Deletion of newly described pro-survival molecule Pellino-1 increases oxidative stress, downregulates cIAP2/NF-κB cell survival pathway, reduces angiogenic response, and thereby aggravates tissue function in mouse ischemic models.

INTRODUCTION: In the present study, we aimed to explore the functional role of Pellino-1 (Peli1) in inducing neovascularization after myocardial infarction (MI) and hindlimb ischemia (HLI) using Peli1 global knockout mice (Peli1-/-). Recently we have shown that Peli1, an E3 ubiquitin ligase, induce angiogenesis and improve survivability, with decreased necrosis of ischemic skin flaps. METHODS: Peli1fl/fl and Peli1-/- mice were subjected to either permanent ligation of the left anterior descending coronary artery (LAD) or sham surgery (S). Tissues from the left ventricular risk area were collected at different time points post-MI. In addition, Peli1fl/fl and Peli1-/- mice were also subjected to permanent ligation of the right femoral artery followed by motor function scores, Doppler analysis for blood perfusion and immunohistochemical analysis. RESULTS: Global Peli1 knockout exacerbated myocardial dysfunction, 30 and 60 days after MI compared to wild type (WT) mice as measured by echocardiogram. In addition, Peli1-/- mice also showed decreased motor function scores and perfusion ratios compared with Peli1fl/fl mice 28 days after the induction of HLI. The use of Peli1 in adenoviral gene therapy following HLI in CD1 mice improved the perfusion ratio at 28 days compared to Ad.LacZ-injected mice. CONCLUSION: These results suggest new insights into the protective role of Peli1 on ischemic tissues and its influence on survival signaling.

Increased survivability of ischemic skin flap tissue in Flk-1+/- mice by Pellino-1 intervention.

OBJECTIVE: Reduced skin flap survival due to ischemia is a serious concern during reconstructive cosmetic surgery. The absence of VEGF and its receptors during ischemia may lead to flap failure. We identified Peli1, a 46-kDa protein, as a proangiogenic molecule and is directly regulated by VEGF. Therefore, we hypothesized that Peli1 acts downstream of Flk-1/VEGFR2 and aids in skin flap survival during ischemia. METHODS: Scratch and matrigel assays were performed to observe cell proliferation, migration, and tube formation in vitro. Western blot analysis was carried out to detect the phosphorylation of Akt (p-Akt) and MAPKAPK2 (p-MK2) in HUVECs. The translational potential of Peli1 pretreatment in the rescue of skin flap tissue was studied in vivo using Flk-1+/- mice. Animals underwent dorsal ischemic skin flap surgery, and the tissue was collected on day 12 for analysis. RESULTS: Western blot analysis revealed a direct relationship between Peli1 and VEGF, as demonstrated by loss-of-function and gain-of-function studies. In addition, pretreatment with Ad.Peli1 restored the phosphorylation of Akt and MK2 and improved the migration potential of Flk-1-knockdown cells. Ad.Peli1 pretreatment salvaged the ischemic skin flap of Flk-1+/- mice by increasing blood perfusion and reducing the inflammatory response and the extent of necrosis. CONCLUSION: Our findings reveal that Peli1 is a proangiogenic molecule that acts downstream of VEGF-Flk-1 and restores angiogenesis and enhances skin flap survivability.

Thioredoxin-1 attenuates sepsis-induced cardiomyopathy after cecal ligation and puncture in mice.

BACKGROUND: Sepsis is a leading cause of mortality among patients in intensive care units across the USA. Thioredoxin-1 (Trx-1) is an essential 12 kDa cytosolic protein that, apart from maintaining the cellular redox state, possesses multifunctional properties. In this study, we explored the possibility of controlling adverse myocardial depression by overexpression of Trx-1 in a mouse model of severe sepsis. METHODS: Adult C57BL/6J and Trx-1Tg/+ mice were divided into wild-type sham (WTS), wild-type cecal ligation and puncture (WTCLP), Trx-1Tg/+sham (Trx-1Tg/+S), and Trx-1Tg/+CLP groups. Cardiac function was evaluated before surgery, 6 and 24 hours after CLP surgery. Immunohistochemical and Western blot analysis were performed after 24 hours in heart tissue sections. RESULTS: Echocardiography analysis showed preserved cardiac function in the Trx-1Tg/+ CLP group compared with the WTCLP group. Similarly, Western blot analysis revealed increased expression of Trx-1, heme oxygenase-1 (HO-1), survivin (an inhibitor of apoptosis [IAP] protein family), and decreased expression of thioredoxin-interacting protein (TXNIP), caspase-3, and 3- nitrotyrosine in the Trx-1Tg/+CLP group compared with the WTCLP group. Immunohistochemical analysis showed reduced 4-hydroxynonenal, apoptosis, and vascular leakage in the cardiac tissue of Trx-1Tg/+CLP mice compared with mice in the WTCLP group. CONCLUSIONS: Our results indicate that overexpression of Trx-1 attenuates cardiac dysfunction during CLP. The mechanism of action may involve reduction of oxidative stress, apoptosis, and vascular permeability through activation of Trx-1/HO-1 and anti-apoptotic protein survivin.

