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1.
Circ Res ; 131(2): e2-e21, 2022 07 08.
Article in English | MEDLINE | ID: mdl-35701867

ABSTRACT

BACKGROUND: Mutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion. METHODS: Various mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration. RESULTS: Piezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development. CONCLUSIONS: Piezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.


Subject(s)
Lymphatic Vessels , Lymphedema , Animals , Endothelial Cells/metabolism , Humans , Ion Channels/genetics , Ion Channels/metabolism , Lymphatic Vessels/metabolism , Lymphedema/metabolism , Mechanotransduction, Cellular/physiology , Mice , Transcription Factors/metabolism , Ubiquitin-Protein Ligases/metabolism
2.
Public Health Nurs ; 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38623869

ABSTRACT

OBJECTIVES: This study aimed to assess the educational needs and analyze the priorities of infection prevention and control (IPC) for community-visiting nurses. DESIGN: This is a cross-sectional descriptive study. SAMPLE: This study was conducted with 144 visiting nurses working in public health centers and long-term care facilities in South Korea. METHOD: A total of 23 questions in five subcategories were used to measure the current knowledge and perceived importance of IPC in community-visiting nursing. Data were collected from June 23 to October 30, 2021, during the COVID-19 pandemic. Data were analyzed paired t-test, the Borich needs assessment, and the Locus for Focus models. RESULTS: Top-priority content was defined as content belonging to two models, the first 10 contents of Borich needs assessment and the contents located in the Quadrant I of the Locus for Focus models. "Reporting in case of infection-related accidents," "Mandatory vaccination for visiting nurses," "Standard precaution," "Airborne precaution," "Contact precautions," "Respiratory infection control," and "Post-visit management." CONCLUSIONS: This study suggests that it is necessary to provide visiting nurses with more opportunities for IPC education and to develop standardized IPC programs that consider educational priorities.

3.
Development ; 147(23)2020 12 13.
Article in English | MEDLINE | ID: mdl-33060128

ABSTRACT

Lymphatic vasculature is an integral part of digestive, immune and circulatory systems. The homeobox transcription factor PROX1 is necessary for the development of lymphatic vessels, lymphatic valves (LVs) and lymphovenous valves (LVVs). We and others previously reported a feedback loop between PROX1 and vascular endothelial growth factor-C (VEGF-C) signaling. PROX1 promotes the expression of the VEGF-C receptor VEGFR3 in lymphatic endothelial cells (LECs). In turn, VEGF-C signaling maintains PROX1 expression in LECs. However, the mechanisms of PROX1/VEGF-C feedback loop remain poorly understood. Whether VEGF-C signaling is necessary for LV and LVV development is also unknown. Here, we report for the first time that VEGF-C signaling is necessary for valve morphogenesis. We have also discovered that the transcriptional co-activators YAP and TAZ are required to maintain PROX1 expression in LVs and LVVs in response to VEGF-C signaling. Deletion of Yap and Taz in the lymphatic vasculature of mouse embryos did not affect the formation of LVs or LVVs, but resulted in the degeneration of these structures. Our results have identified VEGF-C, YAP and TAZ as a crucial molecular pathway in valve development.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Cell Cycle Proteins/genetics , Homeodomain Proteins/genetics , Lymphangiogenesis/genetics , Trans-Activators/genetics , Tumor Suppressor Proteins/genetics , Vascular Endothelial Growth Factor C/genetics , Animals , Embryo, Mammalian , Embryonic Development/genetics , Gene Expression Regulation, Developmental/genetics , Humans , Lymphatic Vessels/cytology , Lymphatic Vessels/metabolism , Mice , Morphogenesis/genetics , Signal Transduction/genetics , Venous Valves/growth & development , Venous Valves/metabolism , YAP-Signaling Proteins
4.
Development ; 146(21)2019 11 05.
Article in English | MEDLINE | ID: mdl-31582413

ABSTRACT

Mutations in the transcription factor GATA2 cause lymphedema. GATA2 is necessary for the development of lymphatic valves and lymphovenous valves, and for the patterning of lymphatic vessels. Here, we report that GATA2 is not necessary for valvular endothelial cell (VEC) differentiation. Instead, GATA2 is required for VEC maintenance and morphogenesis. GATA2 is also necessary for the expression of the cell junction molecules VE-cadherin and claudin 5 in lymphatic vessels. We identified miR-126 as a target of GATA2, and miR-126-/- embryos recapitulate the phenotypes of mice lacking GATA2. Primary human lymphatic endothelial cells (HLECs) lacking GATA2 (HLECΔGATA2) have altered expression of claudin 5 and VE-cadherin, and blocking miR-126 activity in HLECs phenocopies these changes in expression. Importantly, overexpression of miR-126 in HLECΔGATA2 significantly rescues the cell junction defects. Thus, our work defines a new mechanism of GATA2 activity and uncovers miR-126 as a novel regulator of mammalian lymphatic vascular development.


