The tomato yellow leaf curl disease (TYLCD) caused by whitefly (Bemisia tabaci) transmitted begomoviruses (Geminiviridae) has constrained tomato production in Taiwan since 1981. Lisianthus enation leaf curl virus (LELCV), tomato leaf curl Taiwan virus (ToLCTV), and tomato yellow leaf curl Thailand virus (TYLCTHV) were the major viruses associated with TYLCD. In 2019-2020, we investigated TYLCD throughout Taiwan, with a 10-100% incidence on tomato fields. Begomovirus sequences were detected in 321 out of 506 collected samples by PCR with primers PAL1v1978B and PAR1c71H. In 2015-2016, 59 out of 99 samples collected in Hualien-Taitung areas were also found to have begomovirus sequences. Based on the analysis of 68 viral genomic sequences, six begomoviruses were identified, including LELCV, ToLCTV, TYLCTHV, tomato leaf curl Hsinchu virus (ToLCHsV) and two new begomoviruses, tentatively named tomato leaf curl Chiayi virus (ToLCCYV) and tomato leaf curl Nantou virus (ToLCNTV). Various isolates of LELCV and TYLCTHV were grouped into four and two strains, respectively. Recombinants were detected in LELCV-A, -C, and -D, ToLCCYV, ToLCNTV, and TYLCTHV-F. Based on virus specific detection, the majority of TYLCD-associated viruses were mixed-infected by TYLCTHV-B with either TYLCTHV-F, LELCV-A, -B, or -D, and/or ToLCTV. Meanwhile, viral DNA-B was mostly associated with TYLCTHV and all identified DNA-Bs were highly homologous with previous TYLCTHV DNA-B. The pathogenicity of selected begomoviruses was confirmed through agroinfection and whitefly transmission. All tomato plants carrying Ty-1/3 and Ty-2 resistant genes were infected by all LELCV strains and ToLCCYV, although they appeared symptomless, suggesting these viruses could be managed through the use of the resistance pyramid.
Background: Surgical patients with aortic dissection often require multiple antihypertensive drugs to control blood pressure. However, the prescription pattern and effectiveness of antihypertensive drugs for these patients are unclear. We aimed to investigate the prescription pattern and effectiveness of different classes of antihypertensive drugs in surgical patients with aortic dissection. Methods: Newly diagnosed aortic dissection patients who underwent surgery, aged >20 years, from 1 January 2012 to 31 December 2017 were identified. Patients with missing data, in-hospital mortality, aortic aneurysms, or congenital connective tissue disorders, such as Marfan syndrome, were excluded. Prescription patterns of antihypertensive drugs were identified from medical records of outpatient visits within 90 days after discharge. Antihypertensive drugs were classified into four classes: 1) ß-blockers, 2) calcium channel blockers (CCBs), 3) renin-angiotensin system, and 4) other antihypertensive drugs. Patients were classified according to the number of classes of antihypertensive drugs as follows: 1) class 0, no exposure to antihypertensive drugs; 2) class 1, antihypertensive drugs of the same class; 3) class 2, antihypertensive drugs of two classes; 4) class 3, antihypertensive drugs of three classes; or 5) class 4, antihypertensive drugs of four classes. The primary composite outcomes included rehospitalization associated with aortic dissection, death due to aortic dissection, and all-cause mortality. Results: Most patients were prescribed two (28.87%) or three classes (28.01%) of antihypertensive drugs. In class 1, ß-blockers were most commonly used (8.79%), followed by CCBs (5.95%). In class 2, ß-blockers+CCB (10.66%) and CCB+RAS (5.18%) were the most common drug combinations. In class 3, ß-blockers + CCB+RAS (14.84%) was the most prescribed combination. Class 0 had a significantly higher hazard of the composite outcome (HR, 2.1; CI, 1.46-3.02; p < 0.001) and all-cause mortality (HR, 2.34; CI, 1.56-3.51; p < 0.001) than class 1. There were no significant differences in hazards for rehospitalization associated with aortic dissection among classes. Conclusion: Among operated patients with type A aortic dissection, no specific type of antihypertensive drug was associated with a better outcome, whereas among those with type B aortic dissection, the use of ß-blockers and CCBs was related to a significantly lower risk of the composite outcome.
