The role of microRNAs in carcinogenesis and the utility of microRNA determination in diagnosis of gastric cancer development.

Gastric cancer (GC) is one of the most prevalent malignancies worldwide and the six most common cause of cancer-related deaths. GC is a multifactorial disease in which both environmental and genetic factors can influence its occurrence and development. The aim of this paper is to investigate the effect of ncRNAs on the development of gastric cancer. We have reviewed medical databases on the possible relationship between different micro RNA fragments and the development of gastric cancer. In result, our review of medical databases indicated that over the past decade, an increasing number of ncRNAs, including miRNAs and lncRNAs, have been documented to affect gastric cancer. These ncRNAs are abnormally expressed in gastric cancer tissues, play key roles in gastric carcinogenesis and their assessment have potential benefits in the diagnosis, prognosis or treatment of gastric cancer. Although the role of abnormal expression of many ncRNAs in stimulating gastric cancer has been described, the underlying molecular mechanisms regarding the function of these ncRNAs in gastric carcinogenesis are not well understood. In the article, some of the miRNAs associated with gastric cancer are discussed.

Expression of let-7a, miR-106b and miR-29b is changed in human gastric cancer.

MicroRNA (miRNA) are small, noncoding RNA sequences that post-transcriptionally regulate the proliferation, activity and apoptosis of human gastric cancer cells by controlling various signaling cascades. Processes that involve miRNA molecules can create a specific network of interactions in a cell, and disruption of its functioning may contribute to the transformation of normal cells into cancerous cells. Aims of our survey were: 1) study the relationship between the expression of selected miRNA types (let-7a, miR-106b, miR-29b, miR-21, miR-155, miR-222) in the gastric mucosa and pathomorphological changes determined by classical histopathological methods, 2) perform in silico analysis to select target genes for selected miRNAs and to perform functional analysis of these genes. Eighty-three subjects (45 women, 38 men; mean age 39±14 years, range: 21-80 years, were examined). Among them were 18 (21.5%) patients with chronic active gastritis, 42 (50.6%) people with chronic inactive gastritis, 9 (10.8%) patients with gastric cancer and 14 (16.9%) patients without histopathological changes. The study demonstrated that mainly the expression of 3 (miR-29b, let-7a miR-106b) out of 6 selected miRNAs are significantly different depending on the site of biopsy (body of the stomach or antrum) and the group of patients. Expression of miR-106b in the antrum and body was the highest in the group of cancer patients and the lowest in patients with chronic active gastritis. The expression of let-7a differed depending on group of patients and location. The highest expression was in the body in the group with inactive gastritis and the lowest in gastric cancer. Patients with cancer had the lowest expression of miR-29b in stomach body and it was the highest in the patients with inactive gastritis in this location. Expression of miR-21 and miR-155 determinations were not statistically significant in comparison to groups or locations, and of miR-222 was not different between the groups, but only in the control group was higher in the antrum than in the body. We conclude that identification of miRNAs may represent a promising modern complementary method in the diagnosis of gastric diseases, especially cancer.

Progranulin and chemerin plasma level in obese patients with type 2 diabetes treated with a long-acting insulin analogue and premixed insulin analogue.