Conundrum of pathogenesis of diabetic cardiomyopathy: role of vascular endothelial dysfunction, reactive oxygen species, and mitochondria.

Diabetic cardiomyopathy and heart failure have been recognized as the leading causes of mortality among diabetics. Diabetic cardiomyopathy has been characterized primarily by the manifestation of left ventricular dysfunction that is independent of coronary artery disease and hypertension among the patients affected by diabetes mellitus. A complex array of contributing factors including the hypertrophy of left ventricle, alterations of metabolism, microvascular pathology, insulin resistance, fibrosis, apoptotic cell death, and oxidative stress have been implicated in the pathogenesis of diabetic cardiomyopathy. Nevertheless, the exact mechanisms underlying the pathogenesis of diabetic cardiomyopathy are yet to be established. The critical involvement of multifarious factors including the vascular endothelial dysfunction, microangiopathy, reactive oxygen species (ROS), oxidative stress, mitochondrial dysfunction has been identified in the mechanism of pathogenesis of diabetic cardiomyopathy. Although it is difficult to establish how each factor contributes to disease, the involvement of ROS and mitochondrial dysfunction are emerging as front-runners in the mechanism of pathogenesis of diabetic cardiomyopathy. This review highlights the role of vascular endothelial dysfunction, ROS, oxidative stress, and mitochondriopathy in the pathogenesis of diabetic cardiomyopathy. Furthermore, the review emphasizes that the puzzle has to be solved to firmly establish the mitochondrial and/or ROS mechanism(s) by identifying their most critical molecular players involved at both spatial and temporal levels in diabetic cardiomyopathy as targets for specific and effective pharmacological/therapeutic interventions.

The art and science of publishing: reflections from editors of surgery journals.

During the 8th Annual Academic Surgical Congress held in New Orleans, Louisiana, on February 5-7, 2013, the Association for Academic Surgery (AAS) Presidential Session was dedicated to the topic of publishing. A survey consisting of 37 questions on issues related to publishing was administered to the AAS membership 1 mo before the meeting. The results of the survey were then presented during the 2013 AAS Presidential Session. In addition, a panel of five editors from surgery journals relevant to the membership of the AAS was convened to discuss topics addressed in the results of the survey. These topics included: (1) how to publish in high-impact factor journals; (2) top five reasons why manuscripts get rejected; (3) the do's and don'ts of publishing (i.e., ethics of publishing); (4) how to get on an editorial board; and (5) the future of publishing. This review summarizes the contents of this AAS Presidential Session and provides information relevant for any academician, investigator, or scientist.

Patient selection and the volume effect in pancreatic surgery: unequal benefits?

BACKGROUND: The volume effect in pancreatic surgery is well established. Regionalization to high-volume centres has been proposed. The effect of this proposal on practice patterns is unknown. METHODS: Retrospective review of pancreatectomy patients in the Nationwide Inpatient Sample 2004-2011. Inpatient mortality and complication rates were calculated. Patients were stratified by annual centre pancreatic resection volume (low <5, medium 5-18, high >18). Multivariable regression model evaluated predictors of resection at a high-volume centre. RESULTS: In total, 129,609 patients underwent a pancreatectomy. The crude inpatient mortality rate was 4.3%. 36.0% experienced complications. 66.5% underwent a resection at high-volume centres. In 2004, low-, medium- and high-volume centres resected 16.3%, 24.5% and 59.2% of patients, compared with 7.6%, 19.3% and 73.1% in 2011. High-volume centres had lower mortality (P < 0.001), fewer complications (P < 0.001) and a shorter median length of stay (P < 0.001). Patients at non-high-volume centres had more comorbidities (P = 0.001), lower rates of private insurance (P < 0.001) and more non-elective admissions (P < 0.001). DISCUSSION: In spite of a shift to high-volume hospitals, a substantial cohort still receives a resection outside of these centres. Patients receiving non-high-volume care demonstrate less favourable comorbidities, insurance and urgency of operation. The implications are twofold: already disadvantaged patients may not benefit from the high-volume effect; and patients predisposed to do well may contribute to observed superior outcomes at high-volume centres.

