Long-term Helicobacter pylori infection switches gastric epithelium reprogramming towards cancer stem cell-related differentiation program in Hp-activated gastric fibroblast-TGFβTGF\beta dependent manner

Helicobacter pylori (Hp)-induced inflammatory reaction leads to a persistent disturbance of gastric mucosa and chronic gastritis evidenced by deregulation of tissue self-renewal and local fibrosis with the crucial role of epithelial-mesenchymal transition (EMT) in this process. As we reported before, Hp activated gastric fibroblasts into cells possessing cancer-associated fibroblast properties (CAFs), which secreted factors responsible for EMT process initiation in normal gastric epithelial RGM1 cells. Here, we showed that the long-term incubation of RGM1 cells in the presence of Hp-activated gastric fibroblast (Hp-AGF) secretome induced their shift towards plastic LGR5+/Oct4$^{high}$/Sox-2$^{high}$/c-Myc$^{high}$/Klf4$^{low}$ phenotype (l.t.EMT+RGM1 cells), while Hp-non-infected gastric fibroblast (GF) secretome prompted a permanent epithelial-myofibroblast transition (EMyoT) of RGM1 cells favoring LGR−/Oct4$^{high}$/Sox2$^{low}$/c-Myc$^{low}$/Klf4$^{high}$ phenotype (l.t.EMT-RGM1 cells). TGFβ1 rich secretome from Hp-reprogrammed fibroblasts prompted phenotypic plasticity and EMT of gastric epithelium, inducing pro-neoplastic expansion of post-EMT cells in the presence of low TGFβR1 and TGFβR2 activity. In turn, TGFβR1 activity along with GF-induced TGFβR2 activation in l.t.EMT-RGM1 cells prompted their stromal phenotype. Collectively, our data show that infected and non-infected gastric fibroblast secretome induces alternative differentiation programs in gastric epithelium at least partially dependent on TGFβ signaling. Hp infection-activated fibroblasts can switch gastric epithelium microevolution towards cancer stem cell-related differentiation program that can potentially initiate gastric neoplasm

Exogenous asymmetric dimethylarginine (ADMA) in pathogenesis of ischemia-reperfusion-induced gastric lesions : interaction with protective nitric oxide (NO) and calcitonin gene-related peptide (CGRP)

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthesis inhibitor and pro-inflammatory factor. We investigated the role of ADMA in rat gastric mucosa compromised through 30 min of gastric ischemia (I) and 3 h of reperfusion (R). These I/R animals were pretreated with ADMA with or without the combination of l-arginine, calcitonin gene-related peptide (CGRP) or a small dose of capsaicin, all of which are known to afford protection against gastric lesions, or with a farnesoid X receptor (FXR) agonist, GW 4064, to increase the metabolism of ADMA. In the second series, ADMA was administered to capsaicin-denervated rats. The area of gastric damage was measured with planimetry, gastric blood flow (GBF) was determined by H2-gas clearance, and plasma ADMA and CGRP levels were determined using ELISA and RIA. ADMA significantly increased I/R-induced gastric injury while significantly decreasing GBF, the luminal NO content, and the plasma level of CGRP. This effect of ADMA was significantly attenuated by pretreatment with CGRP, l-arginine, capsaicin, or a PGE2 analogue. In GW4064 pretreated animals, the I/R injury was significantly reduced and this effect was abolished by co-treatment with ADMA. I/R damage potentiated by ADMA was exacerbated in capsaicin-denervated animals with a further reduction of CGRP. Plasma levels of IL-10 were significantly decreased while malonylodialdehyde (MDA) and plasma TNF-α contents were significantly increased by ADMA. In conclusion, ADMA aggravates I/R-induced gastric lesions due to a decrease of GBF, which is mediated by a fall in NO and CGRP release, and the enhancement of lipid peroxidation and its pro-inflammatory properties

Moderate exercise training attenuates the severity of experimental rodent colitis : the importance of crosstalk between adipose tissue and skeletal muscles

Although progress has been recently made in understanding of inflammatory bowel diseases (IBD), their etiology is unknown apart from several factors from adipose tissue and skeletal muscles such as cytokines, adipokines, and myokines were implicated in the pathogenesis of ulcerative colitis. We studied the effect high-fat diet (HFD; cholesterol up to 70%), low-fat diet (LFD; cholesterol up to 10%), and the normal diet (total fat up to 5%) in rats with TNBS colitis forced to treadmill running exercise (5 days/week) for 6 weeks. In nonexercising HFD rats, the area of colonic damage, colonic tissue weight, the plasma IL-1β, TNF-α, TWEAK, and leptin levels, and the expression of IL-1β-, TNF-α-, and Hif1α mRNAs were significantly increased and a significant fall in plasma adiponectin and irisin levels was observed as compared to LFD rats. In HFD animals, the exercise significantly accelerated the healing of colitis, raised the plasma levels of IL-6 and irisin, downregulated the expression of IL-1β, TNF-α, and Hif1α, and significantly decreased the plasma IL-1β, TNF α, TWEAK, and leptin levels. We conclude that HFD delays the healing of colitis in trained rats via decrease in CBF and plasma IL-1β, TNF-α, TWEAK, and leptin levels and the release of protective irisin

