Journal of Physiology and Pharmacology最新文献

Laryngeal squamous cell carcinoma (LSCC) is known for its high morbidity and mortality. Long non-coding RNAs and miRNA have been found to play important roles in cancer progression. However, the roles of LINC00958 and miR-627-5p in LSCC and their mechanisms remain unclear. Therefore, it is important to explore its role in LSCC. The results of this study show that the expression of LINC00958 was significantly increased (p<0.001), but the expression of miR-627-5p was significantly decreased in LSCC serum specimens and cell lines (p<0.001). Silencing LINC00958 or overexpression of miR-627-5p could inhibit the proliferation (p<0.05) and migration (p<0.01) of LSCC cells. According to the results of dual luciferase reporter assay, it was known that LINC00958 could target miR-627-5p (p<0.01). ROC experiment results showed that LINC00958 was used to distinguish LSCC patients from healthy controls, OSCC patients from healthy controls and LSCC patients from OSCC patients, and the areas under the curve (AUC) were 0.970, 0.809 and 0.811, respectively. Meanwhile, we found that serum miR-627-5p could also be used to distinguish LSCC patients from healthy controls, oral squamous cell carcinoma (OSCC) patients from healthy controls, and LSCC patients from OSCC patients, with the AUC of 0.975, 0.870, and 0.800, respectively. Pearson analysis showed that the expression level of LNIC00958 was negatively correlated with the expression level of miR-627-5p (r= -0.725, p<0.001). Overall, The results of this study show that LINC00958 and miR-627-5p may be used as new diagnostic markers for LSCC. In addition, LINC00958/miR-627-5p axis opens a new way for the diagnosis and treatment of LSCC.

The pathogenesis of celiac disease is associated with an autoimmune process. The disease causes chronic inflammation of the small intestinal mucosa, which may affect the brain-gut axis. The activation of visceral receptors (gastrointestinal mechanoreceptor and osmoreceptor) in response to stomach distension caused by water ingestion has not been studied before. Our results showed reduced responsiveness of the autonomic nervous system to water ingestion in patients with celiac disease, which may lead to disturbances of gastric myoelectrical activity and depends on baseline autonomic activity. Water intake can induce gastric distension and motility response, without changes in gastrointestinal hormones. It can also increase the activity of the autonomic nervous system. On the other hand, inflammation in celiac disease (CeD) can alter visceral perception (increase sensitization), leading to autonomic dysfunction. We aimed to investigate the effect of water ingestion on autonomic activity measured as heart rate variability (HRV) and gastric myoelectrical activity measured by electrogastrography (EGG) in patients with CeD. The study included 53 patients with CeD and 50 healthy controls: mean (SD) age, 43.4 (14.8) years and 44.1 (9.2) years, respectively. Electrocardiography with HRV analysis and simultaneous 4-channel EGG was performed before and after the water load test (WLT) ingestion 500-ml water over 5 minutes. We found that compared with controls, at fasting, patients with CeD showed a reduced percentage of normogastria (P=0.045) and an average percentage of slow wave coupling (P<0.01) with increased dominant power (DP) (P<0.001). Moreover, water ingestion in CeD patients reduced the percentage of gastric arrhythmia (P<0.01) and increased the percentage of normogastria (P<0.01) and DP (P<0.01). Finally, in the CeD group, water ingestion increased HRV indices: low frequency by 116.9% (P<0.001), high frequency by 125.3% (P<0.01), but they did not reach the values of the control group. Patients with CeD showed a smaller increase in parasympathetic autonomic activity after the WLT than controls. Altered autonomic responsiveness may contribute to the disturbances of gastric myoelectrical activity and depends on baseline autonomic activity.

The pressure-volume (PV) analysis is used for an accurate assessment of load-independent cardiac function and is important for the study of cardiovascular diseases and various therapeutic modalities. PV analysis is often performed on one of the ventricles, or on both ventricles but sequentially. Since both ventricles interact with each other and their functions are mutually interdependent, especially in various disease conditions such as pulmonary hypertension or heart failure, it is important to quantify the function of both ventricles at the same time. Therefore, our aim was to describe a standardized protocol for simultaneous right (RV) and left (LV) ventricle of PV analysis, including an especially controllable preload reduction manoeuver. Our second aim was to test whether simultaneous catheterization of both LV and RV is necessary for the determination of biventricular PV relationship compared to sequential measurement of both ventricles separately. In this article, we showed the feasibility and the value of simultaneous biventricular PV analysis in the measurement of contractility parameters (end-systolic pressure-volume relationship (ESPVR), ventricular pressure over time (dP/dt)max, divided by end-diastolic volume (dP/dt max-EDV)) with a comparison to the sequential measurement of the RV and LV ventricles separately. We described in detail the protocol for simultaneous biventricular PV analysis in rats using a pair of conductance-micromanometer catheters with a preload-reducing manoeuver using balloon catheter inflation in the inferior vena cava. We also described technical tips and show examples of PV loop data obtained in normotensive and hypertensive rats, with and without heart failure due to volume overload. This protocol could be useful for scientists studying hemodynamics and cardiac contractility in various models of cardiovascular diseases with a focus on biventricular differences and ventricular interdependence.