Cucurbits are important economic crops worldwide. However, the cucurbit leaf curl disease (CuLCD), caused by whitefly-transmitted begomoviruses constrains their production. In Southeast Asia, three major begomoviruses, Tomato leaf curl New Delhi virus (ToLCNDV), Squash leaf curl China virus (SLCCNV) and Squash leaf curl Philippines virus (SLCuPV) are associated with CuLCD. SLCuPV and SLCCNV were identified in Luzon, the Philippines. Here, the genetic diversity and geographic distribution of CuLCD-associated begomoviruses in the Philippines were studied based on 103 begomovirus detected out of 249 cucurbit samples collected from 60 locations throughout the country in 2018 and 2019. The presence of SLCCNV and SLCuPV throughout the Philippines were confirmed by begomovirus PCR detection and viral DNA sequence analysis. SLCuPV was determined as a predominant CuLCD-associated begomovirus and grouped into two strains. Interestingly, SLCCNV was detected in pumpkin and bottle gourd without associated viral DNA-B and mixed-infected with SLCuPV. Furthermore, the pathogenicity of selected isolates of SLCCNV and SLCuPV was confirmed. The results provide virus genetic diversity associated with CuLCD for further disease management, especially in developing the disease-resistant cultivars in the Philippines as well as Southeast Asia.
BACKGROUND: Increased neutrophil extracellular trap (NET) formation and abundant NET-associated proteins are frequently found in the inflamed colon of patients with inflammatory bowel disease. Peptidyl arginine deiminase 4 (PAD4) activation is essential for the generation of NET and NET-mediated pathogenesis. However, the role of PAD4-dependent NET formation in murine inflammatory bowel disease models and the molecular mechanisms responsible for the altered gut barrier function are unknown. METHODS: Wild-type and Pad4 knockout (Pad4-/-) mice were administrated 3% dextran sulfate sodium (DSS) in their drinking water. Caco-2 monolayers were used to test the effect of NETs on intestinal barrier function and cytotoxicity. Histones were intrarectally administrated to wild-type mice to determine their effects on intestinal barrier function and cytotoxicity in vivo. RESULTS: PAD4 deficiency reduced the severity of DSS-induced colitis with decreased intestinal NET formation and enhanced gut barrier function and integrity in mice. NETs disrupted the barrier function in intestinal epithelial Caco-2 monolayers through their protein, rather than DNA, components. Pretreatment of NETs with histone inhibitors abrogated the effects on epithelial permeability. Consistent with these observations, adding purified histone proteins to Caco-2 monolayers significantly damaged epithelial barrier function, which was associated with the abnormal distribution and integrity of tight junctions as well as with increased cell death. Furthermore, intrarectal administration of histones damaged the intestinal barrier integrity and induced cytotoxicity in the mouse colon epithelium. CONCLUSIONS: PAD4-mediated NET formation has a detrimental role in acute colitis. NET-associated histones directly inhibit intestinal barrier function, resulting in cytotoxicity in vitro and in vivo.
Peptidyl arginine deiminase 4dependent neutrophil extracellular trap formation is detrimental to intestinal barrier function in acute colitis. Neutrophil extracellular trapassociated histones altered the integrity of tight junction and adherens junction proteins as well as induced intestinal epithelial cell death that resulted in increased gut epithelium permeability.
Colitis , Extracellular Traps , Inflammatory Bowel Diseases , Humans , Animals , Mice , Extracellular Traps/metabolism , Histones/metabolism , Caco-2 Cells , Colitis/chemically induced , Inflammatory Bowel Diseases/pathology , Permeability , Intestinal Mucosa/pathology , Disease Models, Animal , Mice, Inbred C57BL
In the original publication [...].
