Increased Prostaglandin Secretion Research Articles

Gastrointestinal Tract and Kidney Injury Pathogenesis in Post-COVID-19 Syndrome.

COVID-19 is a global health emergency that requires worldwide collaboration to control its spread. The scientific community is working to understand the different aspects of the post-COVID-19 syndrome and potential treatment strategies. Interestingly, there have been reports of gastrointestinal tract (GIT) involvement in the post-COVID-19 syndrome, suggesting the presence of both severe and mild GIT disorders. The development of the post-COVID-19- GIT syndrome involves various factors, such as impaired GIT mucosa cells, disruptions in the feeling of satiety, reduced blood supply due to the formation of small blood clots, and increased prostaglandin secretion caused by an excessive immune response. GIT symptoms have been observed in around 16% of COVID-19 patients. Other complications include kidney damage and prolonged impairment in the filtration and excretion functions of the glomeruli and tubules. The pathogenesis of post-COVID-19 renal syndrome involves factors, like an overactive immune response, reduced lung perfusion and oxygenation, viral infection in kidney tissues, endothelial dysfunction, and decreased blood volume. Roughly 20% of hospitalized patients experience renal manifestations after recovering from COVID-19.

The Effect of Coumestrol on Progesterone and Prostaglandin Production in the Mare: In Vitro and In Vivo Studies.

Coumestrol (Cou) is a plant-derived phytoestrogen that induces various pathologies in the female reproductive tract. Although effects of phytoestrogens on reproductive function in other species are well documented, their influence on progesterone (P4) and prostaglandin (PG) secretion in the mare is unknown. The aim of this study was to determine if Cou directly affects P4 and PG concentrations (in vivo) and endometrial PG secretion (in vitro) in the mare. In experiment 1, the mares (n = 4) were fed for 14 days on a diet containing increasing proportions of alfalfa pellets (250 g-1 kg/day). An additional 4 mares were fed a standard diet (control group). Sequential blood samples were obtained for 8 h after feeding on Days 13 and 14 (1 kg/day alfalfa pellets). Feeding the mares alfalfa pellets up-regulated PGE2 and 13,14-dihydro-15-ketoprostaglandin F2alpha (PGFM) and down-regulated P4 in the blood plasma compared to those in the control group (P < 0.05). In experiment 2, epithelial and stromal cells were exposed to E2 (10-9 M) or Cou (10-8 M) for 24 h. In the in vitro study, Cou increased PG secretion in epithelial and stromal cells (P < 0.05). In both types of endometrial cells, Cou up-regulated PTGS-2 protein expression (P < 0.05). Moreover, PGES and PGFS proteins were up-regulated by Cou in epithelial cells (P < 0.01). These results indicate that Cou can disturb reproductive function by affecting reproductive hormone secretion and altering the endometrial milieu through PG stimulation. Coumestrol therefore may impair physiologic regulation of the estrous cycle and early pregnancy.

Exercise in the prevention and treatment of colorectal neoplasms: effects and mechanisms

Objective. This review examines factors that influence the widely varying estimates of protection against colorectal adenomas and cancers associated with occupational and leisure activity, and it seeks a realistic value for use in the formulation of public policy. Attention is also directed to underlying mechanisms, and brief consideration is given to the merits of exercise programmes after the treatment of colorectal tumours. Methods. The Ovid/Medline data base was searched systematically from January 1996 to November 2015. The terms exercise therapy, physical education/training, athletes, physical fitness and physical activity/motor activity together yielded 205,142 hits, and a combination of the terms colon cancer, rectal cancer, colon adenoma and colon diverticulitis identified 52, 622 unique articles. Combining the 2 searches with a restriction to human subjects identified 286 papers. A review of the abstracts to these articles yielded 3 papers on colorectal adenomas and physical activity, and 41 studies of leisure or occupational activity in relation to colorectal cancer. A further19 articles examined various aspects of the association between colorectal neoplasia and habitual physical activity. This data base was supplemented extensively by articles gleaned from PubMed, Google Scholar and personal files, with a particular emphasis upon occupational studies conducted prior to 1996. Results. Almost all published research has found an association between physical activity and a reduced risk of colorectal adenomas. Risk ratios for sedentary behaviour have varied widely between studies, with a weighted average of 1.64 for 6 occupational studies, and 1.26 for 27 leisure studies; the relationship is apparently stronger in men than in women. A substantial association with a sedentary lifestyle has also been reported for colon cancers, with a weighted average risk ratio of 1.27 in 39 occupational studies, and of 1.59 in 46 leisure studies. Likewise, for rectal cancers, risk ratios average 1.17 in 27 occupational studies and 1.24 in 20 leisure studies. For both colon and rectal cancers, risk ratios associated with a lack of physical activity were at least as great in women as in men. Inter-study differences in the reported risk-ratios reflect, among other variables, sample size, age, sex and race of subjects, choice of covariates, and the method and timing of activity measurements. Underlying mechanisms of benefit probably vary with the pattern of exercise adopted, but may include a reduced formation of colorectal adenomas, increased colonic motility, increased prostaglandin secretion, an increased use of NSAIDs, dietary changes and avoidance of obesity, a reduced risk of diabetes mellitus and a healthy overall lifestyle. There is growing evidence that an active lifestyle also improves the immediate outcome of colorectal surgery, and that subsequent involvement in an exercise programme enhances functional capacity and quality of life, with a reduced risk of tumour recurrence. Conclusions. There is now overwhelming evidence that vigorous habitual activity, either at work or in leisure, is associated with a reduced risk of adenomas and cancers of the colon and rectum. However, the reported benefits are based upon very high levels of weekly energy expenditure, and in terms of public policy the general sedentary population seems unlikely either to attain or to maintain such levels of effort; regular moderate physical activity seems unlikely to yield benefits >20% for colon tumours and >10% for rectal tumours.

