| 1. |
- Cao, Renhai, et al.
(författare)
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Mouse corneal lymphangiogenesis model.
- 2011
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Ingår i: Nature protocols. - : Springer Science and Business Media LLC. - 1750-2799 .- 1754-2189. ; 6:6, s. 817-26
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Tidskriftsartikel (refereegranskat)abstract
- This protocol describes a powerful in vivo method to quantitatively study the formation of new lymphatic vessels in the avascular cornea without interference of pre-existing lymphatics. Implantation of 100 ng of lymphangiogenic factors such as vascular endothelial growth factor (VEGF)-A, VEGF-C or fibroblast growth factor-2, together with slow-release polymers, into a surgically created micropocket in the mouse cornea elicits a robust lymphangiogenic response. Newly formed lymphatic vessels are detected by immunohistochemical staining of the flattened corneal tissue with lymphatic endothelial-specific markers such as lymphatic vessel endothelial hyaluronan receptor-1; less-specific markers such as vascular endothelial growth factor receptor 3 may also be used. Lymphatic vessel growth in relation to hemangiogenesis can be readily detected starting at day 5 or 6 after pellet implantation and persists for ∼14 d. This protocol offers a unique opportunity to study the mechanisms underlying lymphatic vessel formation, remodeling and function.
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| 2. |
- Cao, Yihai, et al.
(författare)
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Forty-Year Journey of Angiogenesis Translational Research
- 2011
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 3:114
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Forskningsöversikt (refereegranskat)abstract
- Forty years ago, Judah Folkman predicted that tumor growth is dependent on angiogenesis and that inhibiting this process might be a new strategy for cancer therapy. This hypothesis formed the foundation of a new field of research that represents an excellent example of how a groundbreaking scientific discovery can be translated to yield benefits for patients. Today, antiangiogenic drugs are used to treat human cancers and retinal vascular diseases. Here, we guide readers through 40 years of angiogenesis research and discuss challenges of antiangiogenic therapy.
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| 3. |
- Dong, Mei, et al.
(författare)
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Cold Exposure Promotes Atherosclerotic Plaque Growth and Instability via UCP1-Dependent Lipolysis
- 2013
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Ingår i: Cell Metabolism. - : Elsevier (Cell Press). - 1550-4131 .- 1932-7420. ; 18:1, s. 118-129
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Tidskriftsartikel (refereegranskat)abstract
- Molecular mechanisms underlying the cold-associated high cardiovascular risk remain unknown. Here, we show that the cold-triggered food-intake-independent lipolysis significantly increased plasma levels of small low-density lipoprotein (LDL) remnants, leading to accelerated development of atherosclerotic lesions in mice. In two genetic mouse knockout models (apolipoprotein E-/- [ApoE(-/-)] and LDL receptor(-/-) [Ldlr(-/-)] mice), persistent cold exposure stimulated atherosclerotic plaque growth by increasing lipid deposition. Furthermore, marked increase of inflammatory cells and plaque-associated microvessels were detected in the cold-acclimated ApoE(-/-) and Ldlr(-/-) mice, leading to plaque instability. Deletion of uncoupling protein 1 (UCP1), a key mitochondrial protein involved in thermogenesis in brown adipose tissue (BAT), in the ApoE(-/-) strain completely protected mice from the cold-induced atherosclerotic lesions. Cold acclimation markedly reduced plasma levels of adiponectin, and systemic delivery of adiponectin protected ApoE(-/-) mice from plaque development. These findings provide mechanistic insights on low-temperature-associated cardiovascular risks.
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| 4. |
- Honek, Jennifer, et al.
(författare)
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Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues
- 2014
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:41, s. 14906-14911
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Tidskriftsartikel (refereegranskat)abstract
- Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti-VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs.
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| 5. |
- Hosaka, Kayoko, et al.