Diabetes, referred to as the first non-infectious epidemic, covers a heterogenous group of metabolic diseases marked by hyperglycemia resulting from a defect of insulin secretion and/or insulin resistance. Highly endocrine active adipocytes, particularly those located in white adipose tissue, constitute a source of cytokines, growth factors and complement component as well as adipocytokines including chemerin and progranulin could be the key molecules in the pathomechanism of hypertension, dyslipidemia, metabolic disorders or diabetes type 2. In this study, it was decided to verify the existence of possible relationships between the plasma concentration of progranulin and chemerin and the values of intermediate indices of insulin sensitivity and insulin resistance in patients, both before and after the 6-month insulin therapy by long-acting insulin analogue and premixed insulin analogue. The level of laboratory parameters in blood plasma collected from the control group and from obese individuals with type 2 diabetes mellitus was estimated with the test kits using enzyme-linked immunosorbent assay (ELISA): the test of Mediagnost E103 GmbH GmbH, Reutlingen, Germany for progranulin; the test of BioVendor R&D, Brno, Czech Republic for chemerin. The aim of this study was to assess the progranulin and chemerin plasma level in obese individuals with type 2 diabetes, before and after 6 months of pharmacological treatment with a long-acting analogue human insulin or premixed insulin. In the blood plasma of untreated diabetics - in contrary to progranulin plasma concentration in diabetic patients after management implementation - progranulin was found to occur in a significantly higher concentration in relation to the level of this protein in the blood plasma of control group individuals. Despite the fact that 6-month therapy, both with the insulin mixture and with the long-acting analogue in people with diabetes, does not significantly affect the plasma chemerin concentration, the high, negative correlation between the progranulin and chemerin levels in the blood of individuals of the control group, and a positive one between the levels of progranulin and chemerin in people with diabetes before and after treatment was found. The conducted studies indicated the modified, in the course of diabetes type 2, mutual quantitative relations between progranulin and chemerin - the biological mediators of systemic metabolism, reflecting their active participation in the pathogenetic changes underlying type 2 diabetes. The obtained study results indicate a modification of mutual relationships of the adipocytokines assessed in the paper - progranulin and chemerin, associated with the development of the systemic inflammatory response occurring in the course of obesity which, by inducing insulin resistance, may consequently lead to type 2 diabetes. Taking into consideration the fact that the plasma progranulin and chemerin concentrations in obese patients with type 2 diabetes subjected to pharmacotherapy have not been assessed so far, it is possible that the obtained study results may cast light on the potential influence of the applied treatment on the systemic changes of the both adipocytokines involved in the pathomechanism of the mentioned disorder and thus create the possibility of implementing new therapeutic strategies in the management of patients with diabetes, which is an increasingly common, fast-spreading metabolic disease considered as a non-infectious epidemic of the 21st century.

Chemerin, vaspin and insulin resistance in chronic hepatitis C.

Adipocytokine profile seems to play a distinct role in the pathogenesis of chronic hepatitis C (CHC). Chemerin and vaspin are recently described adipocytokines with various suggested functions and potential to modulate inflammatory response and insulin resistance (IR). We assessed chemerin, vaspin and leptin serum concentration and studied their association with IR laboratory and morphological features in patients with hepatitis C. The study included 40 patients with hepatitis C and 20 healthy volunteers, similar in age and body mass index (43.6 +/- 11.6 vs 40.9 +/- 11.8 years and 25.0 +/- 4.1 vs 23.9 +/- 3.3 kg/m(2), respectively). Patients had to have a normal lipid profile, and diabetes was an exclusion criteria. Serum chemerin and leptin levels and IR were significantly higher in patients with hepatitis C when compared to the controls (P = 0.02, P = 0.02 and P = 0.02, respectively), whereas vaspin level was significantly decreased (P = 0.01). Serum chemerin was negatively associated with necro-inflammatory grade (r = (-0.49), P = 0.01). The lowest levels of serum chemerin were found in patients with moderate/severe inflammation (P = 0.03). Serum leptin tended to be up-regulated in patients with minimal inflammatory activity. Serum vaspin was higher, although not significantly, when fibrosis was more advanced. IR was positively associated with fibrosis stage (r = 0.33, P = 0.03). Serum chemerin and leptin were related to each other (r = 0.45, P = 0.02).Our findings support a complex interaction between the analysed adipokines and pathogenesis of inflammatory process in CHC. The role of chemerin and vaspin in pathogenesis of inflammatory response should be further investigated.

Visfatin serum levels in chronic hepatitis C patients.

