Evaluation of changes of apelin and apelin receptor (APJ) expression in cervix-uterus and placental axis in an LPS-induced preterm labor model.

Although preterm birth is among the preventable causes of maternal and infant death, its mechanism has not yet been clarified. When evaluated in terms of the results, the psycho-social burden of mother-infant losses and the costs of rehabilitation, care, and treatment for postpartum sequelae are high. When evaluated in terms of its causes, infection/inflammation has an important place. Therefore, it is essential to understand the role of pro- and anti-inflammatory proteins in the process. In our study, apelin and apelin receptor (APJ) expression in the cervix-uterus and placental axis were evaluated at tissue and protein levels in pregnant and non-pregnant control, sham, PBS, and LPS groups in the infection model in which LPS induction was performed by midline laparotomy, in CD-1 mice. The evaluation of this axis regarding apelin and apelin receptor in the preterm birth model is new in the literature. Apelin is expressed more intensely in uterine epithelial cells than in the cervix. In the placenta, expression is more intense in the junctional zone compared to other zones. Apelin protein levels decrease significantly in the cervix and placenta whereas it increases in the uterus. While no change was observed in the expression of the apelin receptor at the tissue and protein level in the cervix and uterus, it increased in both aspects in the placenta in the invasive procedure groups. We propose that the decrease in apelin protein due to LPS in the preterm delivery model may be related to the effort to compensate for the balance deteriorated in the pro-inflammatory direction with post-transitional modification at the tissue level. The tendency of apelin to increase with pregnancy has led to the conclusion that it is necessary for a healthy pregnancy. Although the apelin receptor does not change with inflammation, it is necessary to investigate the mechanisms associated with its stress and trauma-induced increase, since it increases in the invasive procedure group.

Expressions of Notch signalling pathway members during early pregnancy in mice.

Although pregnancy is initiated and maintained through highly complex mechanisms, it is essential to understand the events that occur before and during early pregnancy to understand a healthy implantation process. The Notch signal, thought to be involved in this process, is frequently the subject of research with its different aspects. To better understand the role of Notch signaling in the peri-implantation period of the mouse uterus, we investigated the state of expression and localization of Notch 3, Notch 4, Rbp-J, Hes1, Hes7, Hey2, HeyL, and Fbw7 in the uterus and implantation sites in early pregnancy. Balb/C mice were divided into groups D1, D4, D5, D6, and D8. For D5 and D6 groups, implantation sites were identified by intravenous injection of Chicago blue. IHC, WB, and QRT-PCR methods were used. Notch 3 was very strong positive on the 4th day of pregnancy. Notch 4 was highly expressed on days 4, 5, 6, and 8 of pregnancy when P4 levels were high. Hes 1 level was at the lowest on the 4th day of pregnancy. Hes 7 protein expression gradually increased from D1 to D8 in the uteri and implantation sites. Hey 2 expression was at the highest level on the 1st and 4th days. Hey L expression was on the apical of the glands. Fbxw7 that expression was high on the 1st and 4th days of pregnancy. Notch signaling may play an essential role in regulating endometrial receptivity. In addition, our Hes7 results are new to the literature.

Altered expression of Notch signaling, Tlr receptors, and surfactant protein expression after prostaglandin inhibition may be associated with the delayed labor in LPS-induced mice.