Subject(s)
Endothelial Cells/metabolism , GATA2 Transcription Factor/metabolism , MicroRNAs/metabolism , Mutation , Angiopoietin-2/metabolism , Animals , CRISPR-Cas Systems , Calcium-Binding Proteins/metabolism , Cell Differentiation , Cell Line , Claudin-5/metabolism , EGF Family of Proteins/metabolism , Endothelium, Vascular/metabolism , Female , Gene Deletion , Humans , Lymphatic Vessels/cytology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , RNA-Seq
5.
Am J Pathol ; 190(12): 2355-2375, 2020 12.
Article in English | MEDLINE | ID: mdl-33039355

ABSTRACT

Despite many reports about pulmonary blood vessels in lung fibrosis, the contribution of lymphatics to fibrosis is unknown. We examined the mechanism and consequences of lymphatic remodeling in mice with lung fibrosis after bleomycin injury or telomere dysfunction. Widespread lymphangiogenesis was observed after bleomycin treatment and in fibrotic lungs of prospero homeobox 1-enhanced green fluorescent protein (Prox1-EGFP) transgenic mice with telomere dysfunction. In loss-of-function studies, blocking antibodies revealed that lymphangiogenesis 14 days after bleomycin treatment was dependent on vascular endothelial growth factor (Vegf) receptor 3 signaling, but not on Vegf receptor 2. Vegfc gene and protein expression increased specifically. Extensive extravasated plasma, platelets, and macrophages at sites of lymphatic growth were potential sources of Vegfc. Lymphangiogenesis peaked at 14 to 28 days after bleomycin challenge, was accompanied by doubling of chemokine (C-C motif) ligand 21 in lung lymphatics and tertiary lymphoid organ formation, and then decreased as lung injury resolved by 56 days. In gain-of-function studies, expansion of the lung lymphatic network by transgenic overexpression of Vegfc in club cell secretory protein (CCSP)/VEGF-C mice reduced macrophage accumulation and fibrosis and accelerated recovery after bleomycin treatment. These findings suggest that lymphatics have an overall protective effect in lung injury and fibrosis and fit with a mechanism whereby lung lymphatic network expansion reduces lymph stasis and increases clearance of fluid and cells, including profibrotic macrophages.


Subject(s)
Cell Proliferation/physiology , Fibrosis/pathology , Lung Injury/pathology , Lymphangiogenesis/physiology , Vascular Endothelial Growth Factor C/metabolism , Animals , Fibrosis/metabolism , Lymphatic Vessels/pathology , Macrophages/metabolism , Mice, Transgenic , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Vascular Endothelial Growth Factor A/metabolism
6.
Nano Lett ; 20(5): 3435-3441, 2020 May 13.
Article in English | MEDLINE | ID: mdl-32343588

ABSTRACT

Voltage control of interfacial magnetism has been greatly highlighted in spintronics research for many years, as it might enable ultralow power technologies. Among a few suggested approaches, magneto-ionic control of magnetism has demonstrated large modulation of magnetic anisotropy. Moreover, the recent demonstration of magneto-ionic devices using hydrogen ions presented relatively fast magnetization toggle switching, tsw ∼ 100 ms, at room temperature. However, the operation speed may need to be significantly improved to be used for modern electronic devices. Here, we demonstrate that the speed of proton-induced magnetization toggle switching largely depends on proton-conducting oxides. We achieve ∼1 ms reliable (>103 cycles) switching using yttria-stabilized zirconia (YSZ), which is ∼100 times faster than the state-of-the-art magneto-ionic devices reported to date at room temperature. Our results suggest that further engineering of the proton-conducting materials could bring substantial improvement that may enable new low-power computing scheme based on magneto-ionics.

