPTL4 in regulating leukocyte infiltration during DSS-induced inflammation. Using immortalized human colon epithelial cells, we revealed that the ANGPTL4-mediated upregulation of tristetraprolin expression operates through CREB and NF-κB transcription factors, which in turn, regulates the stability of chemokines. Together, our findings suggest that ANGPTL4 protects against acute colonic inflammation and that its absence exacerbates the severity of inflammation. Our findings emphasize the importance of ANGPTL4 as a novel target for therapy in regulating and attenuating inflammation.MOE (Min. of Education, S’pore)Published versio

Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice

The incidence of nonmelanoma skin cancer (NMSC) has been increasing worldwide. Most studies have highlighted the importance of cancer-associated fibroblasts (CAFs) in NMSC progression. However much less is known about the communication between normal fibroblasts and epithelia; disruption of this communication affects tumor initiation and the latency period in the emergence of tumors. Delineating the mechanism that mediates this epithelial-mesenchymal communication in NMSC could identify more effective targeted therapies. The nuclear receptor PPARβ/δ in fibroblasts has been shown to modulate adjacent epithelial cell behavior, however, its role in skin tumorigenesis remains unknown. Using chemically induced skin carcinogenesis, we showed that FSPCre-Pparb/dex4 mice, whose Pparb/d gene was selectively deleted in fibroblasts, had delayed emergence and reduced tumor burden compared with control mice (Pparb/dfl/fl). However, FSPCre-Pparb/dex4-derived tumors showed increased proliferation, with no difference in differentiation, suggesting delayed tumor initiation. Network analysis revealed a link between dermal Pparb/d and TGF-β1 with epidermal NRF2 and Nox4. In vitro investigations showed that PPARβ/δ deficiency in fibroblasts increased epidermal Nox4-derived H2O2 production, which triggered an NRF2-mediated antioxidant response. We further showed that H2O2 upregulated NRF2 mRNA via the B-Raf-MEK1/2 pathway. The enhanced NRF2 response altered the activities of PTEN, Src, and AKT. In vivo, we detected the differential phosphorylation profiles of B-Raf, MEK1/2, PTEN, Src, and AKT in the vehicle-treated and chemically treated epidermis of FSPCre-Pparb/dex4 mice compared with that in Pparb/dfl/fl mice, prior to the first appearance of tumors in Pparb/dfl/fl. Our study revealed a role for fibroblast PPARβ/δ in the epithelial-mesenchymal communication involved in cellular redox homeostasis.Ministry of Education (MOE)Accepted versionThis research/project is supported by Start-Up Grant (M4082040) and Ministry of Education, Singapore, under Academic Research Fund Tier 1 (2017-T1-002-103) to NST, (2015-T1-001-034) to WW and Start-Up Grant from the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore to WW and XW; the Région Midi-Pyrénées through the Chaire d’Excellence Pierre de Fermat and the Bonizzi-Theler-Stiftung to WW; SERB-DST, Govt. of India funded Ramanujan Fellowship Grant (SB/S2/RJN-087/2014) to M

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified