Jaw-Shiun Tsai

Symptom patterns of advanced cancer patients in a palliative care unit.

This study involved longitudinal evaluations of symptom severity and describes the symptom patterns of 77 terminal cancer patients (median age: 62 years; 61% female), selected from 537 consecutive patients admitted to the Palliative Care Unit of the National Taiwan University Hospital. The most common primary cancer sites in these patients were lung (23.4%), liver (15.6%), and stomach (13%). Nineteen physical and psychological symptoms were assessed using different scales. The median number of symptoms was 11 (range: 1-18) on admission, among which weakness, fatigue, anorexia, pain, and depression were the most common. A comparison of the initial symptom severity scores with those at one week after admission and two days before death suggested six symptom change patterns: A: continuous static (restless/heat, abdominal fullness, constipation, dizziness, and insomnia); B: static-increase (fatigue, weakness, nausea/vomiting, taste alteration, dysphagia, diarrhea, dry mouth, and night sweats); C: decrease-static (pain and depression); D: decrease-increase (anorexia and dyspnea); E: static-decrease (aggression); and F: gradually decrease (anxiety). These six symptom patterns can be divided into two categories on the basis of the relative severity of symptoms between one week after admission and two days before death. The first category included patterns A, C, E and F, and the symptoms improved with palliative care. However, the symptoms in the second category (patterns B and D), which were associated with the anorexia-cachexia syndrome and dyspnea, did not show improvement. As symptom management is an essential component of palliative care, holistic care, which encompasses physical, psychosocial and spiritual aspects, represents a rational approach for the relief of these incurable symptoms at the end stage of life for these patients.

Can a Good Death and Quality of Life Be Achieved for Patients with Terminal Cancer in a Palliative Care Unit

BACKGROUND Lack of evidence supporting the claim that palliative care can improve quality of life and promote good death in patients with terminal cancer. OBJECTIVES This study was designed to evaluate the change of quality of life and quality of death over time and between patients of long and short survival in a palliative care unit. METHODS Patient demography, cancer sites, Eastern Cooperative Oncology Group (ECOG) status were collected at admission. Quality of life, including physical and psychological symptoms, social support, and spirituality was assessed daily after admission. Quality of death was assessed by a Good Death Scale (GDS) at admission and retrospectively for 2 days before death. RESULTS A total of 281 patients (52% women) were admitted and died in the study period. One hundred forty-five patients (51.6%) died within 3 weeks. Although those with short survival (<3 weeks) had more physical symptoms during the first week, there was no difference in quality of life dimensions at admission, at 1 week, and at 2 days before death between survival groups. Physical conditions deteriorated with time but other dimensions continued to improve until death. GDS and subdimensions continued to improve until death. Although those with long survival (≥3 weeks) have better scores for awareness, acceptance, timeliness, comfort, and GDS at admission, there was no difference between the two groups at 2 days before death. CONCLUSION Under comprehensive palliative care, patients with terminal cancer can have good quality of life and experience a good death even with short survival.

Ganoderma lucidum polysaccharides prevent platelet-derived growth factor-stimulated smooth muscle cell proliferation in vitro and neointimal hyperplasia in the endothelial-denuded artery in vivo.

Ganoderma lucidum is used in traditional Chinese medicine to prevent or treat a variety of diseases, including cardiovascular disorders. We previously demonstrated that a glucan‐containing extract of Reishi polysaccharides (EORP) has the potent anti‐inflammatory action of reducing ICAM‐1 expression in lipopolysaccharide (LPS)‐treated human aortic smooth muscle cells (HASMCs) and LPS‐treated mice. In the present study, we examined whether EORP inhibited platelet‐derived growth factor‐BB (PDGF)‐stimulated HASMC proliferation and the mechanism involved. EORP dose‐dependently reduced cell numbers and DNA synthesis of PDGF‐treated HASMCs in vitro. EORP also arrested cell cycle progression in the G0/G1 phase, and this was associated with decreased expression of cyclin D1, cyclin E, CDK2, CDK4, and p21Cip1 and upregulation of the cyclin‐dependent kinase inhibitor p27Kip1. The anti‐proliferative effect of EORP was partly mediated by downregulation of PDGF‐induced JNK phosphorylation. In in vivo studies, the femoral artery of C57BL/6 mice was endothelial‐denuded and the mice were fed a diet containing 100 mg/kg/day of EORP. On day 14, both cell proliferation (proliferating cell nuclear antigen‐positive cells) in the neointima and the neointima/media area ratio (0.67 ± 0.03 vs. 1.46 ± 0.30) were significantly reduced. Our data show that EORP interferes with the mitogenic activation of JNK, preventing entry of HASMCs into the cell cycle in vitro and reducing cell proliferation in the neointima and decreasing the neointimal area in vivo. Thus, EORP may represent a safe and effective novel approach to the prevention and treatment of vascular proliferative diseases. J. Cell. Physiol. 227: 3063–3071, 2012.