Visfatin is a new adipokine involved in several processes. The data concerning visfatin in chronic hepatitis C (CHC) is small. To assess visfatin serum concentration and to study its association with biochemical and morphological features in CHC. Seventy nonobese patients with CHC (Group 1) confirmed by the presence of serum hepatitis C virus (HCV)-RNA and 20 healthy volunteers (Group 2), similar in age and BMI with normal fasting glucose and lipid profile were included. Visfatin was significantly increased in Group 1 compared with Group 2 (55.6 +/- 23.1 vs 23.7 +/- 3.8 ng/mL; P < 0.001). Visfatin was negatively associated with necro-inflammatory activity grade (r = -0.36; P = 0.007). The lowest levels were found in patients with the most advanced inflammation: grades 3-4 - 46.8 +/- 17.1, grade 2 - 52.6 +/- 18.4 and grade 1 - 75.2 +/- 27.6 ng/mL; P = 0.017. A significant difference was also shown comparing patients with minimal inflammatory activity to the rest of the cohort (P = 0.009). Visfatin receiver operating characteristic curve analysis for different necro-inflammatory activity - grade 1 vs grades 3-4 with area under the curve 0.81 indicated a good discriminant power for differentiation of moderate/severe inflammation, with the cut-off set at 57.6 ng/mL (sensitivity 75%, specificity 90%, positive predictive value 0.90, negative predictive value 0.75). Serum visfatin concentration increases significantly in CHC patients. These findings suggest that visfatin is important in the pathogenesis of the inflammatory process in CHC. Visfatin may play a dual role as a pro-inflammatory or/and protective factor. The measurement of visfatin serum concentration may serve as an additional tool in distinguishing more advanced grades of the necro-inflammatory activity.

The expression profile of genes encoding tumor necrosis factor-alpha, interleukin-6 and their receptor in benign adrenal tumors.

In the process of neoplasia, during which benign adrenal tumors are formed, stimulators of new blood vessel growth as well as growth of tumor cells are cytokines, especially tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6). We analyzed the expression profile of genes coding: TNF-α, tumor necrosis factor receptor 1 (TNF-R1), TNF-R2, IL-6, interleukin 6 receptor (IL-6R) in sections of adrenocortical tumor tissue, rated on the Weiss point scale, in patients with clinically diagnosed Conn's and Cushing's syndrome, and the usefulness of determining the examined genes as markers differentiating individual clinical units. There was no correlation between the expression of the examined genes and clinical parameters such as age, BMI or blood pressure, both in the entire study group and in individual subgroups. Elevated expression of the genes coding TNF-α, TNF-R2 and IL-6R was observed, whereas genes encoding TNF-R1 and IL-6 showed relatively low expression. The highest statistically significant differences in the expression of the examined genes were observed between IL-6 and IL-6R. High positive correlation was found in the subgroup of patients with Conn's clinical syndrome, between genes encoding both types of receptors for TNF-α, IL-6 and TNF-R2, TNF-α and IL-6 receptor, and between TNF-R2 and IL6-R receptors, which may suggest the mutual influence of these cytokines and their receptors on their own expression.

Omentin, vaspin and irisin in chronic liver diseases.

Omentin and vaspin are adipokines potentially considered in the development of liver pathology. Irisin is new myokin potentially participating in energy processes in the organisms. The aim of this study was to evaluate the plasma concentration of these cytokines and the relationships of them with selected parameters of laboratory tests and of histopathological changes in selected chronic liver diseases: non-alcoholic fatty liver diseases (NAFLD), primary biliary cholangitis (PBC) and alcoholic cirrhosis (AC). The plasma concentration of omentin was the highest in AC group and the lowest in control group (CG). Irisin plasma concentration was the highest in CG and the lowest in AC. Mean vaspin concentrations did not differ significantly between groups. Among many laboratory parameters, only in the AC group positive relationships were found between omentin concentration and bilirubin, as well as glucose, and negative between omentin level and the number of platelets and erythrocytes; there was a positive relationship between the concentration of vaspin and bilirubin, as well as negative between vaspin level and the number of erythrocytes or hematocrit value in this group. INR value had positive correlation with vaspin concentration and negative with irisin level in NAFLD group. No significant dependences between the concentrations of explored cytokines and laboratory tests were found in PBC group. It was found the positive correlation between the plasma concentration of irisin and fibrosis as well as inflammation in PBC group. The negative correlation between irisin level and inflammation in NAFLD was also showed. Omentin can be considered as an indicator for predicting inflammation, steatosis and balloon degeneration in NAFLD and PBC. Summarizing, it is unclear but possible that explored cytokines have some relationships with certain features of liver damage and development of chronic diseases of this organ.

Pharmacological and dietary factors in prevention of colorectal cancer.

Colorectal cancer (CRC) is the third most prevalent neoplasm worldwide and fourth most frequent reason of cancer-related death throughout the world. About 70% of malignant tumors are related to lifestyle and environmental factors, and better knowledge of their significance might reduce the prevalence of CRC. The cyclooxygenase-2 (COX-2) inhibitory and other direct and indirect pathways of aspirin are translated to inhibition proliferation and enhanced apoptosis of cancer cells. Many studies showed the benefits of aspirin in reducing the risk of CRC development, cancer-related mortality and adenoma prevalence rate in general population, but not in high risk populations. The role of sulindac in CRC prevention is uncertain and the use of this drug is rather uncommon. Celecoxib - COX-2 selective inhibitor- showed efficacy in decreasing of colon adenoma recurrence only in some studies. The protective role of microelements is controversial. The beneficial effects of supplementation of selenium, calcium, folic acid, methionine, antioxidant supplements and probiotics are still not certain. A high energy diet consisting of red meat, animal fat, highly processed foods and unsaturated fats increases the risk of CRC. Carcinogenic role of fat and cholesterol depends on increased production of primary bile acids. The importance of milk and dairy products in CRC prevention is controversial. Fruits, vegetables and grain are considered to have protective effects against adenoma and CRC. Excessive alcohol consumption, smoking, physical inactivity are considered as important CRC risk factors. This article briefly summarizes current state of knowledge about the role of pharmacological and dietary prevention of colorectal cancer. Moreover, it indicates that despite many studies some aspects of this issue are not clear and require future studies.

Serum neutrophil gelatinase-associated lipocalin (NGAL) correlates with clinical and endoscopic activity in ulcerative colitis but fails to predict activity in Crohn's disease.

Serum neutrophil gelatinase-associated lipocalin (NGAL) is a low molecular weight protein released from activated neutrophils and intestine epithelium whose mRNA expression is increased in inflamed intestinal tissue. The purpose of this study was to explore the relationship between serum NGAL level and activity of inflammatory bowel diseases. A total of 120 patients, 79 with Crohn's disease (CD) and 41 with ulcerative colitis (UC) were prospectively included into the study. Serum NGAL was measured by ELISA. The inflammatory activity of UC was assessed by Mayo score and of CD by CDAI and SES-CD scoring systems. Increasing endoscopic severity of UC from remission/mild to moderate/severe was associated with increasing NGAL levels from 46.9 to 66.4 ng/ml (P = 0.002). NGAL concentrations were significantly lower in patients with complete endoscopic and histologic remission than in the active UC (46.9 versus 66.4 ng/ml, P = 0.009). Also deterioration of the clinical activity of UC patients was associated with increasing level of NGAL from 44.9 in remission/mild to 68.0 ng/ml in moderate/severe grade (P = 0.002). NGAL levels correlated with CRP (r = 0.49), ESR (r = 0.48) and iron concentrations (r = -0.63), but not with faecal calprotectin. NGAL showed ability to distinguish endoscopically active from inactive UC with AUC-ROC of 0.758 (sensitivity 96% and specificity 54%). However NGAL levels showed no significant relationship with either clinical or endoscopic activity of CD. We conclude that serum NGAL level corresponds to clinical and endoscopic activity of UC and accurately predicts disease endoscopic remission.

Fibroblast growth factor-21 and omentin-1 hepatic mRNA expression and serum levels in morbidly obese women with non-alcoholic fatty liver disease.