In recent years, silicon-on-insulator substrates have been utilized for high-speed and low-power electronic components. Because of the high refractive index contrast of the silicon wire, its photonic device footprint can be significantly reduced. Moreover, the silicon photonic process is compatible with a complementary metal-oxide-semiconductor fabrication, which will benefit the high-density optoelectronic integrated circuits development. Researchers have recently proposed using the microring resonator (MRR) for label-free biosensing applications. The high-quality factor caused by the substantial electric field enhancement within the ring makes the MRR a good candidate for biomolecule detection under low analyte concentration conditions. This paper proposes an MRR chip to be a biosensor on the silicon platform through the relative displacement between the spatial ring-down interferograms at various cladding layers. The higher-order ring-down of the spatial interference wave packet will enhance the biosensing sensitivity after optimizing the coupling, MRR length, and the optical source bandwidth at the fixed optical waveguide loss. Finally, a typical sensitivity of 642,000 nm per refractive index unit is demonstrated under 0.1 µW minimum optical power detection for an MRR with a 100 µm radius. Higher sensitivity can be executed by a narrow bandwidth and lower silicon wire propagation loss.
Mental health literacy (MHL) plays an important role in public health. Improving MHL can promote mental health at the individual and public levels. To date, no published studies have assessed the effectiveness of MHL curriculum interventions among undergraduate public health students. The participants in this study were undergraduate public health students (n = 48) who were enrolled in an 18-week MHL curriculum for 100 min per week. MHL was assessed using the Mental Health Literacy Scale for Healthcare Students. A paired sample t-test was performed to examine the immediate and delayed effects of the MHL curriculum. The total MHL score significantly improved, and a moderate effect size was found directly after the intervention and six weeks later. There were significant differences in the recognition of mental illness (p < 0.01), help-seeking efficacy (p < 0.05), and help-seeking attitude (p < 0.05) in the five components of MHL between pre- and post-test. Furthermore, significant improvements were obtained for the maintenance of positive mental health (p < 0.05) and reduction of mental illness stigma (p < 0.001) between the pre-test and follow-up. Our findings provide evidence for the development and implementation of an MHL curriculum for public health education.
Health Literacy , Mental Disorders , Curriculum , Humans , Mental Disorders/psychology , Mental Health , Students/psychology , Students, Public Health
The population with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing. However, no medicine is indicated for treating these diseases clinically nowadays. Therefore, there is an urgent need to develop a new drug to overcome NAFLD and NASH. Capillarisin, a 2-phenoxychromone originating from Artemisia capillaris Thunb., is well-known for its liver-protective effects. As a result, a series of 2-phenoxychromones was prepared and evaluated for its protective activity against lipid droplet formation in oleic acid (OA)-treated Huh7 cells by means of high-content screening. In the light of the results, the compounds with trimethoxy groups on the phenyl ring possessed better inhibitory properties against lipid accumulation in Huh7 cells, compared to other functional groups on the same ring. Nonetheless, the compounds with a hydroxy group at the C-5 position of the chromone exhibited apparent cytotoxicity. Finally, the active compound, 5,7-dimethoxy-2-(3,4,5-trimethoxyphenoxy)-chromen-4-one (7e), with an IC50 value of 32.2 ± 2.1 µM against lipid accumulation and no significant cytotoxicity, reduced the accumulation of lipid droplets by up-regulating peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) to facilitate the catabolism of fat, which shows promise for further optimization to manage NAFLD and NASH.