7.
Am J Emerg Med ; 38(8): 1621-1626, 2020 08.
Article in English | MEDLINE | ID: mdl-31706658

ABSTRACT

BACKGROUND: High-flow nasal cannula oxygen (HFNC) creates a positive pressure effect through high-flow rates compared to conventional oxygen therapy. The purpose of this human pilot study is to compare the effects of HFNC and conventional oxygen therapy on the rate of carbon monoxide (CO) clearance from the blood in patients with mild to moderate CO poisoning. METHODS: CO-poisoned Patients randomly received 100% oxygen from a rebreathing reserve mask (NBO2, flow of 15 L/min) or HFNC (flow of 60 L/min). The fraction of COHb value (fCOHb) was measured in 30-min intervals until it fell to under 10%. We determined the Half-life time of fCOHb (fCOHb t1/2). RESULTS: A total of 22 patients had fCOHb levels ≥ 10% at the time of ED arrival, with 9 of them having fCOHb level ranging between 25% and 50%. There was no significant difference in the fCOHbt1/2 between the HFNC group and NBO2 group. However, the mean fCOHbt1/2 in the HFNC group (48.5 ±â€¯12.4 min) has a smaller standard deviation than that in the NBO2 group (99.3 ±â€¯93.38 min). There were significant between-group differences in the mean COHbt1/2 among the patients with fCOHb levels less than 25% (HFNC 43.6 ±â€¯10.6 vs. NBO2 134.2 ±â€¯111.3). CONCLUSIONS: In this pilot randomized controlled trial study, HFNC therapy did not reduce fCOHbt1/2 compared to NBO2 therapy but could be beneficial in maintaining a constant fCOHbt1/2 as well as in reducing fCOHbt1/2 in mild CO poisoning patients compared to conventional NBO2 therapy. However, further studies with a larger number of patients are needed to establish HFNC therapy as an alternative therapy for CO poisoning patients.


Subject(s)
Carbon Monoxide Poisoning/therapy , Oxygen Inhalation Therapy/instrumentation , Adult , Aged , Aged, 80 and over , Carbon Monoxide Poisoning/blood , Carboxyhemoglobin/analysis , Female , Humans , Male , Middle Aged , Pilot Projects , Republic of Korea
8.
Nano Lett ; 19(6): 3684-3691, 2019 06 12.
Article in English | MEDLINE | ID: mdl-31117752

ABSTRACT

Transfer-printing enables the assembly of functional nanomaterials on unconventional substrates with a desired layout in a controllable manner. However, transfer-printing to substrates with complex surfaces remains a challenge. Herein, we show that hydrogels serve as effective template material platforms for the assembly and transfer-printing of conductive nanonetwork patterns for flexible sensors on various topographic surfaces in a very simple yet versatile manner. The non-adherence, nanoporous structure, and molding capability of the hydrophilic hydrogel enable the assembly of conductive nanonetwork patterns on the hydrogel surface and transfer of the nanonetworks onto various flexible and topographic substrates. Flexible strain sensors and pressure sensors that monitor finger motions and arterial pulses are successfully demonstrated using the hydrogel-templated approach. The rich chemistry of polymeric networks, facile molding capability, and biocompatibility of hydrogels could be further combined with additive technology for hydrogels and electronic materials for emerging four-dimensional functional materials and soft bioelectronics.

9.
Circ Res ; 120(9): 1426-1439, 2017 Apr 28.
Article in English | MEDLINE | ID: mdl-28167653

ABSTRACT

RATIONALE: Lymphatic vessels function to drain interstitial fluid from a variety of tissues. Although shear stress generated by fluid flow is known to trigger lymphatic expansion and remodeling, the molecular basis underlying flow-induced lymphatic growth is unknown. OBJECTIVE: We aimed to gain a better understanding of the mechanism by which laminar shear stress activates lymphatic proliferation. METHODS AND RESULTS: Primary endothelial cells from dermal blood and lymphatic vessels (blood vascular endothelial cells and lymphatic endothelial cells [LECs]) were exposed to low-rate steady laminar flow. Shear stress-induced molecular and cellular responses were defined and verified using various mutant mouse models. Steady laminar flow induced the classic shear stress responses commonly in blood vascular endothelial cells and LECs. Surprisingly, however, only LECs showed enhanced cell proliferation by regulating the vascular endothelial growth factor (VEGF)-A, VEGF-C, FGFR3, and p57/CDKN1C genes. As an early signal mediator, ORAI1, a pore subunit of the calcium release-activated calcium channel, was identified to induce the shear stress phenotypes and cell proliferation in LECs responding to the fluid flow. Mechanistically, ORAI1 induced upregulation of Krüppel-like factor (KLF)-2 and KLF4 in the flow-activated LECs, and the 2 KLF proteins cooperate to regulate VEGF-A, VEGF-C, FGFR3, and p57 by binding to the regulatory regions of the genes. Consistently, freshly isolated LECs from Orai1 knockout embryos displayed reduced expression of KLF2, KLF4, VEGF-A, VEGF-C, and FGFR3 and elevated expression of p57. Accordingly, mouse embryos deficient in Orai1, Klf2, or Klf4 showed a significantly reduced lymphatic density and impaired lymphatic development. CONCLUSIONS: Our study identified a molecular mechanism for laminar flow-activated LEC proliferation.