Fibroblast growth factor-21 (FGF21) and omentin-1 have been recognized as potent antidiabetic agents with potential hepatoprotective activity. The aim of this study was to evaluate hepatic FGF21 and omentin-1 mRNA expression as well as their serum levels as predictive markers of liver injury and insulin resistance in morbidly obese women with non-alcoholic fatty liver disease (NAFLD). This study included 56 severely obese women who underwent intraoperative wedge liver biopsy during the bariatric surgery. Hepatic FGF21 and omentin-1 mRNA were assessed by quantitative real-time PCR, while their serum concentrations were measured with commercially available enzyme-linked immunosorbent assays. The FGF21 serum level was significantly higher in patients with a greater extent of steatosis (grade 2 and 3) compared to those without or with mild steatosis (grade 0 and 1) (P = 0.049). Receiver Operating Characteristic analysis, however, showed poor discriminant power for the FGF21 serum levels in differentiating between more and less extensive steatosis with an AUC = 0.666. There was a tendency towards higher levels of hepatic FGF21 mRNA in patients with lobular inflammation and fibrosis and towards lower levels in the case of hepatocyte ballooning and steatosis. There was a positive mutual correlation between hepatic FGF21 and omentin-1 mRNA levels (r = 0.78; P < 0.001). Fibrosis stage was associated with serum glucose and homeostatic model assessment for insulin resistance (HOMA-IR) (P = 0.03 and P = 0.02, respectively). Serum omentin-1 was not associated with histopathological features. The hepatic omentin-1 mRNA levels showed a tendency to be lower in patients with advanced steatosis and hepatocyte ballooning. In conclusion, our study, which focused on hepatic FGF21 and omentin-1 mRNA expression, confirmed marked expression of both molecules in the liver of morbidly obese patients with NAFLD. More extensive steatosis was associated with evident changes in the serum FGF21 concentration in morbidly obese women with NAFLD, but the difference did not reach statistical significance. The vast amount of fat, both visceral and subcutaneous, in severely obese patients may be the additional source and influence the FGF21 and omentin-1 serum levels.

Usefulness of thoracic electrical bioimpedance in detection of ejection fraction changes.

The aim of this study was to evaluate a usefulness of thoracic electrical bioimpedance (TEB) in following adaptive haemodynamic adjustments to postural change and isometric exercise. Sixteen subjects with intact cardiovascular system took part in this study. Haemodynamic parameters were obtained in recumbency and after taking up erect posture. Besides, TEB was performed during handgrip test and the results were compared with baseline resting data. Each time the radionuclide ventriculography (RV) was performed concurrently with TEB to obtain an independent measurement of ejection fraction (EF). Active orthostasis was associated with a change in stroke volume, cardiac output and total vascular resistance by -29.7%, -3.4%, +3.9%, respectively. The handgrip produced a significant increase in cardiac output by 16.3%, however it was not associated with an enhancement of stroke volume. Although there was a moderate correlation between EF calculated by TEB and RV in supine position (r=0.66; p < 0.001), TEB failed to reflect changes of EF in orthostasis and isometric exercise. In conclusion, our results suggest that TEB offers in subjects with normal cardiovascular function a valuable alternative to cardiovascular monitoring of stroke volume and cardiac output, but calculation of EF is associated with a risk of serious error.

Pharmacokinetics of theophylline in obesity.

Pharmacokinetic analysis of theophylline was performed in 16 obese women before and after 3-week weight-reducing treatment. Decrease of clearance, increase of t1/2, AUC, and MRT were observed. There were no differences between the volume of distribution before and after weight-reducing treatment. Our results suggest that ideal body weight should be used to calculate a loading dose of theophylline for obese patients; weight-reducing treatment may be connected with changes in biotransformation and elimination of theophylline more than with its distribution.

Leucine enkephalin level in rat hypothalamus, striatum, hippocampus and adrenal glands in experimental rat uremia.

