ESM-1 siRNA Knockdown Decreased Migration and Expression of CXCL3 in Prostate Cancer Cells

Endothelial cell-specific molecule-1 (ESM-1), also known as endocan, is a soluble proteoglycan expressed by the vascular endothelium, which also circulates in the bloodstream. Inflammatory cytokines and proangiogenic growth factors increase its expression, and increased serum levels have been reported in several cancer types and immunocompetent patients with sepsis. The aim of this study was to analyze the expression profile of CXC-chemokines and the effects of ESM-1 gene knockdown in proliferation, migration and CXC-chemokine expression in highly metastatic human prostate PC-3 cells. Expression profiles of CXC-chemokines were analyzed in metastatic PC-3 and non-tumorigenic PWR-1E cells. siRNA-mediated knockdown of ESM-1 was performed into PC-3 cells, which were subsequently tested for cell migration and proliferation. Effect of siRNA transfection on CXC-chemokine expression was further quantified at the transcript and protein level. RT-qPCR analysis and sandwich ELISA assay revealed higher levels of ESM-1 and several CXC-chemokines in metastatic PC-3 cells compared to non-tumorigenic PWR-1E. Transfection of PC-3 cells with ESM-1-siRNA decreased cell migration with no effect on proliferation, and it was accompanied by decrease in the transcript and protein levels of the angiogenic chemokine CXCL3. We report here for the first time the ESM-1 targeting in PC-3 cells, which resulted in decreased migration, which may be related, at least in part, to decreased expression of the angiogenic CXCL3 chemokine, whose expression was found to be reduced in ESM-1-siRNA transfected cells. Additional studies are required to ascertain the biological role of ESM-1 in prostate cancer cells and the link with the expression of CXCL3

Androgen Activity Is Associated With PD-L1 Downregulation in Thyroid Cancer

Thyroid cancer is the most prevalent endocrine malignancy in the United States with greater than 53,000 new cases in 2020. There is a significant gender disparity in disease incidence as well, with women developing thyroid cancer three times more often than men; however, the underlying cause of this disparity is poorly understood. Using RNA-sequencing, we profiled the immune landscape of papillary thyroid cancer (PTC) and identified a significant inverse correlation between androgen receptor (AR) levels and the immune checkpoint molecule PD-L1. The expression of PD-L1 was then measured in an androgen responsive-thyroid cancer cell line. Dihydrotestosterone (DHT) treatment resulted in significant reduction in surface PD-L1 expression in a time and dose-dependent manner. To determine if androgen-mediated PD-L1 downregulation was AR-dependent, we treated cells with flutamide, a selective AR antagonist, and prior to DHT treatment to pharmacologically inhibit AR-induced signaling. This resulted in a \u3e 90% restoration of cell surface PD-L1 expression, suggesting a potential role for AR activity in PD-L1 regulation. Investigation into the AR binding sites showed AR activation impacts NF-kB signaling by increasing IkBalpha and by possibly preventing NF-kB translocation into the nucleus, reducing PD-L1 promoter activation. This study provides evidence of sex-hormone mediated regulation of immune checkpoint molecules in vitro with potential ramification for immunotherapies

Effect of extended morning fasting upon ad libitum lunch intake and associated metabolic and hormonal responses in obese adults

Background/Objectives: Breakfast omission is positively associated with obesity and increased risk of disease. However, little is known about the acute effects of extended morning fasting upon subsequent energy intake and associated metabolic/regulatory factors in obese adults. Subjects/Methods: In a randomised cross-over design, 24 obese men (n=8) and women (n=16) extended their overnight fast by omitting breakfast consumption or ingesting a typical carbohydrate-rich breakfast of 2183±393 kJ (521±94 kcal), before an ad libitum pasta lunch 3 h later. Blood samples were obtained throughout the day until 3 h post lunch and analysed for hormones implicated in appetite regulation, along with metabolic outcomes and subjective appetite measures. Results: Lunch intake was unaffected by extended morning fasting (difference=218 kJ, 95% confidence interval −54 kJ, 490 kJ; P=0.1) resulting in lower total intake in the fasting trial (difference=−1964 kJ, 95% confidence interval −1645 kJ, −2281 kJ; P<0.01). Systemic concentrations of peptide tyrosine–tyrosine and leptin were lower during the afternoon following morning fasting (Pless than or equal to0.06). Plasma-acylated ghrelin concentrations were also lower following the ad libitum lunch in the fasting trial (P<0.05) but this effect was not apparent for total ghrelin (Pgreater than or equal to0.1). Serum insulin concentrations were greater throughout the afternoon in the fasting trial (P=0.05), with plasma glucose also greater 1 h after lunch (P<0.01). Extended morning fasting did not result in greater appetite ratings after lunch, with some tendency for lower appetite 3 h post lunch (P=0.09). Conclusions: We demonstrate for the first time that, in obese adults, extended morning fasting does not cause compensatory intake during an ad libitum lunch nor does it increase appetite during the afternoon. Morning fasting reduced satiety hormone responses to a subsequent lunch meal but counterintuitively also reduced concentrations of the appetite-stimulating hormone-acylated ghrelin during the afternoon relative to lunch consumed after breakfast