Subject(s)
Cell Proliferation , Endothelial Cells/metabolism , Endothelium, Lymphatic/metabolism , Kruppel-Like Transcription Factors/metabolism , Lymphangiogenesis , Mechanotransduction, Cellular , ORAI1 Protein/metabolism , Animals , Cyclin-Dependent Kinase Inhibitor p57/genetics , Cyclin-Dependent Kinase Inhibitor p57/metabolism , Endothelium, Lymphatic/pathology , Endothelium, Lymphatic/physiopathology , Endothelium, Vascular/metabolism , Gene Expression Regulation , Genotype , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Kruppel-Like Factor 4 , Kruppel-Like Transcription Factors/deficiency , Kruppel-Like Transcription Factors/genetics , Mice, Knockout , ORAI1 Protein/deficiency , ORAI1 Protein/genetics , Phenotype , Receptor, Fibroblast Growth Factor, Type 3/genetics , Receptor, Fibroblast Growth Factor, Type 3/metabolism , Stress, Mechanical , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor C/genetics , Vascular Endothelial Growth Factor C/metabolism
10.
Nurs Educ Perspect ; 36(2): 118-120, 2015.
Article in English | MEDLINE | ID: mdl-29194138

ABSTRACT

: The purpose of this study was to describe learner perception, expected competence, and factors influencing satisfaction with team-based learning in a nursing course. Four-hour TBL sessions were given in a structured three-phase sequence for a cohort of 139 second-year nursing students. TBL was found to be an effective instructional strategy inducing team learning and self-directed learning. Nursing educators should improve TBL quality by focusing on the student team learning process.


Subject(s)
Clinical Competence , Curriculum , Education, Nursing, Baccalaureate/methods , Educational Measurement/methods , Group Processes , Personal Satisfaction , Problem-Based Learning , Students, Nursing/psychology , Adult , Female , Humans , Male , Republic of Korea , Young Adult
11.
Int J Cancer ; 135(1): 232-7, 2014 Jul 01.
Article in English | MEDLINE | ID: mdl-24338666

ABSTRACT

Small chemical compound sulindac has been approved as a preventive approach against colon cancer for its effectiveness in treatment of precancerous adenoma. Due to its severe toxicities in the cardiovascular, gastrointestinal and renal systems, however, a combination of low-dose sulindac with other chemopreventive agents has been sought after as an alternative therapeutic strategy that could increase its effectiveness, while minimizing its adverse effects. To identify the promising alternative approach, we investigated the therapeutic potential of targeting the interleukin (IL)-8/CXCR2 pathway in colon cancer treatment using both loss-of-function (CXCR2 knockout) and gain-of-function (IL-8 overexpression) mouse models, as the IL-8/CXCR2 pathway has been shown to be activated in intestinal tumors of both human and experimental animals. We found that deletion of CXCR2 gene and ectopic expression of IL-8 suppresses and enhances, respectively, intestinal tumor development caused by a mutation in the APC gene. Moreover, a single copy deletion of CXCR2 gene resulted in abrogation of COX-2 and Gro-α upregulation in intestinal tumors caused by the APC mutation. Moreover, a single copy (heterozygote) deletion of CXCR2 gene was sufficient to synergize with a low-dose sulindac treatment in suppressing APCmin-induced intestinal polyposis. Together, our study provides a therapeutic justification of combined inhibition of CXCR2 and sulindac treatment in colon cancer prevention.