The aim of the study was to analyze the effect of experimental uremia elicited in Wistar rats by 5/6 kidney resection on the leu-enkephalin level in hypothalamus, striatum, hippocampus and adrenal glands. We found, that in uremic rats leu-enkephalin levels decreased in striatum and in adrenal glands. The level of leu-enkephalin in adrenal glands was directly related to plasma creatinine. The weight of uremic rats was significantly lower than that of control rats.

Cardiovascular changes after treatment with dexfenfluramine and yohimbine in obese women measured by thoracic electrical bioimpedance.

An anorectic drug, dexfenfluramine (dF) is commonly used in obesity treatment. The aim of our study was to investigate if dexfenfluramine used alone or together with alpha 2-adrenolitic yohimbine (Y), can change cardiovascular state in obese women.

[The values of selected lipid parameters and atrial pressure in persons with hyperinsulinemia and normal glucose tolerance]. / Wartosci wybranych parametrów gospodarki lipidowej i cisnienia tetniczego u osób z hiperinsulinemia i prawidlowa tolerancja weglowodanów.

In 60 healthy non-obese persons we determined fasting plasma insulin concentrations. Afterwards we performed test with oral load with 75 g glucose. We determined plasma concentration of insulin one hour and two hours after this load; we found that 14 of 60 subjects had hyperinsulinemia with normal glucose tolerance. In the group of persons with hyperinsulinaemia we have shown the increase of fasting plasma triglyceride levels and elevated diastolic blood pressure. We suggested that healthy persons with hyperinsulinemia and normal glucose tolerance have an increase risk for cardiovascular diseases.

Plasma catecholamines, neuropeptide Y and leucine-enkephalin in uremic patients before and after dialysis during rest and handgrip.

UNLABELLED: We have studied the effects of handgrip on plasma levels of catecholamines, neuropeptide Y (NPY), and leu-enkephalin before and after hemodialysis of uremic patients. A cuprophan dialyzer was used. We found, that dopamine level was higher in uremia group before hemodialysis both during rest (0.38 +/- 0.39 pmol/ml) and handgrip (1.13 +/- 1.00 pmol/ml) compared to control (0.17 +/- 0.19, and 0.66 +/- 0.83 pmol/ml respectively). Hemodialysis leads to further increase of its level (0.49 +/- 0.35 pmol/ml) at rest. Epinephrine level was almost the same in uremic patients before (0.43 +/- 0.51 pmol/ml) and after dialysis (0.46 +/- 0.60) as in control subjects (0.41 +/- 0.37 pmol/ml) during the rest. Its level measured after the handgrip was the highest in uremic group after dialysis (2.10 +/- 2.00 pmol/ml), significantly lower before dialysis (1.26 +/- 0.85 pmol/ml), and the lowest in control group (0.78 +/- 0.43 pmol/ml). Norepinephrine level were very similar in uremic group before dialysis (1.54 +/- 1.05 pmol/ml), after dialysis (1.79 +/- 1.29 pmol/ml) and in control group (1.46 +/- 1.06 pmol/ml) during the rest. During the handgrip test its level was higher in uremic group after hemodialysis than before it (adequate values 8.78 +/- 4.61 and 6.70 +/- 4.74 pmol/ml). The difference between uremia group before dialysis and control group did not reach significance. The level of NPY has the tendency to increase in uremic patients. Dialysis leads to following increase of its level, but the changes did not reach the significance both in rest and handgrip. Leu-enkephalin level was higher in uremic group (9.21 +/- 7.62 pmol/ml) compared to control (5.22 +/- 1.53 pmol/ml). We observed non-significant fall of this level after dialysis (6.79 +/- 4.76 pmol/ml). We found the same tendency during the handgrip, and the changes were significant. IN CONCLUSION: uremia per se leads to increase the level of dopamine and leu-enkephaline during the rest and handgrip, but the level of epinephrine only during the handgrip; dialysis leads to further increase of dopamine during the rest, but epinephrine, norepinephrine and leu-enkephaline only during the handgrip.