Lipopolysaccharides, cytokines, and nitric oxide affect secretion of prostaglandins and leukotrienes by bovine mammary gland epithelial cells

The aims of this study were to determine the effects of lipopolysaccharides (LPS), tumor necrosis factor (TNF), interleukin 1 alpha (IL-1α), nitric oxide donor (NONOate), or the combination of TNF + IL-1α + NONOate on the following: (i) secretion of prostaglandin (PG)-F2α, PGE2, leukotriene (LT)-B4, and LTC4 by epithelial cells of the teat cavity and lactiferous sinus of bovine mammary gland; (ii) messenger RNA (mRNA) transcription of enzymes responsible for arachidonic acid (AA) metabolism (prostaglandin-endoperoxide synthase 2 [PTGS2], prostaglandin E synthase [PTGES], prostaglandin F synthase [PGFS], and arachidonate 5-lipooxygenase [ALOX5]); and (iii) proliferation of the cells. The cells were stimulated for 24 h. Prostaglandins and LT were measured by enzyme immunoassay, mRNA transcription of enzymes was determined by real-time reverse transcription polymerase chain reaction, and the cell viability was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. All factors increased PG secretion, but the highest stimulation was observed after TNF and IL-1α (P < 0.001). Tumor necrosis factor, NONOate, and TNF + IL-1α + NONOate increased LTB4 production (P < 0.01), whereas LTC4 was increased by LPS, TNF, and IL-1α (P < 0.01). Lipopolysaccharides, TNF, IL-1α, and the reagents combination increased PTGS2, PTGES, and PGFS mRNA transcription (P < 0.01), whereas ALOX5 mRNA transcription was increased only by TNF (P < 0.001). Lipopolysaccharides, TNF, IL-1α, NONOate, and the combination of reagents increased the cell number (P < 0.001). Mediators of acute-clinical Escherichia coli mastitis locally modulate PG and LT secretion by the epithelial cells of the teat cavity and lactiferous sinus, which might be a useful first line of defense for the bovine mammary gland. Moreover, the modulation of PG and LT secretion and the changing ratio of luteotropic (PGE2, LTB4) to luteolytic (PGF2α, LTC4) metabolites may contribute to disorders in reproductive functions.

The Endocrinology of Equine Parturition

Delivery of viable young requires co-ordination of fetal maturation with the onset of labour at term. In turn, this depends on a cascade of fetal and maternal endocrine events. The sequence of these events is broadly similar in most mammals but there are differences in placental hormone synthesis and in the timing and magnitude of key prepartum endocrine changes between species. In most farm animals, maternal progesterone (P4) levels decline and oestrogen levels increase in the last 5 - 10 days before delivery in response to activation of the fetal hypothalamicpituitary-adrenal (HPA) axis and increased fetal cortisol concentrations. This cortisol surge is also responsible for fetal maturation and increasing uteroplacental prostaglandin (PG) synthesis. In the mare, there is little, if any, P4 in the maternal plasma during late gestation and both progestagens and oestrogens are produced by a feto-placental unit which uses precursors supplied by the fetus to synthesise a range of C21 and C18 steroids, many of which are unique to the horse. Regulation of uterine quiescence and activation is, therefore, complex in the mare near term. Indeed, total progestagen concentrations rise and total oestrogen levels fall in the mare during the last 20 - 30 days of gestation and only show the changes typical of impending parturition in other species in the last 24 - 48 h before delivery. Fetal cortisol concentrations also rise late in gestation in the horse compared to other species. In common with other species, the prepartum endocrine cascade appears to begin in the fetal horse with activation of the fetal HPA axis but, initially, the primary product of the fetal equine adrenal appears to be pregnenolone (P5) and not cortisol. This leads to increased progestagen production by the uteroplacental tissues, which maintains uterine quiescence in the face of increasing uterine stretch caused by the rapidly growing fetus. Very close to term in association with increasing fetal ACTH levels, the fetal equine adrenals appear to switch to producing cortisol. This late cortisol surge induces a period of rapid fetal maturation and may also contribute to increased uteroplacental oestradiol-17 beta and PG production. The fall in P5 availability may reduce uteroplacental progestagen production and lift the block on myometrial contractility. Finally, increased PG secretion activates myometrial contractions, which stimulate oxytocin release via a neuroendocrine reflex. The endocrine regulation of equine parturition, therefore, involves progestagens, oestrogens, PGs and oxytocin as in other species. However, further studies are required to establish the causes and consequences of the rise and fall in maternal progestagens and the extent to which initiation of equine labour depends on the fetal HPA axis.