Background: Pulmonary arterial hypertension (PAH) is an incurable pulmonary disease that might result in right heart failure and death. Treatment guidelines recommend upfront or sequential combination therapy for patients with PAH. Recently, several PAH-targeted medications have been approved in Taiwan. This study aimed to investigate treatment patterns and medication adherence in real-world settings. Method: This was a new-user design study on patients treated with PAH-specific medication between 1 January 2014, and 31 December 2019. Data were extracted from the National Health Insurance Research Database. Medication adherence was evaluated by the proportion of days covered (PDC). Adherence was defined as PDC ≥ .8. Statistical analyses were performed to compare the study outcomes. Logistic regression analysis was performed to identify the association between baseline characteristics and adherence. P < .05 indicated statistical significance. Results: A total of 1,900 patients with PAH were identified, and 75.3% of them were females. The mean (standard deviation (SD)) age was 57.2 (17.5) years. Only 23 (1.2%) patients began the initial combination therapy. A total of 148 (7.8%) patients switched their initial treatment to another treatment, and 159 (8.4%) patients had sequential combination therapy. The most common combination therapy was endothelin receptor antagonist (ERA) plus phosphodiesterase-5 inhibitor (PDE5i), mostly macitentan plus sildenafil, for initial or sequential combination. The mean (SD) PDC was .71 (.33), and 1,117 (58.8%) patients were adherent. A significant difference in mean PDC was observed between initial ERA users and PDE5i users (p < .0001). No factor was significantly associated with medication adherence. Conclusion: Patients with PAH mostly initiated sildenafil as monotherapy, and macitentan was added as a sequential combination therapy. The initial ERA and combination groups showed higher medication adherence. Further investigations are needed to identify other factors associated with adherence.
Cucurbits are important crops in the world. However, leaf curl disease constrains their production. Here, begomovirus diversity and pathogenicity associated with the disease in Malaysia were studied based on 49 begomovirus-detected out of 69 symptomatic plants from seven cucurbit crops in 15 locations during 2016 and 2017. The presence of Squash leaf curl China virus (SLCCNV) and Tomato leaf curl New Delhi virus (ToLCNDV) were confirmed by virus detection by polymerase chain reaction, viral DNA sequence analysis and specific detection of the viral components. ToLCNDV Malaysian isolates were further distinguished into strains A, B, C and D. Virus co-infection was detected in bitter gourd, bottle gourd and squash. Among them, eight bitter gourd samples were detected without SLCCNV DNA-A. However, one bottle gourd and five squash samples were without ToLCNDV DNA-B. Pseudorecombination of ToLCNDV DNA-A and SLCCNV DNA-B was detected in two bitter gourd samples. The pathogenic viruses and pseudorecombinants were confirmed by agroinoculation. The viral DNA-B influencing on symptomology and host range was also confirmed. The results strengthen the epidemic of cucurbit-infecting begomovirus in Malaysia as well as Southeast Asia. Especially, the natural pseudorecombinant of begomovirus that extends host range and causes severe symptom implies a threat to crops.
OBJECTIVE: To determine and compare the effectiveness of robotic therapy with a patient-guided suspension system for stroke rehabilitation using a 7-days-a-week model of care with that of conventional rehabilitation. DESIGN: Retrospective cohort study. SETTING: Inpatient rehabilitation unit of an acute general hospital. PARTICIPANTS: A total of 100 consecutive patients with stroke (N=100) admitted within a 7-month period who fulfilled the criteria to undergo robotic therapy with a patient-guided suspension system were enrolled in this study. INTERVENTIONS: Patients either underwent robotic therapy in addition to conventional therapy (robotic group) or conventional therapy only (control group). There were 50 patients in each cohort. MAIN OUTCOME MEASURES: FIM and its derivatives (FIM gain and FIM efficiency); Berg Balance Scale (BBS), functional ambulation category (FAC); modified Rankin Scale (mRS); and National Institutes of Health Stroke Scale. RESULTS: The average FIM gains in both groups were statistically significant (P<.01). The robotic group had greater improvement in FAC scores (1.24 vs 0.78, P=.007). However, other measurements such as FIM efficiency, BBS, and mRS were not significantly different between the 2 groups. The robotics group reported high patient satisfaction rates, with most patients finding the intervention both beneficial and desirable. CONCLUSIONS: Adjunct robotic therapy has the potential to increase the efficacy of stroke rehabilitation. However, further studies are needed to strengthen the evidence.