Subject(s)
Carcinogenesis/drug effects , Colonic Neoplasms/drug therapy , Neoplasms, Experimental/genetics , Receptors, Interleukin-8B/genetics , Sulindac/administration & dosage , Adenomatous Polyposis Coli Protein/biosynthesis , Animals , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Colonic Neoplasms/prevention & control , Cyclooxygenase 2/biosynthesis , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Mice, Knockout , Neoplasms, Experimental/prevention & control , Receptors, Interleukin-8B/antagonists & inhibitors
12.
PLoS Pathog ; 8(6): e1002770, 2012.
Article in English | MEDLINE | ID: mdl-22719258

ABSTRACT

Lymphatic endothelial cells (LECs) are differentiated from blood vascular endothelial cells (BECs) during embryogenesis and this physiological cell fate specification is controlled by PROX1, the master regulator for lymphatic development. When Kaposi sarcoma herpes virus (KSHV) infects host cells, it activates the otherwise silenced embryonic endothelial differentiation program and reprograms their cell fates. Interestingly, previous studies demonstrated that KSHV drives BECs to acquire a partial lymphatic phenotype by upregulating PROX1 (forward reprogramming), but stimulates LECs to regain some BEC-signature genes by downregulating PROX1 (reverse reprogramming). Despite the significance of this KSHV-induced bidirectional cell fate reprogramming in KS pathogenesis, its underlying molecular mechanism remains undefined. Here, we report that IL3 receptor alpha (IL3Rα) and NOTCH play integral roles in the host cell type-specific regulation of PROX1 by KSHV. In BECs, KSHV upregulates IL3Rα and phosphorylates STAT5, which binds and activates the PROX1 promoter. In LECs, however, PROX1 was rather downregulated by KSHV-induced NOTCH signal via HEY1, which binds and represses the PROX1 promoter. Moreover, PROX1 was found to be required to maintain HEY1 expression in LECs, establishing a reciprocal regulation between PROX1 and HEY1. Upon co-activation of IL3Rα and NOTCH, PROX1 was upregulated in BECs, but downregulated in LECs. Together, our study provides the molecular mechanism underlying the cell type-specific endothelial fate reprogramming by KSHV.


Subject(s)
Endothelial Cells/virology , Herpesviridae Infections/metabolism , Homeodomain Proteins/metabolism , Receptors, Interleukin-3/metabolism , Receptors, Notch/metabolism , Tumor Suppressor Proteins/metabolism , Cell Differentiation/physiology , Cell Lineage , Cells, Cultured , Electrophoretic Mobility Shift Assay , Endothelial Cells/metabolism , Herpesvirus 8, Human/metabolism , Humans , Oligonucleotide Array Sequence Analysis , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction
13.
Nat Commun ; 15(1): 1442, 2024 Feb 16.
Article in English | MEDLINE | ID: mdl-38365882

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and multiple types of B cell malignancies. Emerging evidence demonstrates that KSHV reprograms host-cell central carbon metabolic pathways, which contributes to viral persistence and tumorigenesis. However, the mechanisms underlying KSHV-mediated metabolic reprogramming remain poorly understood. Carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) is a key enzyme of the de novo pyrimidine synthesis, and was recently identified to deamidate the NF-κB subunit RelA to promote aerobic glycolysis and cell proliferation. Here we report that KSHV infection exploits CAD for nucleotide synthesis and glycolysis. Mechanistically, KSHV vCyclin binds to and hijacks cyclin-dependent kinase CDK6 to phosphorylate Ser-1900 on CAD, thereby activating CAD-mediated pyrimidine synthesis and RelA-deamidation-mediated glycolytic reprogramming. Correspondingly, genetic depletion or pharmacological inhibition of CDK6 and CAD potently impeded KSHV lytic replication and thwarted tumorigenesis of primary effusion lymphoma (PEL) cells in vitro and in vivo. Altogether, our work defines a viral metabolic reprogramming mechanism underpinning KSHV oncogenesis, which may spur the development of new strategies to treat KSHV-associated malignancies and other diseases.