Plasma Adiponectin Levels Correlate Positively with an Increasing Number of Components of Frailty in Male Elders

Objective Frailty is an important geriatric syndrome. Adiponectin is an important adipokine that regulates energy homeostasis. The aim of this study is to investigate the relationship between plasma adiponectin levels and frailty in elders. Methods The demographic data, body weight, metabolic and inflammatory parameters, including plasma glucose, total cholesterol, triglyceride, tumor necrosis factor alpha (TNF-α), c-reactive protein (CRP) and adiponectin levels, were assessed. The frailty score was assessed using the Fried Frailty Index (FFI). Results The mean (SD) age of the 168 participants [83 (49.4%) men and 85 (50.6%) women] was 76.86 (6.10) years. Judged by the FFI score, 42 (25%) elders were robust, 92 (54.7%) were pre-frail, and 34 (20.3%) were frail. The mean body mass index was 25.19 (3.42) kg/m2. The log-transformed mean (SD) plasma adiponectin (µg/mL) level was 1.00 (0.26). The log-transformed mean plasma adiponectin (µg/mL) levels were 0.93 (0.23) in the robust elders, 1.00 (0.27) in the pre-frail elders, and 1.10 (0.22) in the frail elders, and the differences between these values were statistically significant (p  = 0.012). Further analysis showed that plasma adiponectin levels rose progressively with an increasing number of components of frailty in all participants as a whole (p for trend  = 0.024) and males (p for trend  = 0.037), but not in females (p for trend  = 0.223). Conclusion Plasma adiponectin levels correlate positively with an increasing number of components of frailty in male elders. The difference between the sexes suggests that certain sex-specific mechanisms may exist to affect the association between adiponectin levels and frailty.

Thalidomide inhibits fibronectin production in TGF-β1-treated normal and keloid fibroblasts via inhibition of the p38/Smad3 pathway

Keloids are characterized by the vigorously continuous production of extracellular matrix protein and aberrant cytokine activity in the dermis. There is a growing body of evidence that thalidomide, α-N-phthalimidoglutarimide, has anti-fibrotic properties. The aims were to examine possible therapeutic effects of thalidomide on fibronectin expression in transforming growth factor-β1 (TGF-β1)-treated normal fibroblasts (NFs) and keloid-derived fibroblasts (KFs) and the underlying mechanism of action, especially the involvement of mitogen-activated protein kinase (MAPKs) and Sma- and Mad-related family (Smads) pathways. In surgically removed human tissues, TGF-β1 and fibronectin immunoreactivity was high in keloid tissue, but barely detectable in normal tissue. TGF-β1 induced significant fibronectin expression in NFs and KFs and the effect was inhibited by pretreatment with thalidomide. TGF-β1 also induced phosphorylation of MAPKs (ERK1/2, p38, and JNK) and Smad2/3 and pretreatment with PD98059 (an ERK1/2 inhibitor), SB203580 (a p38 inhibitor), or SP600125 (a JNK inhibitor) inhibited TGF-β1-induced fibronectin expression. Furthermore, pretreatment with thalidomide inhibited the TGF-β1-induced phosphorylation of p38 and Smad3, but not that of ERK1/2, JNK, and Smad2. In addition, thalidomide pretreatment inhibited the TGF-β-induced DNA binding activity of AP-1 and Smad3/4, caused fibronectin degradation by increasing the activity of matrix metalloproteinase 9, and decreased production of TGF-β1 and fibronectin and the number of fibroblasts in an in vivo keloid model. These results show that thalidomide has an antifibrotic effect on keloid fibroblasts that is caused by suppression of TGF-β1-induced p38 and Smad3 signaling. Our findings indicate that thalidomide may be a potential candidate drug for the treatment and prevention of keloids.