Osteoconduction is an important consideration for fabricating bio-active materials for bone regeneration. For years, hydroxyapatite and ß-calcium triphosphate (ß-TCP) have been used to develop bone grafts for treating bone defects. However, this material can be difficult to handle due to filling material sagging. High molecular weight hyaluronic acid (H-HA) can be used as a carrier to address this problem and improve operability. However, the effect of H-HA on bone formation is still controversial. In this study, low molecular weight hyaluronic acid (L-HA) was fabricated using gamma-ray irradiation. The viscoelastic properties and chemical structure of the fabricated hybrids were evaluated by a rheological analysis nuclear magnetic resonance (NMR) spectrum. The L-MH was mixed with H-HA to produce H-HA/L-HA hybrids at ratios of 80:20, 50:50 and 20:80 (w/w). These HA hybrids were then combined with hydroxyapatite and ß-TCP to create a novel bone graft composite. For animal study, artificial bone defects were prepared in rabbit femurs. After 12 weeks of healing, the rabbits were scarified, and the healing statuses were observed and evaluated through micro-computer tomography (CT) and tissue histological images. Our viscoelastic analysis showed that an HA hybrid consisting 20% H-HA is sufficient to maintain elasticity; however, the addition of L-HA dramatically decreases the dynamic viscosity of the HA hybrid. Micro-CT images showed that the new bone formations in the rabbit femur defect model treated with 50% and 80% L-HA were 1.47 (p < 0.05) and 2.26 (p < 0.01) times higher than samples filled with HA free bone graft. In addition, a similar tendency was observed in the results of HE staining. These results lead us to suggest that the material with an H-HA/L-HA ratio of 50:50 exhibited acceptable viscosity and significant new bone formation. Thus, it is reasonable to suggest that it may be a potential candidate to serve as a supporting system for improving the operability of granular bone grafts and enhancing new bone formations.
Over activation of neutrophils has been linked to many inflammatory diseases; one of critical pathologic mechanisms is that generation and exocellular release of superoxide anion from neutrophils results in peripheral tissues damage. Besides, in this study, 2-(3,5-dimethoxyphenoxy)-5,7-dimethoxy-chromen-4-one (4), a 2-phexnoychromone from our compound bank, was demonstrated to have the moderate inhibitory effect on superoxide anion generating. Therefore, serial chromones substituted with phenols or 3-flourothiophenol were designed, synthesized, and examined for suppression of superoxide anion generation. In accordance with the results, the methoxy group at 7 position (R3) of the chromone, as well as a hydrogen bond donor at a meta site of the phenyl ring greatly impacted on the activity. 2-(3-fluorophenyl)sulfanyl-7-methoxy-chromen-4-one (16), a successful example of bioisosteres from a phenol to a thiophenol, exhibited prominent anti-inflammatory effects with the IC50 value against superoxide anion generation of 5.0 ± 1.4 µM.
Chromones/pharmacology , Neutrophils/drug effects , Superoxides/antagonists & inhibitors , Anions/antagonists & inhibitors , Anions/metabolism , Chromones/chemical synthesis , Chromones/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Neutrophils/metabolism , Structure-Activity Relationship , Superoxides/metabolism
Aberrant neutrophil extracellular trap (NET) formation and the loss of barrier integrity in inflamed intestinal tissues have long been associated with inflammatory bowel disease (IBD). However, whether NETs alter intestinal epithelium permeability during colitis remains elusive. Here, we demonstrated that NETs promote the breakdown in intestinal barrier function for the pathogenesis of intestinal inflammation in mouse models of colitis. NETs were abundant in the colon of mice with colitis experimentally induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Analysis of the intestinal barrier integrity revealed that NETs impaired gut permeability, enabling the initiation of luminal bacterial translocation and inflammation. Furthermore, NETs induced the apoptosis of epithelial cells and disrupted the integrity of tight junctions and adherens junctions. Intravenous administration of DNase I, an enzyme that dissolves the web-like DNA filaments of NETs, during colitis restored the mucosal barrier integrity which reduced the dissemination of luminal bacteria and attenuated intestinal inflammation in both DSS and TNBS models. We conclude that NETs serve a detrimental factor in the gut epithelial barrier function leading to the pathogenesis of mucosal inflammation during acute colitis.
