St. John\u27s Wort inhibits adipocyte differentiation and induces insulin resistance in adipocytes

Adipocytes are insulin sensitive cells that play a major role in energy homeostasis. Obesity is the primary disease of fat cells and a major risk factor for the development of Type II diabetes, cardiovascular disease, and metabolic syndrome. Obesity and its related disorders result in dysregulation of the mechanisms that control adipocyte gene expression and function. To identify potential novel therapeutic modulators of adipocytes, we screened 425 botanical extracts for their ability to modulate adipogenesis and insulin sensitivity. We observed that less than 2% of the extracts had substantial effects on adipocyte differentiation of 3T3-L1 cells. Two of the botanical extracts that inhibited adipogenesis were extracts from St. John\u27s Wort (SJW). Our studies revealed that leaf and flower, but not root, extracts isolated from SJW inhibited adipogenesis as judged by examining PPARγ and adiponectin levels. We also examined the effects of these SJW extracts on insulin sensitivity in mature 3T3-L1 adipocytes. Both leaf and flower extracts isolated from SJW substantially inhibited insulin sensitive glucose uptake. The specificity of the observed effects was demonstrated by showing that treatment with SJW flower extract resulted in a time and dose dependent inhibition of insulin stimulated glucose uptake. SJW is commonly used in the treatment of depression. However, our studies have revealed that SJW may have a negative impact on adipocyte related diseases by limiting differentiation of preadipocytes and significantly inducing insulin resistance in mature fat cells. © 2009 Elsevier Inc. All rights reserved

Naringenin inhibits adipogenesis and reduces insulin sensitivity and adiponectin expression in adipocytes

Adipose tissue development and function are widely studied to examine the relationship between obesity and the metabolic syndrome. It is well documented that the inability of adipose tissue to properly increase its lipid storage capacity during the obese state can lead to metabolic dysfunction. In a blind screen of 425 botanicals, we identified naringenin as an inhibitor of adipocyte differentiation. Naringenin is one of the most abundant citrus flavonoids, and recent studies have demonstrated antihyperlipidemic capabilities. These studies have largely focused on the effects of naringenin on the liver. Our biochemical studies clearly demonstrate that naringenin inhibits adipogenesis and impairs mature fat cell function. Naringenin specifically inhibited adipogenesis in a dose-dependent fashion as judged by examining lipid accumulation and induction of adipocyte marker protein expression. In mature 3T3-L1 adipocytes, naringenin reduced the ability of insulin to induce IRS-1 tyrosine phosphorylation and substantially inhibited insulin-stimulated glucose uptake in a dose-dependent manner and over a time frame of 1.5 to 24 hours. Exposure to naringenin also inhibited adiponectin protein expression in mature murine and human adipocytes. Our studies have revealed that naringenin may have a negative impact on adipocyte-related diseases by limiting differentiation of preadipocytes, by significantly inducing insulin resistance, and by decreasing adiponectin expression in mature fat cells. © 2013 Allison J. Richard et al

The cytotoxic and migrastatic potentials of Allium Jesdianum hydroalcoholic extract on glioblastoma multiforme cell line model

OBJECTIVE: Glioblastoma multiforme is one of the most malignant types of central nervous system tumors and temozolomide (TMZ) is currently used as a standard treatment for this type of cancer. However, resistance to temozolomide is a problem in the successful treatment. Plants and herbs are potential sources of cancer therapeutics. This study aimed at evaluating the effect of Allium Jesdianum (AJ) hydroalcoholic extract on glioblastoma multiforme cells. MATERIALS AND METHODS: The plant material was purchased and extracted. The cell line was treated with extract for 24, 48, and 72 hr. Cell viability was assessed by trypan blue staining, MTT assay, and lactate dehydrogenase activity measurement. Tumor invasion potential was evaluated by cell migration, invasion, and adhesion tests. Real-time PCR was used to assess the changes in the expression pattern of genes involved in cancer invasion. RESULTS: Extract treatment caused a concentration- and time-dependent decrease in cell survival. Also, a decrease in cell migration, invasion and adhesion potential and the expression of metalloproteinases 2 and 9 in cells was observed after treatment. CONCLUSIONS: Allium Jesdianum showed promising anti-cancer activity in glioblastoma multiforme cells

Anti-invasion and anti-metastasis effects of Dandelion (Taraxacum officinale) hydroalcoholic extract on glioblastoma multiforme cell line model