Subject(s)
Herpesvirus 8, Human , Sarcoma, Kaposi , Humans , Herpesvirus 8, Human/metabolism , Glycolysis , Carcinogenesis , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Nucleotides/metabolism
14.
Nat Neurosci ; 27(5): 913-926, 2024 May.
Article in English | MEDLINE | ID: mdl-38528202

ABSTRACT

Piezo1 regulates multiple aspects of the vascular system by converting mechanical signals generated by fluid flow into biological processes. Here, we find that Piezo1 is necessary for the proper development and function of meningeal lymphatic vessels and that activating Piezo1 through transgenic overexpression or treatment with the chemical agonist Yoda1 is sufficient to increase cerebrospinal fluid (CSF) outflow by improving lymphatic absorption and transport. The abnormal accumulation of CSF, which often leads to hydrocephalus and ventriculomegaly, currently lacks effective treatments. We discovered that meningeal lymphatics in mouse models of Down syndrome were incompletely developed and abnormally formed. Selective overexpression of Piezo1 in lymphatics or systemic administration of Yoda1 in mice with hydrocephalus or Down syndrome resulted in a notable decrease in pathological CSF accumulation, ventricular enlargement and other associated disease symptoms. Together, our study highlights the importance of Piezo1-mediated lymphatic mechanotransduction in maintaining brain fluid drainage and identifies Piezo1 as a promising therapeutic target for treating excessive CSF accumulation and ventricular enlargement.


Subject(s)
Ion Channels , Lymphatic Vessels , Meninges , Mice, Transgenic , Animals , Lymphatic Vessels/metabolism , Ion Channels/metabolism , Ion Channels/genetics , Mice , Meninges/metabolism , Cerebrospinal Fluid/metabolism , Hydrocephalus/genetics , Mechanotransduction, Cellular/physiology , Mice, Inbred C57BL , Female , Male , Pyrazines , Thiadiazoles
15.
Circulation ; 125(7): 872-82, 2012 Feb 21.
Article in English | MEDLINE | ID: mdl-22275501

ABSTRACT

BACKGROUND: The lymphatic system plays a key role in tissue fluid homeostasis and lymphatic dysfunction caused by genetic defects, or lymphatic vessel obstruction can cause lymphedema, disfiguring tissue swelling often associated with fibrosis and recurrent infections with no available cures to date. In this study, retinoic acids (RAs) were determined to be a potent therapeutic agent that is immediately applicable to reduce secondary lymphedema. METHODS AND RESULTS: We report that RAs promote proliferation, migration, and tube formation of cultured lymphatic endothelial cells by activating fibroblast growth factor receptor signaling. Moreover, RAs control the expression of cell-cycle checkpoint regulators such as p27(Kip1), p57(Kip2), and the aurora kinases through both an Akt-mediated nongenomic action and a transcription-dependent genomic action that is mediated by Prox1, a master regulator of lymphatic development. Moreover, 9-cisRA was found to activate in vivo lymphangiogenesis in animals in mouse trachea, Matrigel plug, and cornea pocket assays. Finally, we demonstrate that 9-cisRA can provide a strong therapeutic efficacy in ameliorating experimental mouse tail lymphedema by enhancing lymphatic vessel regeneration. CONCLUSION: These in vitro and animal studies demonstrate that 9-cisRA potently activates lymphangiogenesis and promotes lymphatic regeneration in an experimental lymphedema model, presenting it as a promising novel therapeutic agent to treat human lymphedema patients.


Subject(s)
Lymphangiogenesis/drug effects , Lymphatic Vessels/physiology , Lymphedema/drug therapy , Regeneration/drug effects , Tretinoin/pharmacology , Alitretinoin , Animals , Aurora Kinases , Cell Movement/drug effects , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p27/genetics , Cyclin-Dependent Kinase Inhibitor p57/genetics , Endothelial Cells/drug effects , Endothelial Cells/physiology , Fibroblast Growth Factors/physiology , Lymphatic Vessels/drug effects , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Promoter Regions, Genetic , Protein Serine-Threonine Kinases/genetics , Tretinoin/therapeutic use
16.
Angiogenesis ; 16(1): 29-44, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22945845