The optimal environment in the oviduct is created by adjusting its ultrastructure and secretory activity to serve the most suitable protection of gametes and to support embryo development. Through gametes/embryo's presence inside the oviduct, the oviductal transcriptomic profile may be altered, and these changes may be caused by DNA methylation. The results of the present study documented that in the epithelial cells of the ampulla and isthmus of the oviducts collected from pigs during the peri-conceptional period, the most differentially expressed genes (DEGs) were down-regulated. Identified DEGs were classified into gene ontology categories as well as annotated into different biological pathways. From evaluated DEGs, genes important for embryo development were selected and the level of DNA methylation was determined. It was documented CLDN18, MUC1, CYP19A3, SOCS1, and ESR1 methylation level have been altered. The presence of embryos in the oviduct changed the transcriptomic profile and the level of DNA methylation in the epithelial cells of ampulla and isthmus during the peri-conceptional period.

The aim of this study was to examine the effects of the hypolipemic drug fenofibrate (FF) and aging on the expression of factors/enzymes involved in brown adipose tissue (BAT) function and browning of white adipose tissue epididymal (eWAT) and subcutaneous (sWAT) depots. Young-adult and old male Wistar rats were fed standard chow (control) or supplemented with 0.1% or 0.5% FF for 30 days. Tissue samples were analysed for gene expression and protein content, and stained with Oil Red O or hematoxylin and eosin. In BAT of young rats, 0.5% FF increased only Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 1 (CITED1) protein content and Fgf21 and Gpr109A mRNA expression. The expression of oxidative metabolism related genes (Pgc1α, Cpt1b, Mcad) decreased after 0.5% FF. In BAT of old rats, FF did not affect UCP1 and CITED1 content and had little effect on gene expression. Oil Red O staining of BAT revealed no changes in lipid droplet area upon treatment in either age group. In eWAT of young rats, 0.1FF elevated UCP1 protein content and Ucp1, Pgc-1α, and Mcad expression, whereas 0.5% FF increased PPARα content and Pgc-1α, Cpt1b, Mcad, and Gpr109A levels. In eWAT of old rats, only 0.1FF increased Pgc1α and Mcad expression. In both age groups median cell area of eWAT adipocytes was reduced after 0.5% FF. In sWAT Ucp1 gene expression was very low and UCP1 protein was undetectable. FF upregulated Ucp1, Cited1, Eva1, and Cpt1b expression in sWAT of young rats, with diminished effects in old rats. In both age groups 0.5% FF increased Fgf21 expression in sWAT. Median cell area of sWAT adipocytes decreased only in young rats treated with 0.5% FF. Our results reveal that fenofibrate differentially affects gene expression in BAT, with diminished effects in old compared to young rats. In WAT of young rats FF modestly stimulates the expression of factors/enzymes involved in lipid oxidative metabolism and browning. Aging reduces both these effects. Gpr109A may present a novel gene target upregulated by FF in BAT and eWAT.

Some studies have shown that electromagnetic fields (EMFs) may impact immune response cells and their functions. The first stage of the defense from pathogens is innate immunity encompassing phagocytosis and phagocytosis-related intracellular effects. Our work aimed to determine the influence of a low-frequency electromagnetic field (7 Hz, 30 mT_rms) on the phagocytosis process of latex beads (LBs), the production of reactive oxygen species (ROS), and viability changes in a human monocytic Mono Mac 6 (MM6) cell line as an experimental model of the phagocytosing cells in in vitro cell culture conditions. For these purposes, cells were firstly activated with infectious agents such as lipopolysaccharide (LPS), Staphylococcal enterotoxin B (SEB), or the proliferatory agent phytohaemagglutinin (PHA), and then a phagocytosis test was performed. Cell viability and range of phagocytosis of latex beads by MM6 cells were measured by flow cytometry, and the level of ROS was evaluated with the use of a cytochrome C reduction test. The obtained results revealed that applied EMF exposure mainly increased the necrosis parameter of cell death when they were pre-stimulated with SEB as an infectious factor and subsequently phagocytosed LBs (P=0.001). Prestimulation with other agents like LPS or PHA preceding phagocytosis resulted in no statistically significant changes in cell death parameters. The level of ROS depended on the used stimulatory agent, phagocytosis, and/or EMF exposure. The obtained effects for EMF exposure indicated only a slight decrease in the ROS level for cells phagocytosing latex beads and being treated with SEB or PHA, while the opposite effect was observed for LPS pre-stimulated cells (data not statistically significant). The results concerning the viability of phagocytosing cells, the effectiveness of the phagocytosis process, and the level of radical forms might result from applied EMF parameters like signal waveform, frequency, flux density, and especially single EMF exposure.

