Mohrgibson3878

Canthin-6-one (Cant) is an indole alkaloid found in several botanical drugs used as medicines, reported to be gastroprotective, anti-inflammatory, anti-microbial, anti-diarrheal and anti-proliferative. We aimed to explore Cant in the management of colitis using a trinitrobenzenesulfonic acid (TNBS)-induced rat model. Cant (1, 5 and 25 mg/kg) was administered by oral gavage to Wistar rats followed by induction of colitis with TNBS. Macroscopic and histopathological scores, myeloperoxidase (MPO), malondialdehyde (MDA) and reduced glutathione (GSH) were assessed in colon tissues. Pro- (TNF-α, IL-1β and IL-12p70) and anti-inflammatory (IL-10) cytokines, and vascular endothelial growth factor (VEGF) were also quantified. Mitogen-activated protein kinase 14 (MAPK14) and Toll-like receptor-8 (TLR8), as putative targets, were considered through in silico analysis. Cant (5 and 25 mg/kg) reduced macroscopic and histological colon damage scores in TNBS-treated rats. MPO and MDA were reduced by up to 61.69% and 92.45%, respectively, compared to TNBS-treated rats alone. Glutathione concentration was reduced in rats administered with TNBS alone (50.00% of sham group) but restored to 72.73% (of sham group) with Cant treatment. TNF-α, IL-1β, IL-12p70 and VEGF were reduced, and anti-inflammatory IL-10 was increased following Cant administration compared to rats administered TNBS alone. Docking ligation results for MAPK14 (p38α) and TLR8 with Cant, confirmed that these proteins are feasible putative targets. Cant has an anti-inflammatory effect in the intestine by down-regulating molecular immune mediators and decreasing oxidative stress. Therefore, Cant could have therapeutic potential for the treatment of inflammatory bowel disease and related syndromes.Natural products are a large source of clinically effective antitumor drugs. Millepachine, a natural product derived from leguminous plants, was reported to display antitumor activity. In this study, the novel compound, (1H-indol-5-yl) (5-methoxy-2,2-dimethyl-2H-chromen-8-yl)methanone (MIL-1), was designed and synthesized by fusing millepachine and indole rings. MIL-1 exerted much better antitumor activity than millepachine, manifesting as a 24- to 201-fold increase in vitro cytotoxicity and a 2.4-fold increase in in vivo antitumor activity in hepatocellular cell lines-derived models. The immunofluorescence and HPLC detection revealed that MIL-1 was a potent microtubule targeting agent by interfering with the equilibrium of tubulin-microtubule dynamics and irreversibly binding to tubulin. MIL-1 displayed remarkable antitumor activity with an IC50 of 31-207 nM towards various human cancer cell lines derived from various organs and tissues, and it exerted no evidence of toxicity against normal cells. Mechanistic studies showed that MIL-1 arrested the cell cycle at G2/M phase and induced apoptosis by activating caspase-3 activity and reactive oxygen species (ROS) accumulation. Moreover, the superior antitumor effect of MIL-1 is worthy of further detailed study for the treatment of hepatocellular carcinoma (HCC).Liver fibrosis is a compensatory response to the tissue repair process. The activation and proliferation of hepatic stellate cells (HSCs) are thought to be related to the occurrence of hepatic fibrosis. Therefore, inhibiting the activation and proliferation of HSCs is a key step in alleviating liver fibrosis. As a non-specific inhibitor of transient receptor potential melastatin 7 (TRPM7), carvacrol has anti-tumor, anti-inflammatory and anti-hepatic fibrosis activities. This study aimed to explore the protective effect of carvacrol on liver fibrosis and related molecular mechanisms. A CCl4-induced liver fibrosis mouse model and platelet-derived growth factor (PDGF-BB)-activated HSC-T6 cells (a rat hepatic stellate cell line) were employed for in vivo and in vitro experiments. C57BL/6J mice were orally administered different concentrations of carvacrol every day for 6 weeks during the development of CCl4-induced liver fibrosis. The results show that carvacrol could effectively reduce liver damage and the progression of liver fibrosis in mice, which are expressed as fibrotic markers levels were reduced and histopathological characteristics were improved. Moreover, carvacrol inhibited the proliferation and activation of HSC-T6 cells induced by PDGF-BB. In addition, it was found that carvacrol inhibits the expression of TRPM7 and mediated through mitogen-activated protein kinases (MAPK). Collectively, our study shows that carvacrol can reduce liver fibrosis by inhibiting the activation and proliferation of hepatic stellate cells, and the MAPK signaling pathway might be involved in this process.Intestinal ischemia is a vascular emergency that arises when blood flow to the intestine is compromised. Reperfusion is necessary to restore intestinal function but might lead to local and systemic inflammatory responses and bacterial translocation, with consequent multiple organ dysfunction syndrome (MODS). During reperfusion occurs production of reactive oxygen species. These species contribute to intestinal injury through direct toxicity or activation of inflammatory pathways. Fullerol is a nanacomposite which has been shown to act as reactive oxygen species and reactive nitrogen species (RNS) scavengers. Thus, our aim was to evaluate whether Fullerol confer anti-inflammatory activity during intestinal ischemia and reperfusion (IIR). Intestinal ischemia was induced by total occlusion of the superior mesenteric artery. Groups were treated with vehicle or Fullerol 10 min before reperfusion. Mice were euthanized after 6 h of reperfusion, and small intestines were collected for evaluation of plasma extravasation, leukocyte influx, cytokine production and histological damage. Bacterial translocation to the peritoneal cavity and reactive oxygen and nitrogen species production by lamina propria cells were also evaluated. Our results showed that treatment with Fullerol inhibited bacterial translocation to the peritoneal cavity, delayed and decreased the lethality rates and diminished neutrophil influx and intestinal injury induced by IIR. Reduced severity of reperfusion injury in Fullerol-treated mice was associated with blunted reactive oxygen and nitrogen species production in leukocytes isolated from gut lamina propria and decreased production of pro-inflammatory mediators. Thus, the present study shows that Fullerol is a potential therapy to treat inflammatory bowel disorders associated with bacterial translocation, such as IIR.Genetic and epigenetic alterations have been under concentrated investigations for many years in order to unearth the molecules regulating human cancer pathogenesis. However, the identification of a wide range of dysregulated genes and their protein products has raised a question regarding how the results of this large collection of alterations could converge into a formation of one malignancy. The answer may be found in the signaling cascades that regulate the survival and metabolism of the cells. Aberrancies of each participant molecule of such cascades may well result in augmented viability and unlimited proliferation of cancer cells. Among various signaling pathways, the phosphatidylinositol-3-kinase (PI3K) axis has been shown to be activated in about one-third of human cancers. One of the malignancies that is mostly affected by this axis is gastric cancer (GC), one of the most fatal cancers worldwide. In the present review, we aimed to illustrate the significance of the PI3K/Akt/mTOR axis in the pathogenesis of GC and also provided a wide perspective about the application of the inhibitors of this axis in the therapeutic strategies of this malignancy.Obesity and type 2 diabetes mellitus (T2DM) associate with increased incidence and mortality from many cancers, including breast cancer. The mechanisms involved in this relation remain poorly understood. Our study aimed to investigate the in vitro effect of high levels of glucose, insulin, leptin, TNF-α, INF-γ and oxidative stress (induced with tert-butylhydroperoxide (TBH)), which are associated with T2DM, upon glucose uptake by breast cancer (MCF-7 and MDA-MB-231) and non-cancer (MCF-12A) cells and to correlate this effect with their effects upon cellular characteristics associated with cancer progression (cell proliferation, viability, migration, angiogenesis and apoptosis). 3H-DG uptake was markedly inhibited by a selective GLUT1 inhibitor (BAY-876) in all cell lines, proving that 3H-DG uptake is mainly GLUT1-mediated. TBH (2.5 μM), insulin (50 nM), leptin (500 ng/ml) and INF-y (100 ng/ml) stimulate GLUT1-mediated 3H-DG (1 mM) uptake by both ER-positive and triple-negative breast cancer cell lines. TBH and leptin, but not insulin and INF-γ, increase GLUT1 mRNA levels. Insulin and leptin (in both ER-positive and triple-negative breast cancer cell lines) and TBH (in the triple-negative cell line) have a proproliferative effect and leptin possesses a cytoprotective effect in both breast cancer cell lines that can contribute to cancer progression. The effects of TBH, insulin, leptin and INF-γ upon breast cancer cell proliferation and viability are GLUT1-dependent. In conclusion, T2DM-associated characteristics induce changes in GLUT1-mediated glucose uptake that can contribute to cancer progression. Metabolism inhibitor Moreover, we conclude that BAY-876 can be a strong candidate for development of a new effective anticancer agent against breast cancer.

