Current Pharmaceutical Design - Volume 20, Issue 7, 2014

In this article we review the role of vascular endothelial growth factor (VEGF) in colon cancer growth and the underlying mechanisms. Angiogenesis, the growth of new capillary blood vessels in the body, is critical for tissue injury healing and cancer growth. In 1971, Judah Folkman proposed the concept that tumor growth beyond 2 mm is critically dependent on angiogenesis. Tumors including colon cancers release angiogenic growth factors that stimulate blood vessels to grow into the tumors thus providing oxygen and nutrients that enable exponential growth. VEGF is the most potent angiogenic growth factor. Several studies have highlighted the role of VEGF in colon cancer, specifically in the stimulation of angiogenesis. This role of VEGF is strongly supported by studies showing that inhibition of VEGF using the blocking antibody, bevacizumab, results in decreased angiogenesis and abrogation of cancer growth. In the United States, bevacizumab in combination with chemotherapy is FDA approved for the treatment of metastatic colon cancer. However, the source of VEGF in colon cancer tissue, the mechanisms of VEGF generation in colon cancer cells and the molecular pathways involved in VEGF mediated angiogenesis in colon cancer are not fully known. The possibility that VEGF directly stimulates cancer cell growth in an autocrine manner has not been explored in depth.

Glucocorticoids may have dual action on the gastric mucosa: gastroprotective and ulcerogenic. In this article, we review the data which suggested that an initial action of endogenous glucocorticoids, including stress-produced ones as well as exogenous glucocorticoids is gastroprotective and consider possible mechanisms of the conversion of physiological gastroprotective action of glucocorticoid hormones to their pathological ulcerogenic effect.

The intestinal inflammation caused by intestinal ischemia reperfusion during acute pancreatitis (AP) often leads to multiple organ dysfunction and aggravation of acute pancreatitis. This review concerns up-date progress of the pathophysiology and molecular mechanism of the excessive production of gut-derived cytokines. The regulation effects of immuno-neuro-endocrine network for pancreatic necrosis are the basis for pharmacological therapeutic in AP. The translation from basic research to clinical trials for the prevention or treatment of severe acute pancreatitis (SAP) is of great value. Early enteral nutrition is necessary for the restitution, proliferation, and differentiation of the intestinal epithelial cells adjacent to the wounded area. Clearance of the excess intestinal bacteria and supplement of probiotics may be helpful to prevent bacterial translocation and infection of pancreas.

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The two main forms of IBD are Crohn's disease and ulcerative colitis. According to the recent concept the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction and the change in microbial flora. Environmental factors, such as changes in diet, antibiotic use, smoking or improved domestic hygiene (e.g. eradication of intestinal helminths) probably contribute to the development and increased prevalence of IBD. Dysregulation of mucosal immunity in IBD causes an overproduction of inflammatory cytokines which resulted in uncontrolled intestinal inflammation. Based on extensive research over the last decade, besides the conventional therapy, there are several novel pathways and specific targets, on which focus new therapeutics. New therapeutics aim 1./ to correct genetic susceptibility by stimulating NOD2 expression, TLR3 signaling or inhibition of TLR4 pathway, 2./ to restore the immune dysregulation by inhibition of pro-inflammatory cytokines (TNF-α, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-γ ), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN-β-1a), 3./ to restore mucosal barrier function and stimulate mucosal healing by different growth factors, such as GH, EGF, KGF, TGF-β, VEGF, 4./ to restore the normal bacterial flora by antibiotics, probiotics. However, in spite of these numerous potential targets, the true value and clinical significance of most of the new biologics and molecules are not clear yet.

Ulcerative colitis (UC) and Crohn’s disease (CD) constitute the two major groups of idiopathic disorders in inflammatory bowel disease (IBD). Environmental factors, genetic factors and immune responses have been considered as the major etiology of IBD. Despite the diversified pathogenesis of the disease, no guaranteed curative therapeutic regimen has been developed so far. This review summarizes the knowledge on the pathophysiology and current treatment approaches of IBD. Since IBD is caused by excessive and tissue- disruptive inflammatory reactions of the gut wall, down-regulation of the immune responses may allow the damaged mucosa to heal and reset the physiological functions of the gut back to normal. Current pharmacotherapy through modulation of neutrophil-derived factors, cytokines, adhesion molecules and reactive oxygen/nitrogen metabolites has been utterly described. Categories of treatment modalities include corticosteroids, aminosalicylates, immunomodulators, antibiotics, probiotics, and a series of unique novel agents. The use of anti-tumor necrosis factor monoclonal antibody (Infliximab), recombinant anti-inflammatory cytokines and related gene therapy has been covered. In addition, discussions on dietary supplementation and heparin treatment are also included. The anti-inflammatory and immunoregulatory potential of investigational agents such as nicotine and the filtered protective compounds from tobacco smoke, as well as active herbal medicinal compounds were tested in our previous experimental works, whereas promising findings have been presented here. With the discovery of novel target-oriented agents, more effective and relatively harmless approaches of IBD therapy could be established to achieve a curative outcome. Indeed, more experimental and clinical studies are needed to confirm the relevance of these therapies.