Patients with type 2 diabetes respond differently to sitagliptin, an oral anti-hyperglycemic medication. Patients whose blood sugar levels were effectively managed while using sitagliptin had significantly lower levels of a protein called suppressor of cytokine signaling 3 (SOCS3), according to our earlier research. In this study, we established an in vitro insulin resistance cell model for human HepG2 cells to investigate the possible mechanism of the effect of sitagliptin on glucose metabolism via the SOCS3/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. Since insulin resistance first develops in the liver, palmitic acid was used to generate an insulin resistance cell model in human HepG2 cells, after which small interfering ribonucleic acid (siRNA)-SOCS3 and sitagliptin were used to intervene. We then examined the changes in cell viability and biochemical indices in the insulin resistance cell model. SOCS3, Akt, and glycogen synthase kinase 3beta (GSK-3β) gene expression levels were quantified using reverse transcription-polymerase chain reaction, and the protein expression levels of SOCS3, Akt, phosphorylated Akt (p-Akt), GSK-3β, and phosphorylated GSK-3β (p-GSK-3β) were quantified using Western blot. In results: the expression of the SOCS3 gene was considerably raised in both the insulin resistance model group and the insulin resistance model + siRNA-negative control group, but decreased following treatment with sitagliptin. After sitagliptin intervention, the protein expression of Akt, p-Akt, and p-GSK-3β were dramatically decreased in the model group, while SOCS3 was significantly decreased. We conclude that sitagliptin can reduce insulin resistance by downregulating SOCS3 and regulating glucose metabolism in a hypoglycemic manner.

Melatonin (MEL) is produced and secreted by the pineal gland as well as the small intestine, liver, retina, lymphocytes, and melanocytes in the skin in both experimental animals as well as in humans. While pineal and retinas MEL is closely related to the light/dark cycle, the production of MEL by other so called extrapineal tissues is independent of such circadian rhythm. Among the primary mechanisms of action of MEL in humans, the most important are interaction of MEL with specific receptors (M1, M2, M3) and the MEL 'scavenging' activity against the formation of free oxygen metabolites as a result of MEL's ability to transfer free electrons and stimulation of the expression of redox reaction enzymes. In addition, MEL binds to intracellular proteins such as calmodulin, thereby affecting the course of cell cycle, and it has been shown to activate of nuclear receptors belonging to the retinoid orphan receptors/retinoid Z receptors (ROR/RZR) subfamily. MEL exerts regulatory effects on the master clock regulating diurnal rhythms. This updated review presents current view on the synthesis and metabolism of MEL and the growing body of experimental evidence transferable to the practical medicine supporting a pleiotropic molecule beneficial effects on the health including protection against various organ abnormalities, including internal organs such as the liver. Although the beneficial effects of MEL in various types of liver damage have been well documented in experimental studies, there are relatively few studies on liver dysfunction in humans. Considering the worldwide obesity pandemic often associated with the occurrence of steatohepatitis and cirrhosis, the beneficial effects of MEL in liver pathology should be proven in randomized trials involving patients presenting with hepatic disorders.

Insulin resistance (IR) is predominantly causal for type 2 diabetes mellitus (T2DM). To solve this problem, this study particularly determined the role of quercetin (Que) in controlling IR in T2DM mice. The T2DM mouse model was established, and given 20 mg/kg/d Que by gavage for 6 weeks, and the lentiviral vector that interfered with microRNA-92b-3p (miR-92b-3p) or early growth response 1 (EGR1) expression was injected into the tail vein of T2DM mice. Blood glucose homeostasis and histopathological changes in the pancreas were observed after the corresponding treatment. miR-92b-3p and EGR1 expressions were assessed in T2DM mice, as well as their interlink. In results we found that Que could improve IR and pancreatic histopathological changes in T2DM mice. Low miR-92b-3p and high EGR1 were expressed in T2DM mice, while Que could upregulate miR-92b-3p to target EGR1. Enhancing miR-92b-3p or reducing EGR1 could further improve IR and pancreatic histopathological changes in T2DM mice after Que administration. Nevertheless, silencing miR-92b-3p or overexpressing EGR1 contributed to the opposite results. We concluded that Que exerted anti-diabetic effects in T2DM mice by regulating the miR-92b-3p/EGR1 axis.

Building a precise alternative neurotoxicological test is of great importance to respond to societal and ethical requirements. In this study, a new developmental neurotoxicity test (DNT) was established with the human neural progenitor cell line. ReNcell CX cells were exposed to neurotoxic chemicals (aphidicolin, hydroxyurea, cytosine arabinoside, 5-fluorouracil, and ochratoxin A) or non-neurotoxic chemicals (sodium gluconate, sodium bicarbonate, penicillin G, and saccharin). Propidium iodide (PI) was used to evaluate cell viability. BrdU and Ki-76 were employed to determine cell proliferation. Based on the cell viability and proliferation, mathematical models were built by linear discriminant analysis. Furthermore, the neurotoxic-considered chemicals inhibited cell cycle progression at the protein level, supporting the biomolecular rationale for the predictive model. Overall, these results show that the new test method can be used to determine the potential developmental neurotoxicants or new drug candidates.