Current Drug Targets (v.16, #3)

Meet the Editorial Board: by Chen Chen (179-179).

Cardiovascular Complications in Inflammatory Bowel Disease by Rudolf Schicho, Gunther Marsche, Martin Storr (181-188).
Over the past years, a growing number of studies have indicated that patients suffering from inflammatory bowel disease (IBD) have an increased risk of developing cardiovascular disease. Both are chronic inflammatory diseases and share certain pathophysiological mechanisms that may influence each other. High levels of cytokines, C-reactive protein (CRP), and homocysteine in IBD patients may lead to endothelial dysfunction, an early sign of atherosclerosis. IBD patients, in general, do not show the typical risk factors for cardiovascular disease but changes in lipid profiles similar to the ones seen in cardiovascular events have been reported recently. Higher levels of coagulation factors frequently occur in IBD which may predispose to arterial thromboembolic events. Finally, the gut itself may have an impact on atherogenesis during IBD through its microbiota. Microbial products are released from the inflamed mucosa into the circulation through a leaky barrier. The induced rise in proinflammatory cytokines could contribute to endothelial damage, artherosclerosis and cardiovascular events. Although large retrospective studies favor a link between IBD and cardiovascular diseases, the mechanisms behind still remain to be determined.

Gastrointestinal disorders are frequently accompanied by symptoms exceeding gastrointestinal tract. This is at least partially connected with the involvement of autonomic nervous system in pathophysiology of diseases such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) or spectrum of motility disorders. In light of the above, involvement of cardiovascular system in natural history of gastrointestinal disorders seems to be of interest. On the other hand, available data regarding the prevalence of cardiac rhythm disturbances in IBD, IBS and motility disorders is limited. What is more, pharmacotherapy of the mentioned diseases includes drugs with possible arrhythmogenic potential. In this review we present current experiences and observations concerning gastrointestinal disorders and cardiac rhythm disturbances.

Prevention and Therapeutic Strategies of Thromboembolic Events in Patients with Inflammatory Bowel Diseases: A Report of Three Cases by Marcin Wlodarczyk, Aleksandra Sobolewska, Jakub Fichna, Maria Wisniewska-Jarosinska (194-198).
Crohn's disease and ulcerative colitis belong to a group of inflammatory bowel diseases (IBD). IBD are characterized by a chronic character of inflammatory process and overlapping immunological abnormalities, which, along with therapeutic strategies are currently available, underlie an increased risk of venous thromboembolic events (VTE). The most common sites of VTE in IBD patients are deep venous thrombosis (DVT) and pulmonary embolism (PE). These complications are particularly important in clinical practice due to a very high mortality rate. Therefore, an early diagnosis of new IBD cases and the control of inflammatory process are thought to play a crucial role in risk reduction for thromboembolic events. Despite considerable evidence supporting the association between IBD and VTE, there is still a lack of recognition of this risk, with dangerous consequences for patients. In this paper authors report three cases of VTE in IBD patients and discuss the most relevant clinical studies found in MEDLINE, Cochrane Library and EMBASE regarding its prevention and management.

Intestinal Microbiota: A Regulator of Intestinal Inflammation and Cardiac Ischemia? by Mohammad Bashashati, Hamid R. Habibi, Ali Keshavarzian, Max Schmulson, Keith A. Sharkey (199-208).
Inflammatory bowel diseases (IBD) are chronic, relapsing and remitting gastrointestinal (GI) disorders of unknown etiology. IBD patients commonly exhibit extra-intestinal manifestations and complications of an inflammatory nature, presenting with disorders such as ankylosing spondylitis, uveitis and vasculitis. Although the metabolic syndrome is less prevalent in patients with IBD, they are at an increased risk for atherosclerosis and cardiovascular events. Considerable evidence supports the role of GI microbiota in the development of IBD. Recent studies have also shown a significant interaction between the metabolites of gut microbiota and the development of cardiovascular disease. Here we hypothesize that dysbiosis and/or abnormalities in the function of the intestinal microbiota promote cardiovascular disease in IBD patients, explaining the increased risk of cardiovascular events in these patients.

