Curcumin-induced cell death depends on the level of autophagic flux in A172 and U87MG human glioblastoma cells.

Glioblastoma is the deadliest neoplasm with the worst 5-year survival rate among all human cancers. Autophagy promotes autophagic cell death or blocks the induction of apoptosis in eukaryotic cells. Here, we investigated whether varying levels of autophagic flux in glioblastoma lead to different efficacies of curcumin treatment using U87MG and A172 human glioblastoma cells. The number of LC3 puncta, the number of cells with LC3 puncta and the level of LC3 II, Atg5 and Atg7 protein were higher in U87MG cells compared with A172 cells. When the cells were incubated with curcumin for 24 or 48 h, the percentage of cell death was higher in A172 cells compared with U87MG cells. Although the level of LC3 was lower, that of curcumin-induced LC3 was higher, in A172 cells than in U87MG cells. The relative increases in cell death and LC3-mediated autophagy were greater under serum starvation in A172 cells compared with U87MG cells. Curcumin-induced A172 cell death was reduced by serum starvation. When both types of cells were transfected with LC3-GFP, the percentage of cell death was higher in A172 cells than that in U87MG cells. Taken together, the data demonstrate that curcumin-mediated tumor cell death is regulated by the basal level of autophagic flux in different glioblastoma cells. This suggests that prior to the use of various curcumin therapeutics, the level of basal or induced autophagic flux should be carefully examined in tumor cells for the best efficacy.

Therapeutic Effect of Guggulsterone in Primary Cultured Orbital Fibroblasts Obtained From Patients with Graves' Orbitopathy.

Purpose: Inflammation, hyaluronan production, and adipogenesis are the main pathological events leading to Graves' orbitopathy (GO). Guggulsterone (GS), a phytosterol found in the resin of the guggul plant, is a well-known treatment for several inflammatory disorders, such as arthritis, obesity, and hyperlipidemia. Here we investigated the effects of GS treatment on GO pathology. Methods: Using primary cultures of orbital fibroblasts from GO patients and non-GO controls, we examined the effects of GS on hyaluronan production and the production of proinflammatory cytokines induced by interleukin (IL)-1ß, using real-time reverse transcription-polymerase chain reaction analysis, western blots, and enzyme-linked immunosorbent assays. Further, adipogenic differentiation was evaluated by quantification of Oil Red O staining and assessment of protein levels of peroxisome proliferator activator gamma (PPARγ), CCAAT-enhancer-binding proteins (C/EBP) α and ß, and sterol regulatory element-binding protein-1 (SREBP-1). Results: Treatment with noncytotoxic concentrations of GS resulted in the dose-dependent inhibition of IL-1ß-induced inflammatory cytokines, including IL-6, IL-8, MCP-1, and COX-2, at both mRNA and protein levels. The hyaluronan level was also significantly suppressed by GS. Moreover, GS significantly decreased the formation of lipid droplets and expression of PPARγ, C/EBP α/ß, and SREBP-1 in a dose-dependent manner. GS pretreatment attenuated the phosphorylation of nuclear factor-kappa B induced by IL-1ß. Conclusions: Our data show significant inhibitory effects of GS on inflammation, production of hyaluronan, and adipogenesis in orbital fibroblasts. To our knowledge, this is the first in vitro preclinical evidence of the therapeutic effect of GS in GO.

End-of-life care needs for noncancer patients who want to die at home in South Korea.

AIM: The awareness for the need for end-of-life care has increased among noncancer patients. However, studies on the topic have rarely targeted the needs of noncancer patients who want to die at home. This study assessed the end-of-life care needs of noncancer patients who were receiving care and wanted to die at home. METHODS: A cross-sectional study design was used and involved 200 participants who were diagnosed as noncancer patients and receiving home care nursing. Data were collected on demographics, disease, Palliative Performance Scale (PPS) scores, and end-of-life care needs, in April and May, 2016. RESULTS: Among the six areas of care, "supporting fundamental needs" of patients required the most care, followed by "coordination among family or relatives." Multivariate analysis revealed that the duration of home care nursing held a significant association with end-of-life care needs. CONCLUSION: By reflecting on the comprehensive care needs of patients with chronic illnesses and including them in the care process, it will be possible to provide better quality palliative care to patients at home in the end-of-life stages.