Effects of COX-2 inhibitor on growth of human gastric cancer cells and its relation to hepatocyte growth factor

It is known that hepatocyte growth factor binding to its receptor regulates gastric cancer progression and metastasis. HGF was found to up-regulate the expression of cyclooxygenase-2 gene and increases prostaglandin (PG) synthesis in gastric mucosa cells. Overexpression of COX-2 and increased PG secretion have also been found to be involved in the regulation of growth and metastasis of gastric cancer. Results from this study showed that c-Met and COX-2 are expressed in 28 cases (93.3%) and 16 cases (53.3%) of 30 human gastric cancer tissues, respectively. Expressions of c-Met positively correlated with that of COX-2 ( r=0.41; P=0.024). Using in vivo and in vitro models to further examine the interaction between c-MET and COX-2, we found that HGF stimulated the growth of SC-M1 cells in a dose-dependent manner. COX-2-specific inhibitor-NS398 inhibited the growth of human gastric cancer SC-M1 cells as well as HGF stimulated the growth of SC-M1 cells in a dose-dependent manner. HGF treatment of SC-M1 cells increased the secretion of PGE2 and this stimulation was blocked by NS398. In vivo SC-M1 tumor model showed that HGF stimulated the tumor growth and NS398 retarded the tumor growth. These results suggest that COX-2-specific inhibitors may play some role on the therapy of gastric cancer patients with high serum HGF level and overexpression of c-Met in tumor.

Nonsteroidal anti-inflammatory drugs for treatment of advanced gastric cancer: cyclooxygenase-2 is involved in hepatocyte growth factor mediated tumor developmentand progression

Surgical treatment of gastric cancer patients is dismal because advanced tumor is often noted at diagnosis. In order to obtain better adjuvant therapy for gastric cancer patients after operation, it is important to understand the mechanism of invasion and metastasis. It is well known that binding of hepatocyte growthfactor (HGF) to its receptor (c-Met) regulates gastric cancer progression and metastasis. Recently, HGF was found to up-regulate the expression of cyclooxygenase-2 (COX-2) gene and increase prostaglandin (PG)synthesis in gastric mucosa cells. Over-expression of COX-2 and increased PG secretion have also been foundto be involved in the growth and metastasis of gastric cancer. These results together suggest that the signaling pathway of HGF and c-Met may be mediated through ERK2 activation, up-regulation of COX-2 and increased production of PGE2in gastric cancer cells. In view of the fact that c-Met is over-expressed in the majority of gastric cancer patients with poor prognosis, COX-2 specific inhibitors may provide beneficial effects in these patients.

Characterization of PPD-specific T-cell lines generated in type I (insulin-dependent) diabetic and healthy individuals.