Role of Pellino-1 in Inflammation and Cardioprotection following Severe Sepsis: A Novel Mechanism in a Murine Severe Sepsis Model †.

OBJECTIVES: Intra-abdominal sepsis is commonly diagnosed in the surgical population and remains the second most common cause of sepsis overall. Sepsis-related mortality remains a significant burden in the intensive care unit despite advances in critical care. Nearly a quarter of the deaths in people with heart failure are caused by sepsis. We have observed that overexpression of mammalian Pellino-1 (Peli1), an E3 ubiquitin ligase, causes inhibition of apoptosis, oxidative stress, and preservation of cardiac function in a myocardial infarction model. Given these manifold applications, we investigated the role of Peli1 in sepsis using transgenic and knockout mouse models specific to this protein. Therefore, we aimed to explore further the myocardial dysfunction seen in sepsis through its relation to the Peli 1 protein by using the loss of function and gain-of-function strategy. METHODS: A series of genetic animals were created to understand the role of Peli1 in sepsis and the preservation of heart function. Wild-type, global Peli1 knock out (Peli1-/-), cardiomyocyte-specific Peli1 deletion (CP1KO), and cardiomyocyte-specific Peli1 overexpressing (alpha MHC (αMHC) Peli1; AMPEL1Tg/+) animals were divided into sham and cecal ligation and puncture (CLP) surgical procedure groups. Cardiac function was determined by two-dimensional echocardiography pre-surgery and at 6- and 24-h post-surgery. Serum IL-6 and TNF-alpha levels (ELISA) (6 h), cardiac apoptosis (TUNEL assay), and Bax expression (24 h) post-surgery were measured. Results are expressed as mean ± S.E.M. RESULTS: AMPEL1Tg/+ prevents sepsis-induced cardiac dysfunction assessed by echocardiographic analysis, whereas global and cardiomyocyte-specific deletion of Peli1 shows significant deterioration of cardiac functions. Cardiac function was similar across the sham groups in all three genetically modified mice. ELISA assay displayed how Peli 1 overexpression decreased cardo-suppressive circulating inflammatory cytokines (TNF-alpha, IL-6) compared to both the knockout groups. The proportion of TUNEL-positive cells varied according to Peli1 expression, with overexpression (AMPEL1Tg/+) leading to a significant reduction and Peli1 gene knockout (Peli1-/- and CP1KO) leading to a significant increase in their presence. A similar trend was also observed with Bax protein expression. The improved cellular survival associated with Peli1 overexpression was again shown with the reduction of oxidative stress marker 4-Hydroxy-2-Nonenal (4-HNE). CONCLUSION: Our results indicate that overexpression of Peli1 is a novel approach that not only preserved cardiac function but reduced inflammatory markers and apoptosis following severe sepsis in a murine genetic model.

Inhibitory effects of (-)-epigallocatechin-3-gallate and pterostilbene on pancreatic cancer growth in vitro.

BACKGROUND: It has been previously shown that the naturally occurring antioxidant (-)-epigallocatechin-3-gallate (EGCG), found in green tea, and pterostilbene, a stilbenoid derived from blueberries, inhibit pancreatic cancer in vitro when used individually. We hypothesized that the combination of EGCG and pterostilbene would reveal additive effects in vitro. METHODS: Using the pancreatic cancer cell lines MIA PaCa-2 and PANC-1, efficacy and synergism were evaluated for cell proliferation and viability (3-(4,5-dimethyltiazol-2-y1)-2,5-diphenltetrazolium bromide assays, cell cycle analysis) and mitochondrial apoptosis (mitochondrial depolarization, cytochrome C release, caspase-3/7 activity, cell death detection using enzyme-linked immunosorbent assay). RESULTS: Cell proliferation assays revealed significant additive antiproliferative effects with pterostilbene and EGCG in both cell lines at the later, 72-h, point (P < 0.05). MIA underwent S-phase arrest with the combination (10-12% increase); however, cell cycle arrest was not observed in PANC. The combination induced mitochondrial depolarization and upregulated cytochrome C (P < 0.05) in MIA, but these effects were not observed in PANC. EGCG increased caspase-3/7 in MIA; however, the combination did not significantly increase the activity in either cell line (P < 0.05). Apoptosis was only observed in PANC (P < 0.05). The reduction in proliferation in MIA in the 3-(4,5-dimethyltiazol-2-y1)-2,5-diphenltetrazolium bromide assays with the combination indicated that cell death occurs, possibly through another mechanism. CONCLUSIONS: Our results are encouraging regarding the future use of EGCG and pterostilbene to improve traditional pancreatic cancer therapies. In conclusion, EGCG and pterostilbene have additive, antiproliferative effects in vitro and alter the apoptotic mechanisms in both cell lines by modulation at different points in the mechanism.