In addition to eradication of Helicobacter pylori, chemotherapy with anticancer agents, and radiation therapy, the treatment with molecular target drugs including rituximab, a CD20 antagonist, is one of the promising new regimens. The mucosa-associated lymphoid tissue (MALT) lymphoma is histologically characterized by rich distribution of the microvascular network consisting of the immature capillaries, lymphatics and venules, and this microvascular network could be the target of the new pharmacotherapy in addition to the direct action on the accumulated B lymphocytes. We have established the animal model of the gastric MALT lymphoma by the Helicobacter heilmannii (H. heilmannii) peroral infection of C57BL/6 mice. The disease induced by this model is very similar to the human counterpart, because of the lymphoepithelial lesion characteristic of the human MALT lymphoma as well as the rich vascularization and localization of vascular endothelial growth factor (VEGF) and its receptors, Flt-1, Flk-1 and Flt-4. By administering VEGF receptor antibodies or celecoxib, one of the cyclooxygenase 2 inhibitors, we were able to induce a significant decrease in the size of the tumor and the apoptotic changes of the endothelial cells of the microvascular network. These antiangiogenic strategies were suggested to be candidates for the new pharmacological treatment of gastric MALT lymphoma, when other treatments are not effective.

The pancreas and salivary glands have similar anatomical structures and physiological functions producing bicarbonate-rich fluid containing digestive enzymes and other components to be delivered into the gut. Despite these similarities, the two organs are also different in numerous respects, especially regarding the inflammatory diseases affecting them. This article will summarize the pathophysiology and current and potential pharmacological treatments of chronic inflammatory diseases such as chronic pancreatitis, autoimmune pancreatitis, Sjögren's syndrome and irradiation-induced salivary gland atrophy. Despite the differences, in both organs the inflammatory process is accompanied by epithelial tissue destruction and fibrosis. Both in pancreatic and in salivary research, an important task is to stop or even reverse this process. The utilization of stem/progenitor cell populations previously identified in these organs and the application of mesenchymal stem cells are very promising for such regenerative purposes. In addition, gene therapy and tissue engineering research progressively advance and have already yielded clinically beneficial preliminary results for salivary gland diseases. For the hard-to-access, hard-to-regenerate pancreas these developments may also offer new solutions, especially since salivary and pancreatic progenitors are very similar in characteristics and may be mutually useful to regenerate the respective other organ as well. These novel developments could be of great significance and may bring new hope for patients since currently used therapeutic protocols in salivary and in pancreatic chronic inflammatory diseases offer primarily symptomatic treatments and limited beneficial outcome.

This review focuses on the described effects of BPC 157 on blood vessels after different types of damage, and elucidate by investigating different aspects of vascular response to injury (endothelium damage, clotting, thrombosis, vasoconstriction, vasodilatation, vasculoneogenesis and edema formation) especially in connection to the healing processes. In this respect, BPC 157 was concluded to be the most potent angiomodulatory agent, acting through different vasoactive pathways and systems (e.g. NO, VEGF, FAK) and leading to optimization of the vascular response followed, as it has to be expected, by optimization of the healing process. Formation of new blood vessels involves two main, partly overlapping mechanisms, angiogenesis and vasculogenesis. The additional mechanism of arteriogenesis is involved in the formation of collaterals. In conjunction with blood vessel function, we at least have to consider leakage of fluid/proteins/plasma, resulting in edema/exudate formation as well as thrombogenesis. Blood vessels are also strongly involved in tumor biology. In this aspect, we have neoangiogenesis resulting in pathological vascularization, vascular invasion resulting in release of metastatic cells and the phenomenon of homing resulting in formation of secondary tumors – metastases.