Molecular action of insulin-sensitizing agents

Związki raka trzonu macicy oraz hiperplazji endometrialnej z cukrzycą znane są od dawna. Hiperinsulinemia może bowiem wywierać bezpośredni wpływ mitogenny na endometrium przeciwstawiając się antyproliferacyjnemu wpływowi progesteronu. Częstość raka endometrialnego w cukrzycy ocenia się na 3-4 razy wyższą niż w populacji. Podobne związki wykazywane są dla oporności tkanek na insulinę i częstości występowania raka trzonu macicy. Istnieją już pierwsze doniesienia o cofaniu się atypowego przerostu endometrialnego opornego na leczenie progesteronem pod wpływem czynników uwrażliwiających na insulinę. Istnieje zatem prawdopodobieństwo uzyskania nowej klasy leków wspomagających profilaktykę tego najczęstszego nowotworu ginekologicznego. Do leków tych należy metformina, przeciwcukrzycowy biguanid stosowany w cukrzycy dorosłych. W odróżnieniu od pochodnych sulfonylomocznika lek ten nie działa pierwotnie na wzmożenie sekrecji insuliny. Odwrotnie, powoduje on obniżenie glukoneogenezy w obecności insuliny. Uważa się go zatem za lek uwrażliwiający na insulinę. Uwrażliwienie na insulinę może poprawiać metaboliczne efekty działania insuliny i hamować jej działanie mitogenne poprzez mechanizmy specyficzne tkankowo. Do mechanizmów tych proponuje się zaliczyć np. ekspresję izoform receptora insulinowego. Izoformy receptora insulinowego IR-A i IR-B różnią się resztą 12 aminokwasów. Ekspresję izoformy IR-A stwierdza się głównie w tkankach nowotworowych, gdzie wywiera efekt mitogenny w komórkach. Jednakże nie jest dotychczas poznane względne nasilenie ekspresji obu izoform w tkankach prawidłowych i nowotworowych. Proponowane są także inne mechanizmy, pozareceptorowe, poprzez które insulina wywiera mitogenny wpływ na tkanki, szczególnie nowotworowe. Takim mechanizmem może być zmiana ekspresji insulinopodobnego czynnika wzrostu 1 (IGF-1) oraz jego białek wiążących (IGFBP) lub też modyfikacja antyproliferacyjnego działania progesteronu. Potwier-dzono istnienie miejsc wiązania dla IGF-1 i IGF-2 zarówno w endometrium prawidłowym jak i nowotworowym. Wiązanie IGF-1 w tkankach raka endometrium jest znamiennie wyższe niż w zdrowej śluzówce jamy macicy. W hodowanej linii raka endometrialnego Ishikawa, IGF-1 jest silniejszym mitogenem niż insulina i IGF-2. Mitogenność insuliny może wzrastać przy zmianach ekspresji białek wiążących. Rodzina tych białek może wykazywać zarówno proliferacyjne jak i antyproliferacyjne działanie. W endometrium stwierdzono ekspresję wszystkich 6 białek wiążących IGF. Najlepiej scharakteryzowanym białkiem jest IGFBP-1. Hiperinsulinemia może obniżać poziom IGFBP-1 nawet w obecności progestreonu, prawdopodobnie hamując jego protekcyjne działanie. Co ciekawe, ekspresja IGFBP 1 w raku endometrium jest niewykrywalna lub istnieje tylko w śladowej ilości. Wieloletnie leczenie środkami antykoncepcyjnymi kobiet z zespołem policystycznych jajników zmniejsza częstość występowania raka endometrialnego oraz redukuje stężenia androgenów w surowicy jak również zmniejsza nasilenie hirsutyzmu i tądzika. Jednakże leczenie to pogarsza wrażliwość tkanek na insulinę. Uwrażliwiacze na insulinę zmniejszają częstość hiperplazji endometrium, indukując regularne miesiączki, ale wykazują niewystarczające działanie antyandrogenne. Należy zwrócić uwagę, że w badaniach Nurses Health Study (NHS) wykazano zwiększone ryzyko cukrzycy przy stosowaniu doustnych środków antykoncepcyjnych. Teoretycznie, metformina używana powszechnie w leczeniu niepłodności kobiet z zespołem policystycznych jajników powinna zapobiegać hiperplazji endometrium poprzez obniżenie stężenia insuliny oraz przywrócenie owulacji. Jednakże należy przeprowadzić dalsze badania, by móc zalecać to leczenie jako profilaktykę raka endometrium.Atypical endometrial hyperplasia has been associated with progression to endometrial cancer, the most common genital malignancy. There are multiple risk factors for endometrial cancer, such as early menarche, exogenous estrogen exposure, obesity and diabetes. Diabetics have a 3-4 fold relative risk of endometrial cancer. Also, several