PURPOSE: This study aims to investigate whether indomethacin (IND) delays preterm birth by regulating the Notch pathway, Tlr receptors, and Sp-A in the placenta in lipopolysaccharide (LPS)-induced preterm labor (PTL) model. METHODS: CD-1 mice were distributed to the pregnant control (PC), Sham, PBS, IND (2 mg/kg; i.p.), LPS (25 µg/100 µl; intrauterine), and LPS + IND groups. The injections were performed on day 14.5 of pregnancy. Placentae were collected on day 15.5 of pregnancy, and immunohistochemical analyzes were performed. Differences in staining intensities between the Cox-1, Notch-1 (N1), Dll-1, Jagged-2 (Jag-2), Tlr-2, and Tlr-4 proteins were compared. RESULTS: Preterm labor rates were 100% and 66% (preterm delivery delayed 5 h) in the LPS and LPS + IND groups, respectively. In LPS-treated mice, a general morphological deterioration was observed in the placenta. Total placental mid-sagittal measurement was significantly reduced in the LPS-treated group, while it was similar to the PC group in the LPS + IND group. Cox-1 expression in the LZ increased, and Sp-A expression decreased after LPS injection, and IND administration diminished this increase. N1 expression increased in the labyrinth zone (LZ) and the junctional zone (JZ). Dll-1 and Jag-2 expression increased in the JZ after LPS injection (p < 0.0001). IND administration diminished Tlr-2 expression in the LZ and Tlr-4 expression in the JZ after LPS injection. CONCLUSION: In conclusion, PG (prostaglandin) inhibition may alter Notch signaling, Tlr, and Sp-A protein expression and may be associated with delayed labor in LPS-induced mice.

Relationship of Notch Signal, Surfactant Protein A, and Indomethacin in Cervix During Preterm Birth: Mast Cell and Jagged-2 May Be Key in Understanding Infection-mediated Preterm Birth.

Although it is thought that there is a close relationship between Notch signal and preterm birth, the functioning of this mechanism in the cervix is unknown. The efficacy of surfactants and prostaglandin inhibitors in preterm labor is also still unclear. In this study, 48 female CD-1 mice were distributed to pregnant control (PC), Sham, PBS, indomethacin (2 mg/kg; intraperitoneally), lipopolysaccharides (LPS) (25 µg/100 µl; intrauterine), LPS + IND, and Surfactant Protein A Block (SP-A Block: SP-A B; the anti-SP-A antibody was applied 20 µg/100µl; intrauterine) groups. Tissues were examined by immunohistochemistry, immunofluorescence, and Western blot analysis. LPS administration increased the expression of N1 Dll-1 and Jagged-2 (Jag-2). Although Toll-like receptor (Tlr)-2 significantly increased in the LPS-treated and SP-A-blocked groups, Tlr-4 significantly increased only in the LPS-exposed groups. It was observed that Jag-2 is specifically expressed by mast cells. Overall, this experimental model shows that some protein responses increase throughout the uterus, starting at a specific point on the cervix epithelium. Surfactant Protein A, which we observed to be significantly reduced by LPS, may be associated with the regulation of the epithelial response, especially during preterm delivery due to infection. On the contrary, prostaglandin inhibitors can be considered an option to delay infection-related preterm labor with their dose-dependent effects. Finally, the link between mast cells and Jag-2 could potentially be a control switch for preterm birth.

Effects of Apixaban, Rivaroxaban, Dabigatran and Enoxaparin on Histopathology and Laboratory Parameters in Achilles Tendon Injury: An in vivo Study.

OBJECTIVES: To compare the effects of apixaban, rivaroxaban, dabigatran and enoxaparin on histopathology and blood parameters in rats with Achilles tendon injury. MATERIALS AND METHODS: Thirty adult, male Wistar albino rats weighting 220-240 g were randomly divided into five (one control and four treatment) groups and placed in a controlled environment. The Achilles tendon was incised and re-sutured in each rat, after which each group was provided the following treatment for 28 days: a) 2 ml saline to the control group, b) apixaban in 1 ml of saline (10 mg/kg/day) +1 ml of saline, c) rivaroxaban in 1 ml of saline (2 mg/kg/day) +1 ml saline, d) dabigatran in 1 ml of saline (30 mg/kg/day) +1 ml of saline, e) enoxaparin (80 µg/kg/day) + 2 ml of saline. RESULTS: Hemogram, biochemical and coagulation parameters differed significantly between the control and treatment groups (P < 0.05). Compared with the control group, in the apixaban group, type I and type III collagen immunoreactivity were severe and moderate, respectively. In the rivaroxaban and dabigatran groups, both type I and type III collagen immunoreactivity were medium and severe, respectively. In the enoxaparin group, type I and type III collagen immunoreactivity were mild and severe, respectively. CONCLUSION: The higher concentration of type I collagen in the apixaban and dabigatran indicates faster tendon healing in these groups, and the higher concentration of the type III collagen in the enoxaparin group indicates slower healing in this group.