Risk of osteoporosis and fracture in long-term breast cancer survivors.

Purpose: High incidence of osteoporosis has been reported in breast cancer patients due to early menopause triggered by adjuvant treatment and temporary ovarian function suppression. In this study, we sought to determine whether long-term breast cancer survivors had an elevated risk of low bone density compared to the general population. Methods: Long-term breast cancer survivors who had been treated for more than 5 years were selected for this study. Data were obtained from medical records and using a questionnaire from the Korea National Health and Nutrition Examination Survey (KNHANES). An age-matched non-cancer control group was selected from the KNHANES records. Incidence of fracture and bone mineral density (BMD) were compared between the two groups. Results: In total, 74 long-term breast cancer survivors and 296 non-cancer controls were evaluated. The incidence of fracture did not differ between the two groups (P=0.130). No differences were detected in lumbar BMD (P=0.051) following adjustment for body mass index, while hip BMD was significantly lower in breast cancer survivors (P=0.028). Chemotherapy and endocrine treatment were not related to low BMD in breast cancer survivors. In more than half of the survivors, the 10-year risk of osteoporotic fracture was less than 1%. Conclusion: Long-term breast cancer survivors had low bone density but a comparable risk of fracture compared to non-cancer age-matched controls. Further studies on the factors related to low bone density in long-term breast cancer survivors are required.

Combined Therapy with Transarterial Chemoembolization and Radiofrequency Ablation for Hepatocellular Carcinoma: Does the Degree of Ethiodized Oil Accumulation within the Tumor Affect the Therapeutic Efficacy?

PURPOSE: To evaluate the effects of the degree of ethiodized oil accumulation achieved by transarterial chemoembolization followed by radiofrequency (RF) ablation on the treatment efficacy for a single intermediate-sized hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A total of 153 consecutive patients who underwent chemoembolization and RF ablation for a single intermediate-sized HCC (2-5 cm) were included. On the basis of the degree of ethiodized oil accumulation in HCC on cone-beam CT images, patients who underwent chemoembolization and RF ablation were classified into 2 groups: compact accumulation (≥ 75%) and noncompact accumulation (< 75%). The rates of cumulative local tumor progression (LTP), disease-free survival (DFS), and overall survival (OS) were compared between groups. RESULTS: Of the 153 patients, 89 were classified into the compact ethiodized oil accumulation group and 64 in the noncompact ethiodized oil accumulation group. There were no significant differences in patient demographic or HCC characteristics between groups except for the incidence of liver cirrhosis (P = .038) and the tumor margin morphology (P = .008). The cumulative LTP rate was significantly lower in the compact accumulation group than in the noncompact accumulation group (P = .013). There were no significant differences in the incidences of complications, DFS rates (P = .055), or OS rates (P = .184). CONCLUSIONS: The degree of ethiodized oil accumulation does not play a role in decreasing the OS or DFS rate after chemoembolization and RF ablation for intermediate-sized HCC; however, it may contribute to reducing the rate of LTP.

Care Needs of Patients at the End of Life With a Noncancer Diagnosis Who Live at Home.