Ischemic Colitis: Current Diagnosis and Treatment by Paula Mosinska, Jakub Fichna (209-218).
Ischemic colitis (CI) is a common form of ischemic injury, which evolves as a consequence of decreased arterial blood flow to the colon. In general, CI is attributed to an elderly with multiple comorbidities; however, it may also occur in young or middle-aged individuals. The etiology of CI is multifactorial and the clinical presentation varies upon the severity of deprivation of the intestinal blood flow, and the development of the microvasculature plexus. Multiple case reports have associations with medications, vascular disorders, pathogens and hematologic diseases. Occlusive and nonocclusive diseases are the major mechanisms, which are simultaneously the causative factor of intestinal ischemia. In this review, we discuss major factors predisposing to occurrence of CI and analyze the mechanisms of action of several classes of medications currently used. We also suggest possible therapies and discuss the latest reports, which may lead to the discovery of novel pharmacological targets for future anti-CI drugs to be used in the clinical treatment.

Platelet Activity in the Pathophysiology of Inflammatory Bowel Diseases by Chunqiu Chen, Yongyu Li, Zhen Yu, Zhanju Liu, Yanhong Shi, Urszula Lewandowska, Marta Sobczak, Jakub Fichna, Martin Kreis (219-225).
Platelets play a crucial role in immune responses. Impaired platelet activation may cause persistent mucosal inflammation through P-selectin, CD40-CD40L and other systems influencing granulocytes, macrophages or endothelial cells. Pharmacological regulation of platelet activation may reduce thromboembolism and limit the interaction of platelets with endothelial and inflammatory cells, in turn weakening the inflammatory responses. In this review we focus on pathophysiological activities of platelets in inflammatory bowel diseases and discuss the studies on currently available anti-platelet therapies in the treatment of gastrointestinal inflammation. Finally, we provide a prospective view to new anti-platelet agents currently under development.

T Cell-Activated Signaling Pathways and Locally Produced Cytokines as Potential Targets in Celiac Disease by Aleksandra Piechota-Polanczyk, Maciej Salaga, Ihor Huk (226-232).
Celiac disease (CD) is an autoimmune disease induced by an autoimmune reaction to indigested gluten, which occurs in genetically predisposed population. The etiology of CD is linked to innate and adaptive immunity, mostly mediated by lymphocytes, especially T cells, infiltrating into the small intestinal wall. The subpopulations of T cells that infiltrate inflamed intestinal tissues comprise various CD4+ T cells and CD8+ T cells. The plethora of T cell subtypes activated in CD leads to simultaneous activation of different signaling cascades including GATA1, NF-kB, JAK or STAT5 the activity of which may be modified by diet or drugs. It was recently showed that food allergens may accelerate CD by altering the interaction between IL-15 and CD4+ T cells in the activation of CD8+ T cells. Increased levels of cytokines like IL-15 are considered to play a role in CD development. Furthermore it was showed that some drugs like tofacitinib or ruxolitinib may influence CD by blocking IL-15 signaling and CD8+ T cell activity. This mini-review will summarize the current knowledge on the role of CD4+ T cell and CD8+ T cell in clinical and experimental CD and will describe how T cell-activated signaling pathways and locally released proteins may be influenced by dietary factors and drugs used in CD treatment.

In recent years, intracellular signal transduction via RAS-RAF-MEK-ERK has been successfully targeted in new treatment approaches for melanoma using small molecule inhibitors against activated BRAF (V600E mutation) and activated MEK1/2. Also mutated c-KIT has been identified as a promising target. Meanwhile, evidence has been provided that combinations between BRAF inhibitors and MEK1/2 inhibitors are more promising than single-agent treatments. Moreover, new treatment algorithms favor sequential treatment using BRAF inhibitors and newly developed immunotherapies targeting common T lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1). In depth molecular analyses have uncovered new mechanisms of treatment resistance and recurrence, which may impact on future treatment decisions. Moreover, next-generation sequencing data have shown that recurrent lesions harbor specific genetic aberrations. At the same time, high throughput sequencing studies of melanoma unraveled a series of new treatment candidates for future treatment approaches such as ERBB4, GRIN2A, GRM3, and RAC1. More recent bioinformatic technologies provided genetic evidence for extensive tumor heterogeneity and tumor clonality of solid tumors, which might also be of relevance for melanoma. However, these technologies have not yet been applied to this tumor. In this review, an overview on the genetic basis of current treatment of melanoma, treatment resistance and recurrences including new treatment perspectives based on recent high-throughput sequencing data is provided. Moreover, future aspects of individualized treatment based on each patient's individual mutational landscape are discussed.