To perform a multicenter study to assess growth failure in hospitalized infants with gastroschisis.

This study included neonates with gastroschisis within sites in the University of California Fetal Consortium. The study's primary outcome was growth failure at hospital discharge, defined as a weight or length z score decrease >0.8 from birth. Regression analysis was performed to assess changes in z scores over time.

Among 125 infants with gastroschisis, the median gestational age was 37weeks (IQR 35-37). Length of stay was 32days (23-60); 55% developed weight or length growth failure at discharge (28% had weight growth failure, 42% had length growth failure, and 15% had both weight and length growth failure). Weight and length z scores at 14days, 30days, and discharge were less than birth (P<.01 for all). Weight and length z scores declined from birth to 30days (-0.10 and -0.11 z score units/week, respectively, P<.001). Length growth failure at discharge was associated with weight and length z score changes over time (P<.05 for both). Lower gestational age was associated with weight growth failure (OR 0.70 for each gestational age week, 95% CI 0.55-0.89, P=.004).

Growth failure, in particular linear growth failure, is common in infants with gastroschisis. These data suggest the need to improve nutritional management in these infants.

Growth failure, in particular linear growth failure, is common in infants with gastroschisis. These data suggest the need to improve nutritional management in these infants.

Transfemoral access is the most common approach for transcatheter aortic valve replacement (TAVR). However, a subset of patients require alternative access. This study describes the evolution and outcomes of alternative access TAVR at Cleveland Clinic.

From January 2006 to January 2019, 2,446 patients underwent TAVR, 414 (17%) via alternative access (247 transapical, 95 transaortic, 56 transaxillary, 2 transcarotid, 10 transiliac, 4 transcaval). Patients undergoing alternative access TAVR had high preoperative risk. Propensity-matched comparisons were targeted at comparing the transfemoral vs. transaxillary approaches since 2012.

Over time, the favored alternative access approach shifted from transapical and transaortic to transaxillary. Pacemaker requirement was similar for alternative access and transfemoral approaches. Compared with transfemoral access, major vascular injuries were higher in the alternative access group (n=12/2.9% vs. n=27/1.3%, P=.02), but minor vascular injuries were lower (n=13/3.