Antiandrogen abiraterone and docetaxel treatments affect Notch1, Jagged1 and Hes1 expressions in metastatic prostate cancer cells.

BACKGROUND: Prostate cancer is the most common cancer in men. A Notch signaling pathway is an important pathway in cell proliferation, differentiation, and fate. However, currently, the effects of abiraterone based-anti-androgene therapy and docetaxel, the most commonly used standard chemotherapy in prostate cancer treatment, on Notch signaling pathway are unknown. This study aimed to investigate the effects of abiraterone acetate and docetaxel on the expression of Notch1, Jagged1 and Hes1 in prostate cancer cell lines. METHODS: In vitro effects of abiraterone acetate and docetaxel were examined on Notch1, Jagged1, and Hes1 expression in LNCaP and PC3 PCa cell lines by immunofluorescence, Western blot, and qRT-PCR. MTT proliferation assay was used to evaluate cell proliferation and survival. RESULTS: We found that in the treatment of PC3 cells with abiraterone acetate, docetaxel, and their combination, only mRNA expressions of Notch1, Jagged1 and Hes1 were affected compared to control, but these expression differences were not observed in protein expression. In LNCaP cells, abiraterone acetate and the combination groups reduced Notch1 protein expression. All treatment groups did not alter Jagged1 expression compared to control, but significantly increased the Hes1 gene and protein expression. CONCLUSION: Our findings suggest that abiraterone and docetaxel treatments affects the expression of Notch signal pathway proteins. But these drugs especially cause significant upregulation in Hes1 expression in PCa cells. Therefore, co-application of Notch signaling inhibitors together with docetaxel and abiraterone chemotherapy, it was thought that decreased Hes1 expression could be stopped the deterioration of the prognosis of the patient.

The relationship between magnesium levels and mortality in the respiratory intensive care unit.

ABSTRACT: Magnesium deficiency is defined as a pathophysiologic factor in numerous illnesses. This study aims to define the effects of magnesium levels on patients in the intensive care unit (ICU) regarding length of stay in the ICU, length of mechanical ventilation (MV), and 28-day mortality.The following data were collected during initial assessment of patients admitted to the ICU with acute respiratory failure (ARF). Demographic data, magnesium and potassium levels, Charlson's Comorbidity Index (CCI), Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores, length of MV, length of hospital stay in the ICU, 28-day mortality, and ICU discharge status.In the initial serum analysis prior to treatment of patients in the ICU, the mortality rate of the patient group with hypermagnesemia was found to be statistically significant when compared with other magnesium levels (P = .018). Apart from renal failure, ICU mortality is higher in the hypermagnesemia group than other groups.Hypermagnesemia is an electrolyte abnormality that is generally seen in older individuals and those with serious comorbidity and it can be used in mortality prediction.

The alveolar-arterial gradient, pneumonia severity scores and inflammatory markers to predict 30-day mortality in pneumonia.

OBJECTIVE: The objective of this study was to evaluate the association of elevated alveolar-arterial oxygen (A-a O2) gradient with risk of mortality in hospitalized patients with community-acquired pneumonia (CAP). METHODS: This prospective study included 206 patients diagnosed with CAP admitted to the ED. Demographics, comorbidities, arterial blood gas, serum electrolytes, liver-renal functions, complete blood count, NLR, PLR, CRP, CAR, procalcitonin, A-a O2 gradient, expected A-a O2 and A-a O2 difference were evaluated. PSI and CURB-65 scores were classified as follow: a) PSI low risk (I-III) and moderate-high risk (IV-V) groups; b) CURB-65; low risk (0-2) and high risk (3-5) groups. RESULTS: The survival rates of the PSI class (I-III) were significantly higher than the ones of the PSI class (IV-V) (92.1% vs. 62.9%, respectively). The percentage of survivors of the CURB-65 score (0-2) group (81.9%) was higher than the survivors of CURB-65 score (3-5) group (27.8%). Creatinine, BUN, uric acid, phosphorus, RDW, CRP, CAR, procalcitonin, lactate, A-a 02 gradient, expected A-a 02 and A-a 02 difference were significantly higher and basophil was lower in non-survivors. A-a O2 gradient (AUC 0.78), A-a O2 difference (AUC 0.74) and albumin (AUC 0.80) showed highest 30-day mortality prediction. NLR (AUC 0.58) and PLR (AUC 0.55) showed lowest 30-day mortality estimation. Procalcitonin (AUC 0.65), PSI class (AUC 0.81) and PSI score (AUC 0.86) indicated statistically significant higher 30-day mortality prediction. CONCLUSION: A-a O2 gradient, A-a O2 difference and albumin are potent predictors of 30-day mortality in CAP patients in the ED.