Rosiglitazone inhibits monocyte/macrophage adhesion through de novo adiponectin production in human monocytes

Rosiglitazone (RSG) has a variety of actions on both insulin sensitization and anti‐atherogenic effects. The molecular effect of RSG on monocyte/macrophage function in terms of de novo synthesis of adiponectin is not fully understood. Here, we examined the regulation of adiponectin expression in human monocytes/macrophages by RSG and its function on monocyte adhesion during initiation of atherosclerosis. Adiponectin expression in monocytes and macrophages was studied by RT‐PCR, quantitative real‐time PCR, Western blot, and immunocytochemistry. Signal transduction and adhesion molecules were studied in order to describe the function of de novo synthesized adiponectin in monocyte adhesion. Adiponectin was expressed and upregulated during monocyte differentiation. The expression of adiponectin was enhanced, albeit at a much lesser degree, by a peroxisome proliferator‐activated receptor gamma (PPARγ) agonist RSG, which was similar to what was found in adipocytes. Monocyte adhesion was remarkably reduced when the cells were treated with RSG for 12 h. This inhibitory effect of RSG was abolished by specific anti‐adiponectin antibodies but not by non‐immune immunoglobulin G in a serum‐free condition. Adiponectin‐induced suppression on monocyte adhesion was inhibited by a selective AMP‐activated protein kinase (AMPK) inhibitor compound C. The reduced expression and/or function of adhesion molecule integrins may underlie the mechanism contributing to reduced monocyte adhesion upon AMPK activation. Our data suggest that the inhibitory effect of RSG on monocyte adhesion might be at least in part through de novo adiponectin expression and activation of an AMPK‐dependent pathway, which might play an important role in atherogenesis. J. Cell. Biochem. 110: 1410–1419, 2010.

The protective effect of eupafolin against TNF-α-induced lung inflammation via the reduction of intercellular cell adhesion molecule-1 expression

ETHNOPHARMACOLOGICAL RELEVANCE Eupafolin, a major bioactive compound found in Phyla nodiflora, has the anti-inflammatory property. Upregulation of cell adhesion molecules in the lung airway epithelium is associated with the epithelium-leukocyte interaction and plays a critical role in the pathogenesis of lung airway inflammatory disorders. To investigate the effects of eupafolin on tumor necrosis factor-α (TNF-α)-induced intercellular cell adhesion molecule-1 (ICAM-1) expression in A549 human lung airway epithelial cells and the underlying mechanisms. MATERIALS AND METHODS The effect of eupafolin on ICAM-1 expression in A549 cells were examined by Western blotting and immunofluorescent staining. The mice were injected intraperitoneally with or without eupafolin and then were left untreated or were injected intratracheally with TNF-α. To detect the effect of eupafolin on ICAM-1 expression, the lung tissues were also examined by Western blotting and immunohistochemical staining. RESULTS Eupafolin pretreatment reduced the TNF-α-induced ICAM-1 expression and also the ERK1/2, JNK, p38, and AKT/PI3K phosphorylation. However, the increase in ICAM-1 expression with TNF-α treatment was unaffected by p38 and PI3K inhibitors. Eupafolin decreased the TNF-α-induced NF-κB p65 activation and its nuclear translocation. Furthermore, eupafolin reduced ICAM-1 expression in the lung tissues of TNF-α-treated mice. CONCLUSIONS Eupafolin exerts its anti-inflammatory activity by suppressing the TNF-α-induced ICAM-1 expression and subsequent monocyte adhesion via AKT/ERK1/2/JNK phosphorylation and nuclear translocation of NF-κB p65. These results suggest that eupafolin may represent a novel therapeutic agent targeting epithelial activation in lung inflammation.