Inflammasomes are intracellular multiple protein complexes that mount innate immune responses to tissue damage and invading pathogens. Their excessive activation is crucial in the development and pathogenesis of inflammatory disorders. Microtubules have been reported to provide the platform for mediating the assembly and activation of NLRP3 inflammasome. Recently, we have identified the microtubule-associated immune molecule guanine nucleotide exchange factor-H1 (GEF-H1) that is crucial in coupling microtubule dynamics to the initiation of microtubule-mediated immune responses. However, whether GEF-H1 also controls the activation of other immune receptors that require microtubules is still undefined. Here we employed GEF-H1-deficient mouse bone marrow-derived macrophages (BMDMs) to interrogate the impact of GEF-H1 on the activation of NLRP3 inflammasome. NLRP3 but not NLRC4 or AIM2 inflammasome-mediated IL-1ß production was dependent on dynamic microtubule network in wild-type (WT) BMDMs. However, GEF-H1 deficiency did not affect NLRP3-driven IL-1ß maturation and secretion in macrophages. Moreover, α-tubulin acetylation and mitochondria aggregations were comparable between WT and GEF-H1-deficient BMDMs in response to NLRP3 inducers. Further, GEF-H1 was not required for NLRP3-mediated immune defense against Salmonella typhimurium infection. Collectively, these findings suggest that the microtubule-associated immune modulator GEF-H1 is dispensable for microtubule-mediated NLRP3 activation and host defense in mouse macrophages.
Inflammasomes/metabolism , Macrophages/metabolism , Microtubules/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Rho Guanine Nucleotide Exchange Factors/metabolism , Acetylation , Animals , Bone Marrow Cells/cytology , Cells, Cultured , Immunity, Innate , Interleukin-1beta/metabolism , Lipopolysaccharides/pharmacology , Macrophages/cytology , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Nigericin/pharmacology , Rho Guanine Nucleotide Exchange Factors/deficiency , Rho Guanine Nucleotide Exchange Factors/genetics , Salmonella Infections/immunology , Salmonella Infections/pathology , Salmonella typhimurium/pathogenicity
In this study, the effect of austenite grain size on acicular ferrite (AF) nucleation in low-carbon steel containing 13 ppm Mg is determined. The average austenite grain size was calculated using OM Leica software. Results show that the predicted and experimental values of austenite grain size are extremely close, with a deviation of less than 20 µm. AF formation is difficult to induce by either excessively small and large austenite grain sizes; that is, an optimal austenite grain size is required to promote AF nucleation probability. The austenite grain size of 164 µm revealed the highest capacity to induce AF formation. The effects of the maximum distance of carbon diffusion and austenite grain size on the microstructure of Mg-containing low carbon steel are also discussed. Next, the pinning ability of different inclusion types in low-carbon steel containing 22 Mg is determined. The in situ observation shows that not every inclusion could inhibit austenite grain migration; the inclusion type influences pinning ability. The grain mobility of each inclusion was calculated using in situ micrographs of confocal scanning laser microscopy (CSLM) for micro-analysis. Results show that the austenite grain boundary can strongly be pinned by Mg-based inclusions. MnS inclusions are the least effective in pinning austenite grain boundary migration.
Periodontitis is an inflammatory disease of the supporting tissues of the teeth induced by periodontopathic bacteria that results in the progressive destruction of periodontal tissues. Treatment of periodontitis is painful and time-consuming. Recently, herbal medicines have been considered for use in treating inflammation-related diseases, including periodontitis. Resveratrol and its derivative 2,3,5,4'-tetrahydroxystilbene-2-O-ß-glucoside (THSG), a polyphenol extracted from Polygonum multiflorum, have anti-inflammatory properties and other medical benefits. Here, we highlight the importance of resveratrol and its glycosylated derivative as possible complementary treatments for periodontitis and their potential for development as innovative therapeutic strategies. In addition, we present evidence and discuss the mechanisms of action of resveratrol and THSG on periodontitis, focusing on Porphyromonas gingivalis-induced inflammatory responses in human gingival fibroblasts and animal modeling of ligature-induced periodontitis. We also illuminate the signal transduction pathways and the cytokines involved.