ABSTRACT

Lymphedema is mainly caused by lymphatic obstruction and manifested as tissue swelling, often in the arms and legs. Lymphedema is one of the most common post-surgical complications in breast cancer patients and presents a painful and disfiguring chronic illness that has few treatment options. Here, we evaluated the therapeutic potential of interleukin (IL)-8 in lymphatic regeneration independent of its pro-inflammatory activity. We found that IL-8 promoted proliferation, tube formation, and migration of lymphatic endothelial cells (LECs) without activating the VEGF signaling. Additionally, IL-8 suppressed the major cell cycle inhibitor CDKN1C/p57(KIP2) by downregulating its positive regulator PROX1, which is known as the master regulator of LEC-differentiation. Animal-based studies such as matrigel plug and cornea micropocket assays demonstrated potent efficacy of IL-8 in activating lymphangiogenesis in vivo. Moreover, we have generated a novel transgenic mouse model (K14-hIL8) that expresses human IL-8 in the skin and then crossed with lymphatic-specific fluorescent (Prox1-GFP) mouse. The resulting double transgenic mice showed that a stable expression of IL-8 could promote embryonic lymphangiogenesis. Moreover, an immunodeficient IL-8-expressing mouse line that was established by crossing K14-hIL8 mice with athymic nude mice displayed an enhanced tumor-associated lymphangiogenesis. Finally, when experimental lymphedema was introduced, K14-hIL8 mice showed an improved amelioration of lymphedema with an increased lymphatic regeneration. Together, we report that IL-8 can activate lymphangiogenesis in vitro and in vivo with a therapeutic efficacy in post-surgical lymphedema.


Subject(s)
Interleukin-8/therapeutic use , Lymphatic Vessels/physiopathology , Lymphedema/drug therapy , Lymphedema/etiology , Postoperative Complications/drug therapy , Postoperative Complications/etiology , Regeneration , Animals , Cell Proliferation/drug effects , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p57/metabolism , Down-Regulation/drug effects , Embryonic Development/drug effects , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Homeodomain Proteins/metabolism , Humans , Interleukin-8/metabolism , Interleukin-8/pharmacology , Lymphangiogenesis/drug effects , Lymphatic Vessels/drug effects , Lymphatic Vessels/pathology , Lymphedema/pathology , Lymphedema/physiopathology , Mice , Mice, Transgenic , Neovascularization, Physiologic/drug effects , Postoperative Complications/pathology , Postoperative Complications/physiopathology , Receptors, Interleukin-8/metabolism , Receptors, Interleukin-8A/metabolism , Receptors, Interleukin-8B/metabolism , Regeneration/drug effects , Tretinoin/pharmacology , Tumor Microenvironment/drug effects , Tumor Necrosis Factor-alpha/pharmacology , Tumor Suppressor Proteins/metabolism
17.
Blood ; 117(1): 362-5, 2011 Jan 06.
Article in English | MEDLINE | ID: mdl-20962325

ABSTRACT

Although the blood vessel-specific fluorescent transgenic mouse has been an excellent tool to study vasculogenesis and angiogenesis, a lymphatic-specific fluorescent mouse model has not been established to date. Here we report a transgenic animal model that expresses the green fluorescent protein under the promoter of Prox1, a master control gene in lymphatic development. Generated using an approximately 200-kb-long bacterial artificial chromosome harboring the entire Prox1 gene, this Prox1-green fluorescent protein mouse was found to faithfully recapitulate the expression pattern of the Prox1 gene in lymphatic endothelial cells and other Prox1-expressing organs, and enabled us to conveniently visualize detailed structure and morphology of lymphatic vessels and networks throughout development. Our data demonstrate that this novel transgenic mouse can be extremely useful for detection, imaging, and isolation of lymphatic vessels and monitoring wound-associated lymphangiogenesis. Together, this Prox1-green fluorescent protein transgenic mouse will be a great tool for the lymphatic research.


Subject(s)
Chromosomes, Artificial, Bacterial/genetics , Gene Expression Regulation , Green Fluorescent Proteins/metabolism , Homeodomain Proteins/genetics , Lymphatic Vessels/cytology , Promoter Regions, Genetic/genetics , Tumor Suppressor Proteins/genetics , Animals , Cells, Cultured , Embryo, Mammalian/cytology , Embryo, Mammalian/metabolism , Female , Green Fluorescent Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Lymphangiogenesis , Lymphatic Vessels/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Tumor Suppressor Proteins/metabolism
18.
Eur J Mass Spectrom (Chichester) ; 19(6): 463-73, 2013.
Article in English | MEDLINE | ID: mdl-24378464