Honokiol produces anti-neoplastic effects on melanoma cells in vitro.

BACKGROUND: Melanoma continues to be a therapeutic challenge for the medical community owing to the scarcity of effective agents available to treat the disease. Honokiol, a traditional Chinese herb, has been proven to have anti-cancer effects in various cell types, therefore we hypothesized it may have similar cytotoxic capabilities against melanoma cells in vitro. METHODS: Two cell lines, SK-MEL2 and MeWo, were grown in culture and exposed to increasing doses of Honokiol. Cell proliferation, cytochrome c release into the cytosol, intra-cellular caspase activity, and mitochondrial depolarization were then evaluated after treatment with honokiol. RESULTS: Melanoma cells in culture underwent cell death, had increased cytosolic cytochrome c, showed greater caspase activity, and demonstrated increased mitochondrial depolarization after treatment when compared to controls. CONCLUSIONS: It appears that honokiol is an effective inhibitor of cultured human melanoma cells.

Engineered resveratrol-loaded fibrous scaffolds promotes functional cardiac repair and regeneration through Thioredoxin-1 mediated VEGF pathway.

Despite recent advancements, mortality due to coronary heart disease (CHD) remains high. Recently, the use of tissue-engineered grafts and scaffolds has emerged as a candidate for supporting the myocardium after an ischemic event. Resveratrol is a naturally occurring plant-based non-flavonoid polyphenolic compound found in many natural foods, including grapes and red wine. We embedded resveratrol in a polycaprolactone (PCL) scaffold and evaluated the cardio-therapeutic effects in a murine model of myocardial infarction (MI), with animals being grouped into Sham (S), Myocardial Infarction (MI), MI + PCL, and MI + PCL-Resveratrol (MI + PCL-R). After 4 and 8 weeks, echocardiography was performed to assess ejection fraction (EF) and fractional shortening (FS), which was followed by immunohistochemistry and immunofluorescence analysis at 8 weeks. The MI + PCL-R group showed a significant improvement in EF and FS compared with the MI + PCL group at 4 and 8-weeks post-surgery. PCL-R scaffolds treated hearts revealed decreased inflammatory cell infiltration, improved collagen extracellular matrix (ECM) secretion and blood vessel network formation following MI. The immunofluorescence analysis revealed resveratrol-loaded scaffolds promote increased expression of cTnT, Cx-43, Trx-1, and VEGF proteins. This study reports resveratrol-mediated rescue of ischemic myocardium when delivered through a biodegradable polymeric scaffold system after MI.

Pterostilbene inhibits lung cancer through induction of apoptosis.

BACKGROUND: Lung cancer remains the leading cause of cancer mortality in the United States. Resveratrol is a potent antioxidant found in grapes that inhibits several types of cancer, including lung cancer. Herein, we investigated the effects of pterostilbene, an analog of resveratrol found in blueberries, on lung cancer, in vitro. We hypothesized that pterostilbene would inhibit lung cancer cell growth in vitro by a pro-apoptotic mechanism. METHODS: Two lung cancer cell lines (NCI-H460 and SK-MES-1) were cultured using standard techniques. Cells were treated with increasing doses of pterostilbene (10-100 microM). Cell viability was measured at 24, 48, and 72h using a MTT assay. Apo-ONE Caspase-3/7 assay was used to evaluate caspase activity. T-test and two-way ANOVA were used for statistical analysis. RESULTS: Pterostilbene significantly decreased cell viability in lung cancer cells in a concentration- and time-dependent manner (P<0.001). Concentrations greater than 20 microM of pterostilbene produced significant growth inhibition by 72h (P<0.001). Apoptosis and caspase-3/7 activity were significantly increased by pterostilbene treatment (P<0.05). CONCLUSIONS: Pterostilbene inhibits growth via apoptosis induction in vitro. Further in vitro mechanistic studies and in vivo experiments are warranted to determine the potential role for pterostilbene in lung cancer treatment or prevention.