(författare)
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Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis
- 2013
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Ingår i: Nature Communications. - : Nature Publishing Group: Nature Communications. - 2041-1723. ; 4:2129
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Tidskriftsartikel (refereegranskat)abstract
- Anti-platelet-derived growth factor (PDGF) drugs are routinely used in front-line therapy for the treatment of various cancers, but the molecular mechanism underlying their dose-dependent impact on vascular remodelling remains poorly understood. Here we show that anti-PDGF drugs significantly inhibit tumour growth and metastasis in high PDGF-BB-producing tumours by preventing pericyte loss and vascular permeability, whereas they promote tumour cell dissemination and metastasis in PDGF-BB-low-producing or PDGF-BB-negative tumours by ablating pericytes from tumour vessels. We show that this opposing effect is due to PDGF-beta signalling in pericytes. Persistent exposure of pericytes to PDGF-BB markedly downregulates PDGF-beta and inactivation of the PDGF-beta signalling decreases integrin alpha 1 beta 1 levels, which impairs pericyte adhesion to extracellular matrix components in blood vessels. Our data suggest that tumour PDGF-BB levels may serve as a biomarker for selection of tumour-bearing hosts for anti-PDGF therapy and unsupervised use of anti-PDGF drugs could potentially promote tumour invasion and metastasis.
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| 6. |
- Ji, Hong, et al.
(författare)
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TNFR1 mediates TNF-alpha-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling
- 2014
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Ingår i: Nature Communications. - : Nature Publishing Group: Nature Communications. - 2041-1723. ; 5:4944
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation and lymphangiogenesis are two cohesively coupled processes that promote tumour growth and invasion. Here we report that TNF-alpha markedly promotes tumour lymphangiogenesis and lymphatic metastasis. The TNF-alpha-TNFR1 signalling pathway directly stimulates lymphatic endothelial cell activity through a VEGFR3-independent mechanism. However, VEGFR3-induced lymphatic endothelial cell tips are a prerequisite for lymphatic vessel growth in vivo, and a VEGFR3 blockade completely ablates TNF-alpha-induced lymphangiogenesis. Moreover, TNF-alpha-TNFR1-activated inflammatory macrophages produce high levels of VEGF-C to coordinately activate VEGFR3. Genetic deletion of TNFR1 (Tnfr1(-/-)) in mice or depletion of tumour-associated macrophages (TAMs) virtually eliminates TNF-alpha-induced lymphangiogenesis and lymphatic metastasis. Gain-of-function experiments show that reconstitution of Tnfr1(+/+) macrophages in Tnfr1(+/+) mice largely restores tumour lymphangiogenesis and lymphatic metastasis. These findings shed mechanistic light on the intimate interplay between inflammation and lymphangiogenesis in cancer metastasis, and propose therapeutic intervention of lymphatic metastasis by targeting the TNF-alpha-TNFR1 pathway.
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| 7. |
- Lim, Sharon, et al.
(författare)
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Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis
- 2016
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 7:25, s. 38282-38291
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Tidskriftsartikel (refereegranskat)abstract
- Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth.
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| 8. |
- Lim, Sharon, et al.
(författare)
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Cold-induced activation of brown adipose tissue and adipose angiogenesis in mice
- 2012
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Ingår i: Nature Protocols. - : Nature Publishing Group. - 1754-2189 .- 1750-2799. ; 7:3, s. 606-615
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Tidskriftsartikel (refereegranskat)abstract
- Exposure of humans and rodents to cold activates thermogenic activity in brown adipose tissue (BAT). This protocol describes a mouse model to study the activation of BAT and angiogenesis in adipose tissues by cold acclimation. After a 1-week exposure to 4 degrees C, adult C57BL/6 mice show an obvious transition from subcutaneous white adipose tissue (WAT) into brown-like adipose tissue (BRITE). The BRITE phenotype persists after continuous cold exposure, and by the end of week 5 BRITE contains a high number of uncoupling protein-1-positive mitochondria, a characteristic feature of BAT. During the transition from WAT into BRITE, the vascular density is markedly increased owing to the activation of angiogenesis. In BAT, cold exposure stimulates thermogenesis by increasing the mitochondrial content and metabolic rate. BAT and the increased metabolic rate result in a lean phenotype. This protocol provides an outstanding opportunity to study the molecular mechanisms that control adipose mass.
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| 9. |
- Lim, Sharon Osmena, et al.