The particular susceptibility to insulin-dependent diabetes mellitus (IDDM) conferred by HLA-DR3,4 heterozygosity has been suggested to be an effect of transcomplementation of HLA class II molecules. To test this hypothesis of special IDDM-specific hybrid determinants and to evaluate the T-cell repertoire towards a specific antigen in IDDM patients we generated a total of 352 PPD-specific T-cell lines by the soft-agar cloning technique and studied their restriction by HLA class II molecules. Of these lines, 227 were from nine IDDM patients, of whom six were DR3,4 heterozygotes, and 125 from 10 healthy controls. Forty-six T-cell lines elicited specific responses in at least two experiments and in addition to T-cell lines demonstrating class-II-restricted PPD specificity, lines with an alloreactivity occurred. HLA-DQ-restricted PPD-specific T-cell lines were not identified and a possible DP restriction (DPw2) was only observed with one line. These data indicate that PPD is preferentially presented to T cells in the context of HLA-DR/Dw. Presentation of PPD by hybrid molecules in IDDM patients or by IDDM-specific class II epitopes recognized by the T-cell lines was not demonstrated. By restriction fragment length polymorphism analysis using a probe for the joining region of the T-cell receptor gamma gene, T-cell lines generated by the soft-agar cloning technique were found to be oligoclonal. It is concluded that soft-agar cloning should be followed by subsequent limiting dilution in order to assure monoclonality. Different preparations of antigen-presenting cells (APC) were tested. In several cases the T-cell lines were not able to respond to PPD presented by Epstein-Barr-virus-transformed lymphoblastoid cell lines (LCL). It was demonstrated that lipopolysaccharides (LPS) of E. coli potently reduce the proliferative response of antigen-specific and alloreactive T cells when T-cell-depleted peripheral blood mononuclear cells (E- cells) were used as APC, whereas only limited inhibition was observed when LCL were used as APC in the presence of LPS. This effect of LPS is suggested to be mediated by increased prostaglandin secretion by monocytes among the E- cells since indomethacin abolished the effect of LPS. This observation may have implications for T-cell cloning procedures since we have found that most commercially available culture media are heavily contaminated with endotoxin.

Tumor-induced alteration in macrophage accessory cell activity on autoreactive T cells.

Using a tumor-model system, differences in the accessory cell capabilities on autoreactive T cells of splenic macrophages from normal and tumor-bearing hosts (TBH) were assessed in the syngeneic mixed lymphocyte reaction. Tumor development caused a drop in autoreactivity. At 0 and 7 days of tumor growth, no drop in reactivity occurred when TBH macrophages were used as accessory cells and L3T4+ autoreactive T cells from normal mice were used as responder cells. However, by day 14, there was a 32% drop in reactivity, and by day 21 only 22% of the T cell reactivity remained when TBH macrophages were used as accessory cells. Alterations in macrophage Ia antigen during tumor growth were first investigated as the potential cause of reduced autoreactivity. Before tumor growth (day 0) 59% of the splenic macrophages were found to be Ia+. Day-7 TBH macrophages showed no difference in Ia antigen expression when compared to day 0 macrophages. However, by day 14, TBH macrophages showed a 9% decrease, and by day 21 they showed a 36% decrease in the number which were Ia+. Concomitant with the decrease in the number of Ia+ cells was a decrease in the density of Ia antigen expression on day-14 and -21 TBH macrophages. In day-14 and -21 TBH macrophages, two populations were seen that were Ia+. The first had a 10%-20% decrease in Ia antigen expression per cell while the second population had a greater than 50% drop in Ia antigen expression per cell. By titrating and mixing TBH macrophages with normal host macrophages, we assessed whether they could actively mediate suppression of autoreactive T cells. A titratable suppressive phenomenon was demonstrated using day-21 TBH macrophages. In contrast, day-7 and -14 TBH macrophages titrated with normal host macrophages had no effect on the syngeneic mixed lymphocyte reactivity. Lastly, we investigated whether the macrophage-mediated suppression was caused by increased prostaglandin secretion. Addition of indomethacin to cultures increased autoreactive T cell reactivity stimulated by normal or TBH macrophages (59% and 99% increase, respectively). Although indomethacin reduced suppression mediated by TBH macrophages, autoreactivity did not return to levels induced by untreated or indomethacin-treated cells from a normal host. Taken together, the data suggested that tumor growth modulates the function of macrophage accessory cells with autoreactive T cells in at least two ways: by decreasing Ia antigen expression and by increasing suppressor activity.

Effect of indomethacin on estrogen-induced luteolysis in the ewe

Three groups of 6 ewes were laparotomized on day 9 of an estrous cycle (estrus = day 0) and the corporà lutea (CL) were marked with India ink. Indwelling cannulae were inserted into the uterine horn adjacent to the CL in groups 2 and 3. Group 1 was injected intramuscularly (i.m.) with corn oil twice daily on day 9. Group 2 received 750 ug 17β-estradiol (E 2) i.m. twice daily on day 9 plus intrauterine injections of indomethacin (INDO) vehicle on days 9 through 13. Group 3 received the same estrogen treatment plus the injection of 20 mg INDO twice daily on days 9 through 13. Jugular venous samples were taken once daily on days 9 through 14 progesterone analysis. At re-laparotmy on day 14, the ovaries were examined for new ovulations, and the ovary bearing the marked CL was removed. Results showed that E 2 induced premature luteal regression as indicated by decreased CL weights and plasma progesterone levels. INDO when given in conjuction with E 2 effectively blocked the luteolytic action of E 2. These results suggest that the luteolytic action of E 2 is mediated via increased prostaglandin secretion and release from the uterus.