We reviewed stable gastric pentadecapeptide BPC 157-NO-system-relation, its close participation in Moncada's (maintained vascular integrity, platelets control) homeostatic healing response of NO-system to injury. Namely, BPC 157’s particular healing effect also affects all events after vascular integrity loss (dependent on circumstances, it reduces either thrombosis (abdominal aorta anastomosis) or bleeding/thrombocytopenia (amputation, heparin, warfarin, aspirin)) and in a series of different injurious models, acute and chronic, BPC 157 consistently advances healing after severe injuries in various tissues spontaneously unable to heal; stimulates egr-1 and naB2 genes; exhibits high safety (LD1 not achieved)). Hypothesis, that BPC 157 (since formed constitutively in the gastric mucosa, stable in human gastric juice, along with significance of NO-synthase and the basal formation of NO in stomach mucosa, greater than that seen in other tissues) exhibits a general, effective competing both with L-arginine analogues (i. e., L-NAME) and L-arginine, and that this has some physiologic importance (NO-generation), later, practically supports its beneficial effects illustrating BPC 157 and NOsystem mutual (with L-NAME/L-arginine; alone and together) relations in (i) gastric mucosa and mucosal protection, following alcohol lesions, in cytoprotection course, NO-generation, and blood pressure regulation; (ii) alcohol acute/chronic intoxication, and withdrawal; (iii) cardiovascular disturbances, chronic heart failure, pulmonary hypertension, and arrhythmias; (iv) disturbances after hypokalemia and hyperkalemia, and potassium-cell membrane dysfunction; and finally, in (v) complex healing failure, proved by the fistulas healing, colocutaneous and esophagocutaneous. However, how this advantage of modulating NO-system (i. e., particular effect on eNOS gene), may be practically translated into an enhanced clinical performance remains to be determined.

Skin and gut represent physical and immunological barriers between internal and external environment. Some affections involving the intestine, such as celiac disease, are reported to be associated with several different cutaneous diseases, like dermatitis herpetiforme or psoriasis. This could be better explained if gut and skin are taken as complex structures that share physio-pathological and immunological aspects. As a proof, we present the case of a woman affected by celiac disease who presented with three different skin manifestations strongly related in terms of onset, response to therapy and improvement during gluten-free diet.

We set up two models of gastric bleeding in rats using low-dose aspirin (ASA) and the antiplatelet drug clopidogrel, a P2Y12 receptor antagonist, and examined the effect of antiulcer drugs on gastric bleeding and ulcerogenic responses under such conditions. Under urethane anesthesia, two catheters were inserted into the rat stomach, one from the esophagus and another through the pylorus via an incision in the duodenum. In the first model, the stomach was perfused with 25 mM ASA dissolved in 50 mM HCl using an infusion pump, and gastric bleeding was measured as the hemoglobin concentration in perfusate collected every 15 min. In the second model, the stomach was perfused with ASA under stimulation of acid secretion by a continuous i.v. infusion of histamine (8 mg/kg/hr). Clopidogrel (30 mg/kg) was given p.o. 24 h before the ASA perfusion, while antiulcer drugs were given i.d. or i.v. 30 min before. Perfusion of the stomach with acidified ASA or ASA under histamine-stimulated acid secretion caused minimal bleeding in the stomach with few lesions. The ulcerogenic and bleeding responses to ASA under these conditions were markedly aggravated by pretreatment with clopidogrel, which by itself provoked neither bleeding nor damage. Antiulcer drugs, such as prostaglandin E2, irsogladine, rebamipide and teprenone, reduced the severity of gastric bleeding and damage in response to ASA plus clopidogrel in the presence of both exogenous and endogenous acid. In contrast, antisecretory drugs such as a proton pump inhibitor and histamine H2 receptor antagonists markedly suppressed the gastric bleeding and lesion responses to ASA plus clopidogrel under histamine-stimulated acid secretion, but had no effect on the responses to acidified ASA plus clopidogrel. These results suggest that clopidogrel increases gastric bleeding induced by ASA and that antiulcer drugs are useful for preventing gastric bleeding caused by the dual antiplatelet therapy.

A growing body of experimental and clinical evidence supports the hypothesis that the intestinal microbiota markedly influences function and the structure of the mucosal lining. Intestinal microbiota can potentially cause damage to the mucosa either directly by releasing toxins or indirectly by causing a detrimental immune response. Probiotic bacteria have been defined as live microorganisms, which when consumed in adequate amounts, confer a health benefit for the host. In recent years, the therapeutic and preventive application of probiotics for several gastrointestinal and liver disorders has received increasing attention. Probiotics appear to be beneficial for premature infants who suffer necrotizing enterocolitis. The effectiveness of certain probiotics as treatment for infectious and antibioticassociated diarrhea in adults and for allergic disorders in children has been supported by clinical studies; however, the potential mechanism( s) remains to be studied. Experimental studies and clinical trials for probiotic treatment of inflammatory bowel diseases (IBD) have yielded conflicting results. Daily intake of selected probiotics was effective in the prevention of ulcerative colitis and the attenuation of the active onset of Crohn’s disease or ulcerative colitis but others failed to show a beneficial effect. The combination of Lactobacillus, Bifidobacterium, Saccharomyces boulardi and the treatment with Escherichia coli Nissle were found beneficial in inducing and maintaining remission of disease activity of gut inflammation and moderately severe ulcerative colitis. Probiotic bacteria were considered in some studies as a safe adjuvant when added to triple eradication therapy against the symptoms induced by the major gastric pathogen, Helicobacter pylori. This review attempted to overview these new exciting advances in the role of these microbes in the pathogenesis, management and treatment of gastrointestinal disorders.