Magnolol Reduced TNF-α-Induced Vascular Cell Adhesion Molecule-1 Expression in Endothelial Cells via JNK/p38 and NF-κB Signaling Pathways

Expression of cell adhesion molecules by the endothelium and the attachment of leukocytes to these cells play major roles in inflammation and cardiovascular disorders. Magnolol, a major active component of Magnolia officinalis, has antioxidative and anti-inflammatory properties. In the present study, the effects of magnolol on the expression of vascular cell adhesion molecule-1 (VCAM-1) in human aortic endothelial cells (HAECs) and the related mechanisms were investigated. TNF-α induced VCAM-1 protein expression and mRNA stability were significantly decreased in HAECs pre-treated with magnolol. Magnolol significantly reduced the phosphorylation of ERK, JNK, and p38 in TNF-α-treated HAECs. The decrease in VCAM-1 expression in response to TNF-α treatment was affected by JNK and p38 inhibitors, not by an ERK inhibitor. Magnolol also attenuates NF-κB activation and the translocation of HuR (an RNA binding protein) in TNF-α-stimulated HAECs. The VCAM-1 expression was weaker in the aortas of TNF-α-treated apo-E deficient mice with magnolol treatment. These data demonstrate that magnolol inhibits TNF-α-induced JNK/p38 phosphorylation, HuR translocation, NF-κB activation, and thereby suppresses VCAM-1 expression resulting in reduced leukocyte adhesion. Taken together, these results suggest that magnolol has an anti-inflammatory property and may play an important role in the prevention of atherosclerosis and inflammatory responses.

Pigment epithelium-derived factor reduces the PDGF-induced migration and proliferation of human aortic smooth muscle cells through PPARγ activation

Our previous study demonstrated that pigment epithelium-derived factor (PEDF) plays an important role in the proliferation and migration of human aortic smooth muscle cells (HASMCs). In the present study, we examined whether PEDF inhibited platelet-derived growth factor (PDGF)-stimulated HASMC migration and proliferation. PEDF dose-dependently reduced PDGF-induced HASMC migration and proliferation in vitro and also arrested cell cycle progression in the G0/G1 phase, and this was associated with decreased expression of cyclin D1, cyclin E, CDK2, CDK4, and p21(Cip1) and increased expression of the cyclin-dependent kinase inhibitor p27(Kip1). The antiproliferative and antimigratory effects of PEDF were partially blocked by the PPARγ antagonist GW9662, but not by the PPARα antagonist MK886. In in vivo studies, the femoral artery of C57BL/6 mice was endothelial-denuded and the mice injected intravenously with PEDF or vehicle. After 2 weeks, both the neointima/media area ratio and cell proliferation (proliferating cell nuclear antigen-positive cells) in the neointima were significantly reduced and again these effects were partially reversed by GW9662 pretreatment. Our data show that PEDF increases PPARγ activation, preventing entry of HASMCs into the cell cycle in vitro and reducing the neointimal area and cell proliferation in the neointima in vivo. Thus, PEDF may represent a safe and effective novel target for the prevention and treatment of vascular proliferative diseases.

Indoxyl sulfate enhances IL-1β-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NFκB/AP-1 pathway

Uremic toxins are considered a risk factor for cardiovascular disorders in kidney diseases, but it is not known whether, under inflammatory conditions, they affect adhesion molecule expression on endothelial cells, which may play a critical role in acute kidney injury (AKI). In the present study, in cardiovascular surgery-related AKI patients, who are known to have high plasma levels of the uremic toxin indoxyl sulfate (IS), plasma levels of IL-1β were found to be positively correlated with plasma levels of the adhesion molecule E-selectin. In addition, high E-selectin and IL-1β expression were seen in the kidney of ischemia/reperfusion mice in vivo. We also examined the effects of IS on E-selectin expression by IL-1β-treated human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. IS pretreatment of HUVECs significantly increased IL-1β-induced E-selectin expression, monocyte adhesion, and the phosphorylation of mitogen-activated protein kinases (ERK, p38, and JNK) and transcription factors (NF-κB and AP-1), and phosphorylation was decreased by pretreatment with inhibitors of ERK1/2 (PD98059), p38 MAPK (SB202190), and JNK (SP600125). Furthermore, IS increased IL-1β-induced reactive oxygen species (ROS) production and this effect was inhibited by pretreatment with N-acetylcysteine (a ROS scavenger) or apocynin (a NADPH oxidase inhibitor). Gel shift assays and ChIP-PCR demonstrated that IS enhanced E-selectin expression in IL-1-treated HUVECs by increasing NF-κB and AP-1 DNA-binding activities. Moreover, IS-enhanced E-selectin expression in IL-1β-treated HUVECs was inhibited by Bay11-7082, a NF-κB inhibitor. Thus, IS may play an important role in the development of cardiovascular disorders in kidney diseases during inflammation by increasing endothelial expression of E-selectin.