BACKGROUND: As the population ages, the prevalence of various chronic diseases increases. Palliative care for patients at the end of life with a noncancer diagnosis is currently limited because of the difficulties of demarcating the boundaries of the end-of-life care period and of determining the various care needs of patients at the end of life. PURPOSE: This study aimed to investigate the levels of importance and difficulty of the multidimensional care needs for patients with a noncancer diagnosis during various end-of-life stages. METHODS: This study is a retrospective survey. Home healthcarenurse specialists (HHNS) reviewed medical and nursing records and responded to a structured questionnaire. The caring experiences of HHNS with 115 patients, who were 40 years or older, had received home care nursing throughout the stable (between the onset of the end-of-life stage and 1 week before death) and near-death (1 week before death) stages at Seoul St. Mary's Hospital in Korea, and had died between September 1, 2014, and December 31, 2015, were analyzed. RESULTS: The care needs of "coordination among family or relatives" and "support for fundamental needs" were more important in the stable stage than in the near-death stage. The care need of "loss, grief care" was more important in the near-death stage than in the stable stage. The care need of "physical symptoms management" was the most difficult to meet in both stages. Lower Palliative Performance Scale score was associated with a higher level of care need, particularly in the "management of physical symptoms" and "psychological support" realms in the stable stage and in the "coordination among family or relatives" realm in both stages. CONCLUSIONS: End-of-life stage and initial score on the Palliative Performance Scale were found to have a significant influence on the multidimensional care needs of patients with a noncancer diagnosis. Thus, healthcare professionals should assess patient care needs according to disease trajectory to provide continuous and holistic care.

Cerebroprotective effects of red ginseng extract pretreatment against ischemia-induced oxidative stress and apoptosis.

Panax ginseng C.A. Meyer has been traditionally used as a medicinal plant and has beneficial effects due to pharmacological properties. Although ginseng is thought to be protective under abnormal conditions, the effects of pretreatment with red ginseng (RG) extract on ischemic stroke have not been fully elucidated. We investigated the protective effects of RG extract after focal cerebral ischemia in mice. Crude RG extract (360 mg/kg) was administered intraperitoneally for 2 weeks. Mice were then subjected to occlusion of the middle cerebral artery for 1 hour, followed by reperfusion for 4 and 24 hours. Pretreatment with RG extract followed by ischemia/reperfusion (I/R) resulted in significant reduction of oxidized hydroethidine signals in ischemic areas. At 4 and 24 hours after I/R, the number of 8-hydroxyguanosine and apoptosis signal-regulating kinase 1 (ASK1)-positive cells decreased in the ischemic penumbra as seen using immunofluorescent staining. Western blotting showed that RG efficiently attenuated the protein levels of activated ASK1 in the ischemic penumbra. Consequently, DNA fragmentation and the infarct volume were reduced by RG extract pretreatment 24 hours after I/R. Also, RG extract resulted in better performance in rotarod test after I/R. Thus, RG pretreatment demonstrates a protective effect at suppressing ischemia-induced oxidative stress and apoptosis in ischemic lesions. Pretreatment with crude RG extract may be an effective strategy for preventing brain injury after an ischemic stroke.

Adiponectin as a new paradigm for approaching Alzheimer's disease.

Adiponectin is an adipocytokine released by the adipose tissue and has multiple roles in the immune system and in the metabolic syndromes such as cardiovascular disease, Type 2 diabetes, obesity and also in the neurodegenerative disorders including Alzheimer's disease. Adiponectin regulates the sensitivity of insulin, fatty acid catabolism, glucose homeostasis and anti-inflammatory system through various mechanisms. Previous studies demonstrated that adiponectin modulates memory and cognitive impairment and contributes to the deregulated glucose metabolism and mitochondrial dysfunction observed in Alzheimer's disease. Here, we aim to summarize recent studies that suggest the potential correlation between adiponectin and Alzheimer's disease.

Enhancement of anti-inflammatory and antinociceptive actions of red ginseng extract by fermentation.

OBJECTIVES: This work aimed to compare some pharmacological properties of red ginseng extract (RG) and fermented red ginseng extract (FRG). METHODS: Antinociceptive activity was analysed using the acetic acid-induced abdominal constriction response. Anti-inflammatory activity was evaluated using acetic acid-induced vascular permeability and carrageenan-induced inflammation in the air pouch, and analysed through the measurement of nitrite content in the lipopolysaccharide (LPS)-stimulated macrophage cells. Anti-angiogenic activity was determined using the chick chorioallantoic membrane assay. KEY FINDINGS: In-vivo anti-inflammatory activity of FRG was stronger than that of RG in two animal models, vascular permeability and air-pouch models. In the vascular permeability model, the doses of RG and FRG required for half-maximal inhibition (IC50) were 181 and 59mg/kg, respectively. FRG exhibited significantly stronger antinociceptive activity than RG. In the acetic acid-induced abdominal constriction response, the IC50 values of RG and FRG were 153 and 27mg/kg, respectively. Although both RG and FRG were able to suppress production of nitric oxide in the LPS-stimulated RAW264.7 macrophage cells, the suppressive activity of FRG appeared to be stronger than that of RG. However, RG and FRG showed similar anti-angiogenic activity. CONCLUSIONS: FRG possesses enhanced anti-inflammatory and antinociceptive activity but similar anti-angiogenic activity than RG.