Anti-Inflammatory Agents/therapeutic use , Glucosides/therapeutic use , Periodontitis/drug therapy , Stilbenes/therapeutic use , Fibroblasts/drug effects , Glucosides/pharmacology , Humans , Porphyromonas gingivalis/drug effects , Resveratrol , Stilbenes/pharmacology , Treatment Outcome
Nonpeptide hormones, such as thyroid hormone, dihydrotestosterone, and estrogen, have been shown to stimulate cancer proliferation via different mechanisms. Aside from their cytosolic or membrane-bound receptors, there are receptors on integrin αv ß3 for nonpeptide hormones. Interaction between hormones and integrin αv ß3 can induce signal transduction and eventually stimulate cancer cell proliferation. Resveratrol induces inducible COX-2-dependent antiproliferation via integrin αv ß3 . Resveratrol and hormone-induced signals are both transduced by activated extracellular-regulated kinases 1 and 2 (ERK1/2); however, hormones promote cell proliferation, while resveratrol induces antiproliferation in cancer cells. Hormones inhibit resveratrol-stimulated phosphorylation of p53 on Ser15, resveratrol-induced nuclear COX-2 accumulation, and formation of p53-COX-2 nuclear complexes. Subsequently, hormones impair resveratrol-induced COX-2-/p53-dependent gene expression. The inhibitory effects of hormones on resveratrol action can be blocked by different antagonists of specific nonpeptide hormone receptors but not integrin αv ß3 blockers. Results suggest that nonpeptide hormones inhibit resveratrol-induced antiproliferation in cancer cells downstream of the interaction between ligand and receptor and ERK1/2 activation to interfere with nuclear COX-2 accumulation. Thus, the surface receptor sites for resveratrol and nonpeptide hormones are distinct and can induce discrete ERK1/2-dependent downstream antiproliferation biological activities. It also indicates the complex pathways by which antiproliferation is induced by resveratrol in various physiological hormonal environments. .
Apoptosis/drug effects , Cell Proliferation/drug effects , Dihydrotestosterone/pharmacology , Estrogens/pharmacology , Signal Transduction/drug effects , Stilbenes/pharmacology , Thyroid Hormones/pharmacology , Animals , Phosphorylation/drug effects , Resveratrol
Ovarian cancer is the leading cause of death in gynecological diseases. Thyroid hormone promotes proliferation of ovarian cancer cells via cell surface receptor integrin αvß3 that activates extracellular regulated kinase (ERK1/2). However, the mechanisms are still not fully understood. Thyroxine (T4) at a physiologic total hormone concentration (10-7 M) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3'-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Thyroid hormone (T4 and T3) treatment of human ovarian cancer cells resulted in enhanced activation of the Ras/MAPK(ERK1/2) signal transduction pathway. An MEK inhibitor (PD98059) blocked hormone-induced cell proliferation but not ER phosphorylation. Knock-down of either integrin αv or ß3 by RNAi blocked thyroid hormone-induced phosphorylation of ERK1/2. We also found that thyroid hormone causes elevated phosphorylation and nuclear enrichment of estrogen receptor α (ERα). Confocal microscopy indicated that both T4 and estradiol (E2) caused nuclear translocation of integrin αv and phosphorylation of ERα. The specific ERα antagonist (ICI 182,780; fulvestrant) blocked T4-induced ERK1/2 activation, ERα phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin αv and phosphorylated ERα was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T4- and E2-induced nuclear co-localization of phosphorylated ERα and integrin αv are dissimilar. Chromatin immunoprecipitation results showed that T4-induced binding of integrin αv monomer to ERα promoter and this was reduced by ICI. In summary, thyroid hormone stimulates proliferation of ovarian cancer cells via crosstalk between integrin αv and ERα, mimicking functions of E2.
Estrogen Receptor alpha/metabolism , Integrin alphaVbeta3/metabolism , Ovarian Neoplasms/metabolism , Signal Transduction , Thyroid Hormones/metabolism , Cell Line, Tumor , Cell Proliferation , Female , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Ovarian Neoplasms/pathology , Protein Binding