OBJECTIVE: Glioblastoma multiforme is one of the malignant brain tumors and despite recent advancements in cancer treatment remains largely incurable. Cancer invasion has a cascade of interrelated and sequential steps, including cell adhesion, extracellular matrix degradation, and cell movement. Hence, inhibition of the invasion-associated steps could be a potential strategy for prolonging the life of patients. This study aimed to evaluate the anti-invasion and anti-metastasis effects of Dandelion (Taraxacum officinale) hydro-alcoholic extract on glioblastoma multiforme cell line (U87MG). MATERIALS AND METHODS: The hydro-alcoholic extract was prepared, and the cell line was treated with 1000, 500, 250, 125, and 62.5 µg / ml of extract for 24, 48, and 72 hr. Cell viability was evaluated. The effect of extract (IC50 concentration) on cancer cell invasion potential was tested. The expression levels of MMP-2, MMP-9, TIMP-1, TIMP-2, uPA, uPAR, p38MAPK, ERK1/2, and SAPK/JNK were analyzed. Comparisons between groups were performed by Tukey’s test one-way analysis of variance and differences were considered significant when p < 0.05. RESULTS: After treatment with extract, the cells viability was decrease in a concentration- and time-dependent. IC50 concentration of dandelion extract significantly decreased the cell migration by 32% (p<0.05), cell invasion potential by 77% (p<0.05) and cell adhesion by 51% (p<0.05). Also, the expression levels of proteolytic enzymes associated with matrix and base membrane degradation (MMP-2, MMP-9, and uPA) were decreased and the levels of their endogenous inhibitors (TIMP1 and TIMP2) were increased. Moreover, the p38MAPK and SAPK/JNK signaling pathway, which stimulates proteolytic enzymes and matrix degradation, was inhibited by extract treatment. CONCLUSIONS: Dandelion extract reduced the viability and invasion potential of the glioblastoma cells by regulating proteolytic enzymes and matrix dynamics through the p38MAPK and SAPK/JNK pathway

Anti-proliferative and apoptotic effects of Rosa canina fruit extract on thyroid cancer cells (B-CPAP and Thr.C1-PI 33)

OBJECTIVE: Thyroid cancer is one of the most common endocrine malignancies. Although most thyroid cancers respond to surgery and treatment, drug-resistant is a problem that necessitates new therapeutic strategies. Rosa canina from the Rosaceae family is suggested as an herbal remedy for numerous human ailments. Due to the need to identify new therapies for thyroid cancer and due to the therapeutic properties of Rosa canina, this study aimed to investigate the effect of Rosa canina fruit extract on two thyroid cancer cell lines (B-CPAP and Thr.C1-PI 33). MATERIALS AND METHODS: After preparation of hydro-alcoholic extract of Rosa canina fruits and treatment of thyroid cancer cells, the cell survival, and proliferation were evaluated. Apoptosis cell death and nitric oxide production were estimated. Real-time PCR was used to investigate the expression of apoptosis-related genes. Statistical evaluation was performed using one-way analysis of variance (ANOVA) and differences were considered not significant when p > 0.05. RESULTS: The extract reduced the viability of the cells in a concentration- and time-dependent manner. Nitric oxide production was decreased in a concentration- and time-dependent manner. The extract stimulated apoptosis cell death by decreasing the expression of Bcl-2 and increasing the expression of Bax, p53, and Caspase 3. CONCLUSIONS: This extract can be promising in the treatment of patients with thyroid cancer

Oncogenic role of connective tissue growth factor is associated with canonical TGF-β cascade in colorectal cancer

TGF-β signaling pathways promote tumour development and control several downstream genes such as CTGF and MMPs. This study aimed to investigate the association between CTGF and MMP-1 mRNA expressions with clinicopathological status and survival rate in colorectal cancer patients. We investigated expression levels of CTGF and MMP-1 genes in paraffin-embedded tumours and adjacent normal tissue blocks (ADJ) by Real Time-PCR. Then, the expression of Smad2 and Smad4 proteins in the TGF-β canonical pathway was evaluated by immunohistochemistry. Finally, the correlation between CTGF, MMP-1, and the canonical TGF-β-signalling pathway with the clinicopathological features was investigated. Expression levels of MMP-1and CTGF were higher in tumours compared with adjacent normal tissues. Overexpression levels of MMP-1 and CTGF were associated with lymph node metastasis, distant metastasis, tumour histopathological grading, advanced stage, and poor survival (p 0.05). Additionally, a significant association between the upregulation of MMP-1 and tumour location was noted. Upregulation of Smad2 and Smad4 proteins were also significantly correlated with lymph node metastasis, distant metastasis, advanced stage, and poor survival (p 0.0001). This study showed that canonical TGF-β signalling regulates both CTGF and MMP-1 expression and CRC progression. Moreover, TGF-β signalling and its downstream genes could be used as novel biomarkers and novel approaches for targeted therapy in CRC

Prevalence of Internet Addiction and its Association with General Health Status among High School Students in Isfahan, Iran

Background: Internet has played an increasingly important role in people's lives; however, there is a global concern that it may cause negative effects on health. The purpose of this study was to assess the prevalence of Internet addiction (IA), and its relationship with general health status among high school students. Materials and Methods: A cross-sectional study using a multistage proportionate sampling technique conducted among 10-15 year-old students in Isfahan, Iran. Data were collected from 721 students in 5 educational areas of Isfahan. A total of 721 students filled out a self-report questionnaire consisted of two parts; the first was Young Internet Addiction Test and the second was General Health Questionnaire (GHQ28). Data was analyzed using SPSS software version 16.0. Results: Of the 721 students, 52 (375 students) were male. The average age of students was 15.75 +/- 1.5 years old. The prevalence rate of Internet addiction among adolescents was 41.2 nonaddicts, 53.7 exposed to IA, and 5.1 Internet addicts. Whereas there was a significant difference between boys and girls in IA (P.004). In this study, Internet addiction was found to have an independent relationship with parent education and household income but it had a significant negative relationship with the general health aspect including physical health (r=0.3, P<0.001), depression (r=0.4, P<0.001), sleep (r=0.4, P<0.001), and social function (r.25, P<0.001). Conclusion: Based on the results, the prevalence of Internet addiction was high among high school students and overuse of the Internet by students may cause depression, decreased mental health and academic performance. Therefore, education about the proper use of the Internet is necessary for high school students