Aims: The aims of this study were to determine a mechanism and general timeline for statin related anti-inflammatory activity. Methods: Healthy male subjects received rosuvastatin (20 mg daily) for 3 weeks. Blood samples before and after treatment were collected for clinical laboratories and research procedures. Toll-like receptor-4 (tlr-4) expression on blood monocytes was measured using flow cytometry before and after rosuvastatin treatment. Inflammatory molecules were measured before and after rosuvastatin and after blood samples were incubated for 3 hours with or without lipopolysaccharide. Plasma was collected and analyzed for IL-6, TNF-α, IL-8, IGF-1, and sCD14. Comparisons were made using Mann-Whitney rank sum test and paired Student’s t-test with significance defined as p≤0.05. Key findings: The expression oftlr-4on blood monocytes was significantly lower after 3 weeks of rosuvastatin (p = 0.046). Consistent with the reduced expression of tlr-4, the TNF-α release from blood receiving LPS trended lower (p = 0.08). None of the other inflammatory markers (IL-8, sCD14, IL-6, IGF-1, C-reactive protein) were modified with rosuvastatin treatment. There were significant declines in total cholesterol (p<0.0001), low-density lipoprotein cholesterol (LDL-C) (p<0.0001), and total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio (p<0.0001) after 3 weeks of treatment. There was no significant effect on triglycerides, very low-density lipoprotein cholesterol (VLDL-C), or HDL-C. Significance: The decline in tlr-4 expression on blood monocytes and TNF-α plasma concentrations after 3 weeks of rosuvastatin treatment suggest a potential mechanism for the anti-inflammatory activity of rosuvastatin.

Background and Aims: Polyphenolic acetates (PAs) have antioxidant/ pro-oxidant properties and can also acetylate proteins (enzymes) by a novel acetoxy drug: calreticulin transacetylase acetylation system. While PAs have been investigated as pharmacological agents for the treatment of various diseases, their potential as anti-cancer agents or their efficacy as an adjuvant in anti-cancer therapeutics remains to be explored. In the present study we investigated the cytotoxic and radio-sensitizing effects of 7, 8- diacetoxy-4-methyl coumarin (DAMC) and 7- acetoxy-4-methyl coumarin (7-AMC) in a human glioma cell line (BMG-1). Methods: Cytotoxic and radio-sensitizing effects were investigated by studying reactive oxygen species (ROS) levels, metabolic viability, clonogenic survival, growth inhibition, cell cycle perturbation, DNA repair and cytogenetic damage, besides analyzing the histone (H3) acetylation. Results: Exposure of cells to DAMC and 7-AMC for 24 h showed a dose dependent increase in toxicity as indicated by reduced metabolic viability, clonogenic survival and cell proliferation, with DAMC being more toxic than 7-AMC. The degree of radiosensitization by DAMC was also higher as compared to 7-AMC as reflected by a decrease in the clonogenicity, enhanced radiation-induced cell cycle perturbation and apoptosis. DAMC impaired the removal of radiation-induced DNA double stranded breaks (measured by γH2AX immuno- fluorescence) and enhanced the cytogenetic damage (micronuclei formation), leading to an increase in mitotic death. While DAMC alone induced pan nuclear γH2AX fluorescence, both pan nuclear and spatially restricted foci was observed with the combined treatment (DAMC + Radiation) suggesting a complex nature of DNA damage and repair. DAMC- induced cytotoxic and radio-sensitizing effects were independent of its pro-oxidant activity, whereas histone H3 lysine (9/14) hyperacetylation appeared to be a potential target, regulating cellular responses to ionizing radiation (IR). Conclusions: The polyphenolic acetate 7, 8- diacetoxy-4-methyl coumarin (DAMC) demonstrates both anticancer effects and radiosensitizing potential under in vitro conditions.