Cancer represents a major health problem worldwide, therefore on the basis of current research results constantly more effective therapeutic strategies are expected. Chronic, unchecked inflammation has widely been suggested to trigger carcinogenesis. The innate immune system ensures a first line host defense in which the inflammasome is essential maintaining a delicate balance betweeen pro- and anti-inflammatory signals in order to generate an appropriate immune response without harming the host. Studies have revealed a remarkable, but contradictory link of host inflammatory responses to tumorigenesis. Indeed, activation of the multiprotein complex inflammasome by danger signals seems to play diverse and sometimes conflicting, suppressive or stimulatory role in cancer development and progression with a significant context-dependency. The pleitropic inflammasomes may act at cellautonomous level to eliminate malignant cells via the programmed cell death type of inflammatory pyroptosis, but on the contrary, may favor the production of gowth and trophic factors for tumor cells and their microenvironment. Further, upon caspase-1 activation the inflammasome can provoke sterile inflammation, and thus facilitate carcinogenesis, though in antigen- presenting cells it can elicit anti-tumor immune responses. Clarifying the exact, context-specific impact of inflammasomes on tumorigenesis represents a new research area with the potential to introduce promising novel targets for cancer therapeutics.

Hedgehog Signaling and Urological Cancers by Katsumi Shigemura, Masato Fujisawa (258-271).
Hedgehog (Hh) signaling is aberrantly activated in several hematological and solid cancers. Therapeutic options are sometimes lacking for urological cancers because their mechanisms of progression are imperfectly understood. Studies establishing the anti-tumor effects and safety of inhibitors of Hh pathways are needed for tumors in which the Hh pathways are activated. At present vismodegib is clinically available for basal cell carcinoma, and is expected to be extended to treat other cancers. Cholecalciferol, the precursor of active vitamin D3, is a strong inhibitor of Shh-Gli signaling and may have growth inhibitory effects in renal cancer. As a supplementary therapy it may promote tumor regression. Preclinical data in prostate cancer suggest that while suppressing Hh signaling could reduce invasion and metastasis, it may also result in acquired drug resistance after long-term use. Combining Hh inhibitors with ionizing radiation and/or chemotherapy could improve treatment while lessening the risk of acquired drug resistance. Expression of Shhrelated ligand gene and Shh-Gli-inducible target genes like FOXM1 or IGF2 is characteristic of urothelial tumor samples. Overexpression of Shh is observed in 96% of non-muscle invasive bladder cancer and 52% of muscle invasive bladder cancer samples. This review summarizes recently reported trends in Hh signaling activation studies in urological cancer, especially focusing on possible clinical applications.

Neisseria gonorrhoeae is a common causative microorganism of male urethritis. The most important problem with this infectious disease is antibiotic resistance. For instance, in the 1980's-1990's, most studies showed almost 100 % susceptibility of N. gonorrhoeae to the representative cephalosporins, cefixime and cefpodoxime. By the late 1990s, the reported susceptibility decreased to 93.3-100 % and further decreased to 82.9-100 % in the early 2000's. However, reported susceptibility was revived to 95.8-100 % in the late 2000's to 2010's. The susceptibility of N. gonorrhoeae to penicillins varied in different countries and regions. A 2002 Japanese study showed a resistance ratio of about 30% and while Laos, China and Korea showed 80-100 % resistance. Fluoroquinolones have shown a dramatic change in their effect on N. gonorrhoeae. In the early 1990's, 0.3-1.3 % of N. gonorrhoeae showed low susceptibility or resistance to ciprofloxacin in the US but this figure jumped to 9.5 % by 1999. In Asia, N. gonorrhoeae ciprofloxacin resistance or lower susceptibility was about 80-90 % in the early 2000's and this trend continues to the present day. Azithromycin is currently the possible last weapon for N. gonorrhoeae treatment per oral administration. The susceptibility of N. gonorrhoeae to azithromycin was 100 % in Indonesia in 2004 and the latest study from Germany showed 6 % resistance in strains from 2010-2011. This review summarizes the history and epidemiology of N. gonorrhoeae antibiotic susceptibilities, for which the most frequently used antibiotics vary between countries or regions.