studies have demostrated an association between insulin resistance and endometrial cancer. There is known the first describtion of atypical endometrial hyperplasia resistant to progestogen therapy, which was subsequently treated with an insulin-sensitizng agent, metformin. Metformin is a biguanide antihyperglycemic agent used in the treatment of adult-onset diabetes. Unlike the sulfonylureas, metformin does not act primarily by increasing insulin secretion. In contrast, metformin lowers the rate of gluconeogenesis in the presence of insulin. Therefore, it is considered an insulin-sensitizer. Increased insulin sensitivity may improve the metabolic effect of insulin and decrease its mitogenic effect by tissue-specific mechanisms. One explanation for tissue specific differences in insulin binding and action may be through the relative expression of the insulin receptor (IR) isoforms. The IR isoforms IR-A and IR-D differ by 12 amino acid residues, owing to the alternative splicing of exon. The IR-A is predominantly expressed in malignant tissues and may lead to mitogenic effects within the cell. The relative expressions of IR-A and IR-B in normal and malignant endometrial tissue is not known. Besides direct effects on the IR, several additional mechanisms have been proposed for the mitogenic effect of insulin in endomerial cancer. In addition to the possible direct mitogenic effects of insulin through the IR-A, insulin resistance may be associated with alterations in expression of insulin-like growth factors (IGFs) and the IGF binding proteins (IGFBPs) or may inhibit the protective effect of progestagens. Binding sites for IGF-1 and IGF-2 have been confirmed in both normal and malignant endometrium. Binding of IGF-1 is significantly higher in endometrial cancer compared to normal endometrium. In the Ishikawa human endometrial cancer cell line IGF-1 was a more potent mitogen than insulin or IGF-2. Insulin may increase mitogenicity by regulating the expression of IGFBPs. The IGFBPs are a family of proteins that have both proliferative and anti-proliferative effects. While all six high-affinity IGFBPs are expressed in the endometrium, IGFBP-1 is the best characterized. Hyperinsulinemia can decrease IGFBP-1 even in the presence of progesterone, perhaps inhibiting progesterone’s protective effects. Interestingly, IGFBP-1 was undetectable or minimally expressed in endometrial cancers. Nestler discussed results of a 6-month treatment of 100 nonebese women with PCOS, which showed a somewhat greater effect of metformin than rosiglitazone and no benefit of administering both agents in combination. Long-term treatment with oral contraceptives decreases endometrial cancer, with a reduction in serum androgens and a decreases in hirsutism and acne, but may worsen insulin resistance and lead to deteriration in glucose tolerance. Insulin sensitizers, on the other hand, should decrease endometrial hyparplasia by inducing regular menses, but may not be as beneficial in improving androgen – related symptoms. Note that the Nurses Health Study (NHS) showed increased risk of diabetes in oral contraceptive users. These considerations may be related to the finding that women who used oral contraceptives have increased risk of myaocardial infarction. Thus, in view of the particular increase in CVD risk among women with PCOS, one might be less likely to recommend oral contraceptives, while insulin sensitizers may be of particular benefit, decreaseing androgens, improving ovulation and fertility, and reducing the risk of diabetes and CVD. Theoretically, metformin, a treatment which is now widely used to treat infertile women with PCOS, may have a role in preventing endometrial hyperstimulation by lowering insulin concentrations and restoring ovulation. However, the long-term effects of this drug in women with PCOS are not known and more studies are required before suggesting its use for preventing endometrial cancer

Novel concept in the mechanism of injury and protection of gastric mucosa : role of renina-angiotensin system and active metabolites of angiotensin