ABSTRACT

The pH dependent reactivity of an analog methanobactin peptide (amb) with the sequence acetyl-His1-Cys2-Gly3-Pro4-His5-Cys6 (Mw = 694.79 Da) was investigated for its binding ability for a series of biologically active metal ions using ion mobility-mass spectrometry. Cu(II), Zn(II) and, to a lesser extent, Ni(II) were observed to form complexes with amb from 1 : 1 molar equivalent amb:metal(II) solutions at pH > 6, indicating the deprotonation of the imidazole N of His (pKa = 6.0) must occur to allow the initial anchoring of the metal(II) ion. The amb-metal(II) complexes were observed as both positive and negative ions, although the Zn(II) complexes preferred forming an overall negative ion complex which is consistent with the two thiolate groups of Cys2 and Cys6 being involved in Zn(II) coordination. The Cu(II) addition, however, always resulted in a Cys-Cys disulfide bridge in both Cu-free amb and Cu-bound amb, which excluded thiolate coordination to Cu(II). Collision cross- section measurements showed the Zn(II) and Cu(II) negative ion complexes were smaller than the positive ion complexes, suggesting Zn(II) binds most compactly via the imidazole N of His and the thiolate groups of Cys, whereas Cu(II) binds most compactly via the imidazole N of His and two deprotonated N of two amide groups on the peptide backbone. The lowest energy structures from the B3LYP/LanL2DZ level of theory showed the functional groups of His5, Cys2 and Cys6 coordinated to Zn(II), whereas the His1 and the amide nitrogens of Cys2 and Gly3 coordinated to Cu(II), producing an overall negative charged complex. The positive ion complexes of Zn(II) and Cu(II) were both shown to coordinate via the two imidazole nitrogens of His1 and His5 and either the oxygen of the backbone carbonyl of Cys6 or the oxygen of the C-terminal, respectively.


Subject(s)
Bacterial Proteins/metabolism , Copper/metabolism , Imidazoles/metabolism , Mass Spectrometry/methods , Methylosinus trichosporium/metabolism , Oligopeptides/metabolism , Zinc/metabolism , Bacterial Proteins/chemistry , Copper/chemistry , Cysteine/metabolism , Disulfides/chemistry , Disulfides/metabolism , Homeostasis , Hydrogen-Ion Concentration , Peptides/chemistry , Peptides/metabolism , Protein Binding , Structure-Activity Relationship , Zinc/chemistry
19.
Front Oncol ; 13: 1088038, 2023.
Article in English | MEDLINE | ID: mdl-36756156

ABSTRACT

Immune checkpoint molecules function to inhibit and regulate immune response pathways to prevent hyperactive immune activity from damaging healthy tissues. In cancer patients, targeting these key molecules may serve as a valuable therapeutic mechanism to bolster immune function and restore the body's natural defenses against tumors. CD200, an immune checkpoint molecule, is a surface glycoprotein that is widely but not ubiquitously expressed throughout the body. By interacting with its inhibitory receptor CD200R, CD200 suppresses immune cell activity within the tumor microenvironment, creating conditions that foster tumor growth. Targeting the CD200/CD200R pathway, either through the use of monoclonal antibodies or peptide inhibitors, has shown to be effective in boosting anti-tumor immune activity. This review will explore CD200 and the protein's expression and role within the tumor microenvironment, blood endothelial cells, and lymph nodes. This paper will also discuss the advantages and challenges of current strategies used to target CD200 and briefly summarize relevant preclinical/clinical studies investigating the immunotherapeutic efficacy of CD200/CD200R blockade.

20.
Behav Sci (Basel) ; 13(2)2023 Feb 09.
Article in English | MEDLINE | ID: mdl-36829375

ABSTRACT

Drawing on the job demands-resources model, we suggest and test a motivational mechanism that underlies the relationship between leader boundary-spanning behavior and employee voice behavior. Based on the field survey data of 383 leader-employee pairs collected from various organizations in South Korea, the results of our mediation model showed that leader boundary-spanning behavior, as a potential job resource, enhances employee voice behavior by increasing employee self-efficacy. The results of our moderated mediation model also showed that the focal leader's abusive supervision, as a potential job demand, could attenuate the beneficial effect of leader boundary-spanning behavior on employee voice behavior by diminishing employee self-efficacy. These findings highlight the importance of leader boundary-spanning behavior in enhancing employee voice behavior, the roles of employee self-efficacy as a key mediating mechanism, and the focal leader's abusive supervision as a preventable boundary condition within these relationships. Theoretical and practical implications are discussed.

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