Decaffeinated Coffee and Glucose Metabolism in Young Men

OBJECTIVE The epidemiological association between coffee drinking and decreased risk of type 2 diabetes is strong. However, caffeinated coffee acutely impairs glucose metabolism. We assessed acute effects of decaffeinated coffee on glucose and insulin levels. RESEARCH DESIGN AND METHODS This was a randomized, cross-over, placebo-controlled trial of the effects of decaffeinated coffee, caffeinated coffee, and caffeine on glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) levels during a 2-h oral glucose tolerance test (OGTT) in 11 young men. RESULTS Within the first hour of the OGTT, glucose and insulin were higher for decaffeinated coffee than for placebo (P \u3c 0.05). During the whole OGTT, decaffeinated coffee yielded higher insulin than placebo and lower glucose and a higher insulin sensitivity index than caffeine. Changes in GIP could not explain any beverage effects on glucose and insulin. CONCLUSIONS Some types of decaffeinated coffee may acutely impair glucose metabolism but less than caffeine

Episodic Memory and Appetite Regulation in Humans

Psychological and neurobiological evidence implicates hippocampal-dependent memory processes in the control of hunger and food intake. In humans, these have been revealed in the hyperphagia that is associated with amnesia. However, it remains unclear whether 'memory for recent eating' plays a significant role in neurologically intact humans. In this study we isolated the extent to which memory for a recently consumed meal influences hunger and fullness over a three-hour period. Before lunch, half of our volunteers were shown 300 ml of soup and half were shown 500 ml. Orthogonal to this, half consumed 300 ml and half consumed 500 ml. This process yielded four separate groups (25 volunteers in each). Independent manipulation of the 'actual' and 'perceived' soup portion was achieved using a computer-controlled peristaltic pump. This was designed to either refill or draw soup from a soup bowl in a covert manner. Immediately after lunch, self-reported hunger was influenced by the actual and not the perceived amount of soup consumed. However, two and three hours after meal termination this pattern was reversed - hunger was predicted by the perceived amount and not the actual amount. Participants who thought they had consumed the larger 500-ml portion reported significantly less hunger. This was also associated with an increase in the 'expected satiation' of the soup 24-hours later. For the first time, this manipulation exposes the independent and important contribution of memory processes to satiety. Opportunities exist to capitalise on this finding to reduce energy intake in humans

Effects of cereal breakfasts on postprandial glucose, appetite regulation and voluntary energy intake at a subsequent standardized lunch; focusing on rye products

<p>Abstract</p> <p>Background</p> <p>Rye products have been demonstrated to lower the acute insulin demand, induce a low and prolonged blood glucose response (high Glycemic Profile, GP) and reduce subclinical inflammation. These products may therefore contribute to a lowered risk of obesity, type 2 diabetes and cardio vascular disease. The objective of the present paper was to evaluate the mechanism for a reduced postprandial insulin demand with rye products, and to explore possible appetite regulating properties.</p> <p>Methods</p> <p>10 healthy subjects were served breakfast meals (50 g of available starch) with endosperm- or whole grain rye breads, with and without lactic acid, boiled whole grain rye- (RK) or wheat (WK) kernels, or white wheat bread reference (WWB) in random order in a cross-over design. Plasma concentrations of glucose, ghrelin, serum insulin, free fatty acids, adiponectin, breath hydrogen excretion (H₂), and subjective satiety was evaluated during the postprandial phase. 270 min after the breakfast, an ad lib lunch buffet was served and the voluntary energy intake (EI) was registered.</p> <p>Results</p> <p>All rye products and WK induced lower insulinemic indices (II) than WWB. A lower incremental insulin peak following breakfast correlated with a lower EI at lunch (r = 0.38). A low II was related to improved satiety in the early postprandial phase (fullness AUC 0-60 min, r = -0.36). RK induced a higher GP compared to WWB and WK. A higher GP was related to a lowered <it>desire to eat </it>before lunch (AUC 210-270) and to a lower concentration of ghrelin in the late postprandial phase after breakfast (270 min), r = -0.29 and -0.29), which in turn was related to a lower voluntary EI (r = 0.43 and 0.33). The RK breakfast improved satiety in the early postprandial phase (0-60 min) compared to WWB, and induced a lower EI at lunch (-16%). A high content of indigestible carbohydrates in the breakfast products was related to improved satiety (0-60 min, r = 0.68 for fullness), and a higher breath H₂in the late postprandial phase (120-270 and 270-390 min, r = 0.46 and 0.70). High H₂(AUC 120-270 min) also correlated with lower EI (r = -0.34).</p> <p>Conclusions</p> <p>Rye products, rich in indigestible carbohydrates, induce colonic fermentation already post the breakfast meal, and lowers acute insulin responses. A high excretion of breath H2 also correlated with a higher GP. Especially, rye kernels induced a high GP which was associated with a 16% lowering of energy intake at a subsequent lunch meal. The bulking effect of rye fiber, colonically derived fermentation metabolites, a high GP and a low insulin response possibly all contributes to the benefits on glucose- and appetite regulation seen in an acute and semi-acute perspective.</p

The Complex and Important Cellular and Metabolic Functions of Saturated Fatty Acids

This review summarizes recent findings on the metabolism and biological functions of saturated fatty acids (SFA). Some of these findings show that SFA may have important and specific roles in the cells. Elucidated biochemical mechanisms like protein acylation (N-myristoylation, S-palmitoylation) and regulation of gene transcription are presented. In terms of physiology, SFA are involved for instance in lipogenesis, fat deposition, polyunsaturated fatty acids bioavailability and apoptosis. The variety of their functions demonstrates that SFA should no longer be considered as a single group