The term cytoprotection pioneered by Robert and colleagues has been introduced to describe the remarkable ability of endogenous and exogenous prostaglandins (PGs) to prevent acute gastric hemorrhagic lesions induced by noxious stimuli such as ethanol, bile acids, hiperosmolar solutions and nonsteroidal anti-inflammatory agents such as aspirin. Since that time many factors were implicated to possess gastroprotective properties such as growth factors including epidermal growth factor (EGF) and transforming factor alpha (TGFα), vasodilatory mediators such as nitric oxide (NO) and calcitonin gene related peptide (CGRP) as well as appetite gut hormones including gastrin and cholecystokinin (CCK), leptin and recently ghrelin. This protective action of gut peptides has been attributed to the release of PG but question remains whether another peptide angiotensin, the classic component of the systemic and local renin-angiotensin system (RAS) could be involved in the mechanism of gastric integrity and gastroprotection. After renin stimulation, the circulating angiotensin I is converted to angiotensin II (ANG II) by the activity of the Angiotensin Converting Enzyme (ACE). The ANG II acting via its binding to two major receptor subtypes the ANG type 1 (AT1) and type 2 (AT2) has been shown be activated during stress and to contribute to the pathogenesis of cold stress- and ischemia-reperfusion-induced gastric lesions. All bioactive angiotensin peptides can be generated not only in systemic circulation, but also locally in several tissues and organs. Recently the new functional components of RAS, such as Ang-(1-7), Ang IV, Ang-(1-12) and novel pathways ACE2 have been described suggesting the gastroprotective role for the novel ANG II metabolite, Ang-(1-7). The fact that Ang-(1-7) is produced in excessive amounts in the gastric mucosa of rodents and that pretreatment by Ang-(1-7) exhibits a potent gastroprotective activity against the gastric lesions induced by cold-restraint stress suggests that this and possibly other vasoactive metabolites of ANG II pathway could be involved in the mechanism of gastric integrity and gastroprotection. This review summarizes the novel gastroprotective factors and mechanisms associated with metabolic fate of systemic and local RAS activation with major focus to recent advancement in the angiotensin pathways in the gut integrity

Intestinal alkaline phosphatase combined with voluntary physical activity alleviates experimental colitis in obese mice : involvement of oxidative stress, myokines, adipokines and proinflammatory biomarkers

Intestinal alkaline phosphatase (IAP) is an essential mucosal defense factor involved in the process of maintenance of gut homeostasis. We determined the effect of moderate exercise (voluntary wheel running) with or without treatment with IAP on the course of experimental murine 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis by assessing disease activity index (DAI), colonic blood flow (CBF), plasma myokine irisin levels and the colonic and adipose tissue expression of proinflammatory cytokines, markers of oxidative stress (SOD2, GPx) and adipokines in mice fed a standard diet (SD) or high-fat diet (HFD). Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant decrease in CBF, and a significant increase in the colonic expression of tumor necrosis factor-alpha (TNF-α), IL-6, IL-1β and leptin mRNAs and decrease in the mRNA expression of adiponectin. These effects were aggravated in sedentary HFD mice but reduced in exercising animals, potentiated by concomitant treatment with IAP, especially in obese mice. Exercising HFD mice demonstrated a substantial increase in the mRNA for adiponectin and a decrease in mRNA leptin expression in intestinal mucosa and mesenteric fat as compared to sedentary animals. The expression of SOD2 and GPx mRNAs was significantly decreased in adipose tissue in HFD mice, but these effects were reversed in exercising mice with IAP administration. Our study shows for the first time that the combination of voluntary exercise and oral IAP treatment synergistically favored healing of intestinal inflammation, strengthened the antioxidant defense and ameliorated the course of experimental colitis; thus, IAP may represent a novel adjuvant therapy to alleviate inflammatory bowel disease (IBD) in humans

Disposal of medical rescue teams in injuries brain injury in adults

Urazy czaszkowo-mózgowe stanowią ogromny problem dla służb ratowniczych i obarczone są dużą śmiertelnością. Od ratowników wymagana jest znajomość budowy anatomicznej czaszki, patomechanizmów urazu oraz umiejętność prawidłowej oceny stanu chorego. Urazy głowy można podzielić na otwarte i zamknięte, natomiast ze względu na obrażenia - na pierwotne i wtórne. Stanem bezpośredniego zagrożenia życia w urazach głowy, jest wzrost ciśnienia wewnątrzczaszkowego. Ze względu na brak możliwości pomiaru tego parametru na miejscu zdarzenia, przy objawach wgłobienia mózgu (triada Cushinga) należy utrzymywać CTK na poziomie 110-120mmHg. Postępowanie z pacjentami po urazach głowy będzie przyczynowe i w zależności od obrażeń będą nadawane priorytety . Warto dokładnie oceniać skalę GCS, która może nam pomóc w podejmowaniu decyzji np. dotyczącej intubacji .Szybki i ostrożny transport oraz odpowiednie postępowanie będą miały kluczowe znacznie w dalszym leczeniu pacjenta . Słowa klucze: urazy czaszkowo-mózgowe, następstwa, postępowanie przedszpitaln