Consensus on Molecular Subtypes of High-grade Serous Ovarian Carcinoma

Purpose: The majority of ovarian carcinomas are of high-grade serous histology, which is associated with poor prognosis. Surgery and chemotherapy are the mainstay of treatment, and molecular characterization is necessary to lead the way to targeted therapeutic options. To this end, various computational methods for gene expression-based subtyping of high-grade serous ovarian carcinoma (HGSOC) have been proposed, but their overlap and robustness remain unknown. Experimental Design: We assess three major subtype classifiers by meta-analysis of publicly available expression data, and assess statistical criteria of subtype robustness and classifier concordance. We develop a consensus classifier that represents the subtype classifications of tumors based on the consensus of multiple methods, and outputs a confidence score. Using our compendium of expression data, we examine the possibility that a subset of tumors are unclassifiable based on currently proposed subtypes. Results: HGSOC subtyping classifiers exhibit moderate pairwise concordance across our data compendium (58.9%-70.9%, p \u3c 10-5) and are associated with overall survival in a metaanalysis across datasets (p \u3c 10-5). Current subtypes do not meet statistical criteria for robustness to re-clustering across multiple datasets (Prediction Strength \u3c 0.6). A new subtype classifier is trained on concordantly classified samples to yield a consensus classification of patient tumors that correlates with patient age, survival, tumor purity, and lymphocyte infiltration. Conclusion: A new consensus ovarian subtype classifier represents the consensus of methods, and demonstrates the importance of classification approaches for cancer that do not require all tumors to be assigned to a distinct subtype

Effectiveness of Disease-Modifying Therapies in Patients With Late-Onset Relapsing-Remitting Multiple Sclerosis

Background and Objectives: The benefit of disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) is believed to decrease with age. We aimed to compare disease outcomes with DMTs between patients with late-onset RRMS (LO-RRMS) and adult-onset RRMS (AO-RRMS). / / Methods: This was a single-center, longitudinal, prospective analysis of patients who fulfilled the following criteria: (1) a diagnosis of RRMS and (2) initiation of a new DMT (dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and ocrelizumab) within 3 months. Patients were followed up at years 1 and 2. We compared treatment outcomes (relapses, radiologic activity, disability progression, and no evidence of disease activity [NEDA]) between LO-RRMS (defined as age at onset of first symptom >45 years) and AO-RRMS (≥18 years and 45 years) using Poisson, logistic, and Cox regression models while adjusting for baseline variables. The analyses were repeated with an age cutoff of 50 years. / / Results: We studied 1,494 patients with AO-RRMS (mean age at onset: 29.6 years, 71% female) and 150 patients with LO-RRMS (50.2 years, 73% female) at treatment initiation. At DMT commencement, patients with LO-RRMS had shorter disease duration, higher Expanded Disability Status Scale (EDSS), more comorbidities, and were more likely to be treatment naive than patients with AO-RRMS. However, when adjusted, there were no differences in the probability of relapses (Coeff = −0.07; 95% CI −0.19 to 0.04, p = 0.24), EDSS progression (odds ratio [OR] 1.43, 95% CI 0.69–2.93, p = 0.33), MRI activity (OR 0.77; 95% CI 0.21–2.83, p = 0.70), and losing NEDA status (hazard ratio [HR] 0.93; 95% CI 0.73–1.18, p = 0.58) at year 1. Similar results were observed at year 2 in relapses (Coeff = −0.04; 95% CI −0.19 to 0.11, p = 0.60), EDSS progression (OR 1.33; 95% CI 0.69–2.93, p = 0.33), MRI activity (OR 1.30; 95% CI 0.38–4.38, p = 0.67), and loss of NEDA status (HR 0.99; 95% CI 0.77–1.26, p = 0.96). Similar results were observed using an age cutoff of 50 years. The percentages of patients who stopped DMTs because of side effects were similar between AO-RRMS and LO-RRMS. / / Discussion: Treatment outcomes over 2 years were similar between LO-RRMS and AO-RRMS. This indicates that care should be taken not to bias treatment decisions due to older age at onset of MS when patients demonstrate evidence of inflammatory activity. Limitations are the observational design, the single-center setting, and a relatively small LO-RRMS group. / / Classification of Evidence: This study provides Class III evidence that patients with LO-RRMS have comparable outcomes with DMTs as patients with AO-RRMS over a 2-year period; this rating is because of baseline imbalances between treatment groups and a nonmasked outcome assessment