(författare)
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Cosmetic preservative labeling in Philippine products in accordance with Philippine regulations
- 2022
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Ingår i: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 86:6, s. 524-530
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Tidskriftsartikel (refereegranskat)abstract
- Background: Preservatives are usually added to a wide array of consumer products to prevent growth of microbes and to prevent product destabilization and degradation. However, many of these preservatives are common skin sensitizers and may cause allergic contact dermatitis. The amount of preservatives may vary per country or region according to their respective legislation and may be reported in differences in prevalence rates of contact dermatitis. Objective: To examine and identify preservatives in consumer products in accordance with Philippine legislation. To verify the accuracy of the list of ingredients of Philippine cosmetic products as legislated by the Philippine Bureau of Food and Drug Administration. Methods: A total of 65 commonly used Philippine consumer products ranging from liquid facial and body washes, bar soaps, laundry detergents, feminine hygiene washes and wipes, shampoos and conditioners, sunblock, and moisturizers were selected. Ingredients noted on labels were documented. Products were subsequently investigated chemically for the presence of methylchloroisothiazolinone, methylisothiazolinone, or formaldehyde. Results: The preservatives most commonly used in cosmetic products in the Philippine market are methylchloroisothiazolinone (MCI), methylisothiazolinone (MI), and/or formaldehyde. In accordance with Philippine legislation, almost all products provided a detailed ingredient list as printed on the packaging. Measurements of MCI/MI ranged from less than 1 ppm to 16 ppm, and MI ranged from only less than 1 ppm to 66 ppm, whereas formaldehyde was noted to range from less than 2.5 ppm to greater than 40 ppm in the products tested. Most products are manufactured by international brands, with a few products being manufactured locally. Conclusions: The preservatives found in cosmetic products were MCI, MI, and formaldehyde. Discrepancies were found in the preservatives and labeling of these products, with a majority of investigated Philippine products labeled inaccurately with varying concentrations of preservatives.
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| 10. |
- Lim, Sharon Siew Hoon
(författare)
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Angiogenic mechanims in adipose tissue and tumor
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Angiogenesis is involved in the development and progression of many human diseases, including cancer, cardiovascular diseases, chronic inflammation, and metabolic diseases. Despite differences in microenvironment under various pathological settings, angiogenic blood vessels share some common features in numerous diseases. This thesis reveals novel molecular mechanisms of angiogenesis in tumors and adipose tissues, as well as defining potential therapeutic targets for treatment of cancer and obesity-associated metabolic diseases. In Paper I, we showed that PDGF-BB is a tumor-derived vascular remodeling factor that promotes tumor growth through activation of stromal fibroblasts and perivascular cells in tumor microenvironment. Tumor-derived PDGF-BB activates stromal fibroblasts to produce erythropoietin (Epo), which in turn triggers extramedullary hematopoiesis thereby enhancing oxygen perfusion in tumor vasculatures leading to an accelerated tumor growth rate. Epo is also known as a potent angiogenic factor which acts directly on endothelial cells (ECs) to induce tumor neovascularization. Therefore, PDGF-BB modulates tumor angiogenesis, vascular remodeling and hematopoiesis, via activation of the Epo signaling pathway, thus facilitating tumor growth, invasion and possibly reduces drug responsiveness. Understanding the role of Epo in promoting tumor growth and angiogenesis not only provides novel mechanistic insights into the complex interplay between various signaling pathways involved in the stimulation of angiogenesis, but also highlights the risk associated with using Epo in treatment of cancer-associated anemia. In Paper II, we used mouse tumor models to propose a novel mechanism underlying the combination therapy consisting of anti-angiogenic and chemotherapeutic agents commonly used in human patients. We showed that tumorderived VEGF induces severe aplastic anemia in mice, and delivery of chemotherapeutics to these tumor-bearing mice led to an earlier demise due to the synergistic or additive suppression of bone marrow hematopoiesis by VEGF and chemotherapy. Switching to a sequential delivery of anti-angiogenic drugs prior to administration of chemotherapeutics drugs resulted in significant recovery of bone marrow hematopoiesis, and thus markedly increased tolerance to chemotoxicity. Given the fact that a significant number of cancer patients die of chemotoxicity, our findings provide an important mechanism in which anti-angiogenic drugs decreases chemotoxicity. In Paper III, we discuss the novel methods we developed for the study of adipose angiogenesis, which are becoming increasingly used by other scientists. In Paper IV, we showed for the first time that cold acclimation of mice markedly activates an angiogenic phenotype via sympathetic upregulation of VEGF expression. Importantly, inhibition of angiogenesis significantly modulates adipose metabolism. This work provides the first example where targeting adipose vasculature might provide a novel therapeutic approach for the treatment of obesity and metabolic diseases.
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