Pterostilbene inhibits breast cancer in vitro through mitochondrial depolarization and induction of caspase-dependent apoptosis.

BACKGROUND: Epidemiologic studies suggest that diets high in fruits and vegetables reduce cancer risk. Resveratrol, a compound present in grapes, has been shown to inhibit a variety of primary tumors. Pterostilbene, an analogue of resveratrol found in blueberries, has both antioxidant and antiproliferative properties. We hypothesized that pterostilbene would induce apoptosis and inhibit breast cancer cell growth in vitro. METHODS: Breast cancer cells were treated with graduated doses of pterostilbene. Cell viability was measured by MTT assay. Apoptosis was evaluated via DNA fragmentation assay and TUNEL assay. Apo-ONE caspase-3/7 assay was used to evaluate caspase activity. Flow cytometry was used to evaluate mitochondrial depolarization, superoxide formation, and cell cycle. Student's t-test and two-way ANOVA with Bonferroni posttests were utilized for statistical analysis. RESULTS: Pterostilbene decreased breast cancer cell viability in a concentration- and time-dependent manner. Pterostilbene treatment increased caspase-3/7 activity and apoptosis in both cell lines. Caspase-3/7 inhibitors completely reversed pterostilbene's effects on cell viability. Pterostilbene treatment triggered mitochondrial depolarization, increased superoxide anion, and caused alteration in cell cycle. CONCLUSIONS: Pterostilbene treatment inhibits the growth of breast cancer in vitro through caspase-dependent apoptosis. Mitochondrial membrane depolarization and increased superoxide anion may contribute to the activation downstream effector caspases. Caspase inhibition leads to complete reversal of pterostilbene's effect on cell viability. Further in vitro mechanistic studies and in vivo experiments are warranted to determine its potential for the treatment of breast cancer.

Peptide YY mediates inhibition of tumor growth and inflammation.

Peptide YY (PYY) orchestrates the functions of the gut and the pancreas by regulating growth, digestion and absorption. In addition to its physiological role, PYY exhibits immune and antitrophic properties in the pancreas by decreasing cytokine and amylase release. Although the exact mechanism(s) of action are still incompletely understood, PYY interacts at the acinar level with numerous intracellular transcription factors. In addition to ameliorating pancreatic inflammation, novel synthetic analogs of PYY have been developed that are potent inhibitors of pancreatic cancer proliferation, in vitro and in vivo. Additionally, PYY and its analogs have been shown to inhibit the growth of breast, esophagus, and gastric cancer in vitro. We, herein, plan to review some of the methods employed in the laboratory while investigating the utility of PYY in the treatment of inflammation and cancer.

Corn-derived carbohydrate inositol hexaphosphate inhibits Barrett's adenocarcinoma growth by pro-apoptotic mechanisms.

Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate that is found in food sources high in fiber content. IP6 has been reported to have significant inhibitory effects against a variety of primary tumors. We hypothesized that IP6 would inhibit the cell growth rate of Barrett's adenocarcinoma in vitro. Two Barrett's-associated adenocarcinoma cell lines, SEG-1 and BIC-1, were treated with IP6 at 0.5, 1.0 and 5.0 mM concentrations. Cell viability was measured by MTT assay. Apoptosis and necrosis were evaluated by the Annexin V FITC assay. Reductions (P<0.001) in cellular proliferation were observed in both cell lines. IP6 decreased late apoptosis and necrosis in BIC cells, whereas in SEG-1 cells, early apoptosis, late apoptosis and necrosis were all increased by IP6. IP6 decreases cellular growth by pro-apoptotic mechanisms. Our findings suggest that IP6 has the potential to become an effective adjunct for Barrett's adenocarcinoma. Further studies are needed to evaluate safety and clinical utility of this agent in patients with Barrett's adenocarcinoma.

Cystic pancreatic neoplasms: an emerging problem.

Widespread usage of advanced abdominal imaging has resulted in an increased finding of cystic lesions in the pancreas in asymptomatic patients. Greater than 90% of cystic pancreatic lesions are of inflammatory origin, the well-known pancreatic pseudocysts. The critical issue confronting specialists is differentiating inflammatory lesions from neoplastic lesions.

Thioredoxin-1 augments wound healing and promote angiogenesis in a murine ischemic full-thickness wound model.

