ultrasound-guided-intracardiac-injection-human-mesenchymal-stem-cells

Ultrasound-guided Intracardiac Injection of Human Mesenchymal Stem Cells to Increase Homing to the Intestine for Use in Murine Models of Experimental Inflammatory Bowel Diseases

Crohn&#39;s disease (CD) is a common chronic inflammatory disease of the small and large intestines. Murine and human mesenchymal stem cells (MSCs) have ...

Case Western Reserve University

Gliobastoma (GB), the most common adult brain tumor, infiltrates normal brain area rendering impossible the complete surgical resection, resulting in a poor median survival (14-15 months), despite the aggressive multimodality treatments post-surgery, such as radiation and chemo-therapy. GB is characterized by hypoxic and necrotic regions due to a poorly organized tumor vascularization, leading to inadequate blood supply and consequently to hypoxic and necrotic areas. We have previously shown that, under hypoxia GB primary cells increased the expression of stemness markers as well as the expression of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and also the crucial role played by PPARs in mouse neural stem cells maintenance and differentiation. Due to the importance of lipid signaling in cell proliferation and differentiation, in this work, we analyzed the expression of PPARs in GB neurospheres both in normoxic and hypoxic conditions. The results obtained suggest a differential regulation of the three PPARs by hypoxia, thus indicating a possible therapeutic strategy to counteract GB recurrencies.

Hypoxia modulation of peroxisome proliferator-activated receptors (PPARs) in human glioblastoma stem cells. Implications for therapy.

Ketoprofen L-lysine salt (KLS), a NSAID, is widely used for its analgesic efficacy and tolerability. L-lysine salification was reported to increase the solubility and the gastric absorption and tolerance of ketoprofen. Since the management of NSAIDs gastrotoxicity still represents a major limitation in prolonged therapies, mainly when gastric lesions are present, this study investigated the gastro-protective activity of L-lysine by using a well-established model of gastric mucosa injury, the ethanol-gastric injury model. Several evidences show that the damaging action of ethanol could be attributed to the increase of ROS, which plays a key role in the increase of lipid peroxidation products, including malonyldialdehyde and 4-hydroxy-2-nonenal. With the aim to unravel the mechanism of L-lysine gastroprotection, cellular MDA levels and 4-HNE protein adducts as markers of lipid peroxidation and a panel of key endogenous gastro-protective proteins were assayed. The data obtained indicate a gastroprotective effect of L-lysine on gastric mucosa integrity.

Gastroprotective effects of L-lysine salification of ketoprofen in ethanol-injured gastric mucosa.

Inflammatory bowel disease causes chronic, relapsing intestinal inflammation that can lead to the development of colorectal cancer. Members of the TNF superfamily are key regulators of intestinal inflammation. In particular, TNF-like weak inducer of apoptosis (TWEAK) and its receptor, Fn14, are involved in normal and pathologic intestinal tissue remodeling. In this study, we show that the TWEAK/Fn14 signaling complex plays a protective role during the acute stage of intestinal inflammation and contributes to the prevention of colitis-associated cancer during chronic inflammation through its proapoptotic effects. Colitis was induced in Fn14(-/-) and Fn14(+/+) wild-type littermates by administering 3% dextran sodium sulfate (DSS) for 7 days followed by 2-week recovery; azoxymethane (AOM) administration followed by two cycles of DSS/recovery was used to induce tumors. Reciprocal bone marrow chimeric mice were generated to compare hematopoietic and nonhematopoietic-specific effector tissues. Fn14(-/-) mice had enhanced susceptibility to colitis compared with Fn14(+/+) controls as assessed by endoscopic and histologic inflammatory scores, daily weight loss, and mortality rates during recovery after DSS administration. Bone marrow transfer experiments showed that both hematopoietic and nonhematopoietic components are involved in protection against colitis. Tumor lesions were found in the colons of most Fn14(-/-) mice, but not Fn14(+/+) controls. AOM/DSS administration enhanced susceptibility to tumorigenesis in Fn14(-/-) mice. Overall, these findings show that Fn14 plays a protective role during the acute stages of intestinal inflammation, and its absence promotes the development of colitis-associated cancer. Cancer Res; 76(22); 6533-42. ©2016 AACR.

Protective Role for TWEAK/Fn14 in Regulating Acute Intestinal Inflammation and Colitis-Associated Tumorigenesis.

Patients with inflammatory bowel disease (IBD) are at increased risk for developing colorectal cancer. Evidence suggests that colonic dysplasia and colitis-associated cancer (CAC) are often linked to repeated cycles of epithelial cell injury and repair in the context of chronic production of inflammatory cytokines. Several mouse models of CAC have been proposed, including chemical induction through exposure to dextran sulfate sodium (DSS) with the genotoxic agents azoxymethane (AOM), 1,2-dymethylhydrazine (DHM) or targeted genetic mutations. However, such models are usually performed on healthy animals that usually lack the underlying genetic predisposition, immunological dysfunction and dysbiosis characteristic of IBD. We have previously shown that inbred SAMP1/YitFc (SAMP) mice develop a progressive Crohn's disease (CD)-like ileitis in the absence of spontaneous colitis. We hypothesize that SAMP mice may be more susceptible to colonic tumorigenesis due to their predisposition to IBD. To test this hypothesis, we administered AOM/DSS to IBD-prone SAMP and their non-inflamed parental control strain, AKR mice. Our results showed that AOM/DSS treatment enhanced the susceptibility of colitis in SAMP compared to AKR mice, as assessed by endoscopic and histologic inflammatory scores, daily weight loss and disease activity index (DAI), during and after DSS administration. SAMP mice also showed increased colonic tumorigenesis, resulting in the occurrence of intramucosal carcinoma and a higher incidence of high-grade dysplasia and tumor burden. These phenomena occurred even in the absence of AOM and only upon repeated cycles of DSS. Taken together, our data demonstrate a heightened susceptibility to colonic inflammation and tumorigenesis in AOM/DSS-treated SAMP mice with CD-like ileitis. This novel model represents a useful tool to investigate relevant mechanisms of CAC, as well as for pre-clinical testing of potential IBD and colon cancer therapeutics.

Article	Year
Hypoxia modulation of peroxisome proliferator-activated receptors (PPARs) in human glioblastoma stem cells. Implications for therapy. Journal of cellular biochemistry\| PubMed ID: 22644833	2012
Gastroprotective effects of L-lysine salification of ketoprofen in ethanol-injured gastric mucosa. Journal of cellular physiology\| PubMed ID: 25287669	2015
Protective Role for TWEAK/Fn14 in Regulating Acute Intestinal Inflammation and Colitis-Associated Tumorigenesis. Cancer research\| PubMed ID: 27634763	2016
A novel model of colitis-associated cancer in SAMP1/YitFc mice with Crohn's disease-like ileitis. PloS one\| PubMed ID: 28301579	2017

Paola Menghini

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