CAN COMPLETE BLOOD CELL COUNT PARAMETERS PREDICT DEEP VEIN THROMBOSIS?

The aim of this study was to evaluate complete blood cell count parameters including red blood cell indices, white blood cell subtypes, and platelet indices for predicting deep vein thrombosis (DVT). A total of 71 (44 male and 27 female) patients with acute femoral and popliteal DVT diagnosed by doppler ultrasonography during a period of seven years (2011-2017) were included in the study. By matching age and gender, 142 (88 male and 54 female) subjects diagnosed with venous insufficiency in the same time interval were assigned as control group. Data were obtained by reviewing hospital records of the study participants, including clinical and demographic characteristics and complete blood cell parameters. Frequencies of hypertension, diabetes mellitus, chronic obstructive pulmonary disease, chronic renal failure, and coronary arterial disease were higher in DVT group as compared to non-DVT group (p<0.05). Hemoglobin and lymphocyte values were lower, and red blood cell distribution width, neutrophil, neutrophil to lymphocyte ratio, and platelet to lymphocyte ratio higher in DVT group as compared with non-DVT group (p<0.05). There was no significant between-group difference in terms of mean corpuscular volume, platelet, mean platelet volume, mean platelet volume to platelet ratio, and platelet distribution width (p>0.05). Hypertension, hemoglobin, neutrophil to lymphocyte ratio, and platelet to lymphocyte ratio were independent risk factors for DVT. We found that hypertension, anemia, neutrophil to lymphocyte ratio, and platelet to lymphocyte ratio were independent risk factors for DVT. In particular, neutrophil to lymphocyte ratio and hemoglobin may be used as novel, inexpensive, and reliable diagnostic tools for DVT.

The effect of docosahexaenoic acid on apelin distribution of nervous system in the experimental mouse model of Parkinson's disease.

Parkinson's disease (PD) is a degenerative disorder of the human central and peripheral nervous systems. n-3 fatty acids docosahexaenoic acid (DHA, C22: 6n-3) and eicosapentaenoic acid (EPA) as well as apelin have anti-inflammatory effects in various cells. At the same time, apelin has anti-oxidative and anti-apoptotic effects. The study was conducted to determine the effect of DHA on the distribution of apelin and apelin receptor (APJ) in the central nervous system in 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine (MPTP)-induced PD model. DHA treatment decreased the return time and total down time in the Parkinson group which were measured by pole test. Besides, the ambulatory activity, distance and total locomotor activity were increased by DHA in the PD model of animals. The time mice remained on the rotating rod mile was also significantly increased by DHA treatment in MPTP injected animals. The apelin expression in the pons of mice in the Parkinson, DHA and Parkinson + DHA groups were lower compared to the Control group. When apelin and apelin receptor expressions in cerebrum were examined, there was no statistically significant difference between the groups. When apelin receptor expression in cerebellum was examined, the difference between the Control and Parkinson + DHA, Parkinson and Parkinson + DHA, DHA and Parkinson + DHA groups were statistically significant. Apelin receptor expressions in pons of the Parkinson, DHA and Parkinson + DHA groups were lower compared to the Control group. Apelin protein levels of cerebellum and pons were found to be decreased in DHA group compare with Control group. In conclusion; DHA has been implicated in the expression of the apelin receptor and has reduced the expression of APJ receptor.