BACKGROUND: Nonhealing wounds are a continuing health problem in the United States. Overproduction of reactive oxygen species is a major causative factor behind delayed wound healing. Previously we reported that thioredoxin-1 treatment could alleviate oxidative stress under ischemic conditions, such as myocardial infarction and hindlimb ischemia. In this study, we explored the potential for thioredoxin-1 gene therapy to effectively aid wound healing through improved angiogenesis in a murine ischemic wound model. METHODS: Full-thickness, cutaneous, ischemic wounds were created in the dorsum skin flap of 8- to 12-week-old CD1 mice. Nonischemic wounds created lateral to the ischemic skin flap served as internal controls. Mice with both ischemic wounds and nonischemic wounds were treated with Adeno-LacZ (1 × 109 pfu) or Adeno-thioredoxin-1 (1 × 109 pfu), injected intradermally around the wound. Digital imaging was performed on days 0, 3, 6, and 9 to assess the rate of wound closure. Tissue samples collected at predetermined time intervals were processed for immunohistochemical analysis. RESULTS: No significant differences in wound closure were identified among the nonischemic wounds control, nonischemic wounds-LacZ, and nonischemic wounds-thioredoxin-1 groups. Hence, only mice with ischemic wounds were further analyzed. The ischemic wounds-thioredoxin-1 group had significant improvement in wound closure on days 6 and 9 after surgery compared with the ischemic wounds control and ischemic wounds-LacZ groups. Immunohistochemical analysis indicated increased thioredoxin-1, vascular endothelial cell growth factor, and ß-catenin levels in the ischemic wounds-thioredoxin-1 group compared with the ischemic wounds control and ischemic wounds-LacZ groups, as well as increased capillary density and cell proliferation, as represented by Ki-67 staining. CONCLUSION: Taken together, thioredoxin-1 gene therapy promotes vascular endothelial cell growth factor signaling and re-epithelialization and activates wound closure in mice with ischemic wounds.

Disruption of VEGF Mediated Flk-1 Signaling Leads to a Gradual Loss of Vessel Health and Cardiac Function During Myocardial Infarction: Potential Therapy With Pellino-1.

Background The present study demonstrates that the ubiquitin E3 ligase, Pellino-1 (Peli1), is an important angiogenic molecule under the control of vascular endothelial growth factor (VEGF) receptor 2/Flk-1. We have previously reported increased survivability of ischemic skin flap tissue by adenovirus carrying Peli1 (Ad-Peli1) gene therapy in Flk-1+/- mice. Methods and Results Two separate experimental groups of mice were subjected to myocardial infarction ( MI ) followed by the immediate intramyocardial injection of adenovirus carrying LacZ (Ad-LacZ) (1×109 pfu) or Ad-Peli1 (1×109 pfu). Heart tissues were collected for analyses. Compared with wild-type ( WTMI ) mice, analysis revealed decreased expressions of Peli1, phosphorylated (p-)Flk-1, p-Akt, p- eNOS , p- MK 2, p-IκBα, and NF -κB and decreased vessel densities in Flk-1+/- mice subjected to MI (Flk-1+/- MI ). Mice ( CD 1) treated with Ad-Peli1 after the induction of MI showed increased ß-catenin translocation to the nucleus, connexin 43 expression, and phosphorylation of Akt, eNOS , MK 2, and IκBα, that was followed by increased vessel densities compared with the Ad-LacZ-treated group. Echocardiography conducted 30 days after surgery showed decreased function in the Flk1+/- MI group compared with WTMI , which was restored by Ad-Peli1 gene therapy. In addition, therapy with Ad-Peli1 stimulated angiogenic and arteriogenic responses in both CD 1 and Flk-1+/- mice following MI . Ad-Peli1 treatment attenuated cardiac fibrosis in Flk-1+/- MI mice. Similar positive results were observed in CD 1 mice subjected to MI after Ad-Peli1 therapy. Conclusion Our results show for the first time that Peli1 plays a unique role in salvaging impaired collateral blood vessel formation, diminishes fibrosis, and improves myocardial function, thereby offering clinical potential for therapies in humans to mend a damaged heart following MI .

PYY and the pancreas: inhibition of tumor growth and inflammation.

Peptide YY (PYY) orchestrates function of the gut and pancreas by regulating growth, digestion and absorption. In addition to its physiological role, PYY exhibits immune and antitrophic properties in the pancreas by decreasing cytokine and amylase release. Although the exact mechanism(s) of action are still not fully understood, PYY interacts at the acinar level with numerous intracellular transcription factors. In addition to ameliorating pancreatic inflammation, novel synthetic analogs of PYY have been developed that are potent inhibitors in the proliferation of pancreatic cancer. The present paper reviews our current findings with PYY and examines the therapeutic implications of its utility in treating inflammation and cancer.