Autophagy regulates embryonic survival during delayed implantation.

Delayed implantation, considered a state of suspended animation, is widespread in mammals. Blastocysts under this condition remain dormant for an extended period but resume implantation competence upon favorable conditions. The underlying mechanism by which extended longevity of dormant blastocysts is maintained is not clearly understood. Using autophagy markers and the well-defined delayed implantation model in mice, we show that autophagy is important for the extended longevity of dormant blastocysts in utero during delayed implantation. However, prolonged dormancy leads to reduced developmental competency of blastocysts and cellular damage with compromised pregnancy outcome. Estrogen supplementation, which activates implantation of dormant blastocysts, induces the formation of multivesicular bodies in the trophectoderm in vivo. Collectively, our results suggest that autophagy is a critical cellular mechanism that is utilized for the prolonged survival of dormant blastocysts.

Agmatine attenuates brain edema through reducing the expression of aquaporin-1 after cerebral ischemia.

Brain edema is frequently shown after cerebral ischemia. It is an expansion of brain volume because of increasing water content in brain. It causes to increase mortality after stroke. Agmatine, formed by the decarboxylation of L-arginine by arginine decarboxylase, has been shown to be neuroprotective in trauma and ischemia models. The purpose of this study was to investigate the effect of agmatine for brain edema in ischemic brain damage and to evaluate the expression of aquaporins (AQPs). Results showed that agmatine significantly reduced brain swelling volume 22 h after 2 h middle cerebral artery occlusion in mice. Water content in brain tissue was clearly decreased 24 h after ischemic injury by agmatine treatment. Blood-brain barrier (BBB) disruption was diminished with agmatine than without. The expressions of AQPs-1 and -9 were well correlated with brain edema as water channels, were significantly decreased by agmatine treatment. It can thus be suggested that agmatine could attenuate brain edema by limiting BBB disruption and blocking the accumulation of brain water content through lessening the expression of AQP-1 after cerebral ischemia.

Soybeans ameliolate diabetic nephropathy in rats.

Diabetic nephropathy is one of the most frequent and serious complications of diabetes mellitus. Soybeans have been shown to reduce urinary albumin excretion and total cholesterol in non-diabetic patients with nephrotic syndrome. However, reports focusing specifically on diabetic nephropathy are scarce and the available results are inconsistent. It was reported that soybean consumption reduced urinary protein excretion in type 1 diabetic patients with diabetic nephropathy, whereas it was found to elicit an increase in urinary protein excretion when soybeans were consumed by type 2 diabetic patients. This study aims to investigate the effects of soybean in diabetic nephropathy, particularly the effects of consuming soybeans on the histopathology of diabetic nephropathy, using aquaporin (AQP) and osteopontin (OPN) expression as diagnostic markers. Male Sprague-Dawley rats were assigned to one of three groups: control, diabetic with red chow diet and diabetic with soybean diet. For histological examination, the expression of OPN and AQP, renal function and hemoglobin A1c were evaluated at the end of the study. Improvements in glomerular and tubulointerstitial lesions were demonstrated in the diabetic rat group given a soybean diet. OPN and AQP expression were suppressed in the kidney specimens of diabetic rats with the soybean diet. In conclusion, soybeans may prevent the weight loss and morphological disruption of the kidney associated with diabetes mellitus. Soybeans also may improve glycemic control. It seems likely that long-term control of blood glucose levels using a soybean diet could prevent the progression of diabetes mellitus, and therefore, nephropathy could be prevented.