Current Pharmaceutical Design - Volume 22, Issue 30, 2016

Background: Cardiorenal syndrome (CRS) is the term used to describe a complex disorder of the heart and kidneys, in which acute or chronic dysfunction of one organ initiates and perpetuates disease in the other. CRS is recognized as an important clinical condition that is increasingly becoming a major public health problem due to the high associated morbidity and mortality rates. Methods: This review discusses current understanding of the pathogenetic pathways involved in CRS and future therapeutic implications of such pathways for patients. Results: Multiple pathophysiological pathways are implicated in CRS, complicating the pathogenic features of this disease. Regarding hemodynamic factors, accumulating evidence now suggests that the importance of renal blood flow reduction as a mediator of CRS is limited and that increased venous pressure seems to be more crucial. Other non-hemodynamic mechanisms such as the renin-angiotensin system, sympathetic nervous system, oxidative stress, inflammation, anemia, and obesity have also been implicated in the pathogenesis of CRS and could play important roles in the clinical disease course. It is likely that several of these mechanisms operate simultaneously and that the relative importance of each mechanism differs among patients and clinical situations. However, despite the growing bank of experimental and clinical data, knowledge about the underlying pathophysiology of CRS remains limited as do the current therapeutic options. Conclusion: CRS is an important clinical condition that can be complicated by multiple pathophysiological mechanisms. Consequently, the underlying pathophysiology of CRS remains ill-defined and current therapeutic options for CRS patients have limitations. Ongoing studies and the emerging research fields such as epigenetics are expected to reconcile the multiple pathogenetic pathways at play in CRS and lead to the development of novel and more effective therapeutic approaches.

Background: Over the last decades, the reduction of the mortality and morbidity of stroke has been a high- priority objective worldwide. Statins, or 3-hydroxy-3- methylglutaryl coenzyme A (HMG- CoA) reductase inhibitors, have emerged as the predominant preventive strat egy to tackle the worldwide stroke burden. Currently, statins are considered the most important advance in stroke prevention since the introduction of aspirin and antihypertensive treatments. Methods: In this paper we review the current evidence regarding the role of statins in the stroke prevention and future directions in this field. Results: A meta-analysis of random ised trials of statins has shown that each 1 mmol/L (39 mg/dL) decrease in low-density lipoprotein cholesterol, equates to a reduction in relative risk for stroke of 21.1%. Statins are now recommended for the primary prevention of ischemic stroke in patients estimated to have a high 10-year risk for cardiovascular events. Nevertheless, until recently there was little evidence that statin therapy reduced the risk of stroke recurrence. The SPARCL, published in 2006, was the first trial to show the benefits of statin therapy in preventing recurrent stroke. Now we know that statins reduce the risk of stroke recurrence by 12-16% and statins are recommended among patients with ischemic stroke or TIA presumed to be of atherosclerotic origin or with other comorbid atherosclerotic cardiovascular disease. Conclusion: Traditionally, there has been no clear data demonstrating that adding other lipid-modifying drugs to statins results in a further decrease in stroke or other cardiovascular event, but now things have changed and future directions include combinations with ezetimibe and new treatments such as PCSK9 inhibitors. Only time will tell the real roll of these new promising non-statin lipidmodifying therapies on stroke prevention.

Background: The intestinal barrier is a layer that constitutes the most important barrier against the external environment. It can be partially disrupted in several frequent scenarios, leading to autoimmune and inflammatory diseases. Translocation of intestinal luminal contents into the intestinal mucosa may induce inflammatory disorders and therefore tissue injuries. Disruption of the intestinal barrier may induce local and systemic injuries and may play a role in inflammatory bowel disease, liver diseases, the aging process and in the systemic inflammatory response syndrome, including lung, heart and brain dysfunctions. Conclusion: Here, we discuss how the maintenance of it selectively permeability is crucial to adequate absorption of nutrients, electrolytes and water while maintaining effective host defense properties in order to avoid intestinal injury, systemic inflammation and distant organ damage.

Background: Ischemia reperfusion injury is an important pathophysiological process in many fields such as transplantation, stroke, atherosclerosis, trauma and myocardial infarction. Recent advances in gene silencing may help to reduce ischemic effects, targeting molecules related to this pathological process. Methods and results: Here, we review the different silencing approaches in ischemic injury, highlighting the role of co-stimulatory molecules in renal transplantation. Conclusion: Gene silencing appears as a new strategy to prevent the inflammation and injury associated with ischemia.

In the last decades, many factors thought to be associated with the atherosclerotic process and cardiovascular events have been studied, and some of these have been shown to correlate with clinical outcome, such as arterial stiffness, endothelial dysfunction and immunoinflammatory markers. Arterial stiffness is an important surrogate marker that describes the capability of an artery to expand and contract in response to pressure changes. It can be assessed with different techniques, such as the evaluation of PWV and AIx. It is related to central systolic pressure and it is an independent predictor of cardiovascular morbidity and mortality in hypertensive patients, type 2 diabetes, end-stage renal disease and in elderly populations. The endothelium has emerged as the key regulator of vascular homeostasis, in fact, it has not merely a barrier function but also acts as an active signal transducer for circulating influences that modify the vessel wall phenotype. When its function is lost, it predisposes the vasculature to vasoconstriction, leukocyte adherence, platelet activation, thrombosis and atherosclerosis. Non-invasive methods were developed to evaluate endothelial function, such as the assesment of FMD, L-FMC and RHI. Moreover in the last years, a large number of studies have clarified the role of inflammation and the underlying cellular and molecular mechanisms that contribute to atherogenesis. For clinical purposes, the most promising inflammatory biomarker appears to be CRP and a variety of population-based studies have showed that baseline CRP levels predict future cardiovascular events. Each of the markers listed above has its importance from the pathophysiological and clinical point of view, and those can also be good therapeutic targets. However, it must be stressed that assessments of these vascular markers are not mutually exclusive, but rather complementary and those can offer different views of the same pathology. The purpose of this review is to analyze the role of arterial stiffness, endothelial dysfunction and immunoinflammatory markers as surrogate endpoint, assessing the correlations between these markers and evaluating the therapeutic perspectives that these offer.

Background: IgG4-related disease is a rare, clinical and pathologic disease entity of unknown etiology. Its main features are increased serum concentrations of IgG4 > 1,35 g/l, lymphocyte and IgG4+plasma-cell infiltration within tissues, fibrosis or sclerosis. The classical presentation of IgG4-RSD is pancreatitis which is combined with the involvement of biliary ducts in 74 percent of patients. Extrapancreatic manifestations include: abdominal or mediastinal lymphadenopathy; the involvement of salivary glands and lacrimal glands, kidneys, lung, retroperitoneum. Since IgG4-related disease is a multiorgan lymphoproliferative syndrome, it requires a careful differential diagnosis from other distinct disorders (sarcoidosis, immune rheumatic diseases, hematologic diseases, malignancies). Another distinctive feature is a fairly fast response to steroids, that represents the first-choice therapy. Immunosuppressant drugs (azathioprine, mycophenolate mofetil, methotrexate) might be chosen as glucocorticoid-sparing medications or to maintain steroid-induced remission (Fig. 1). Methods: We report the case of a 70-year-old man and we performed a brief review of loiterature. Results: Our patient has a clinical history including bronchial asthma, aortic aneurysm, histologically confirmed retroperitoneal fibrosis causing hydroureteronephrosis, prostatitis, interstitial pulmonary fibrosis, sclerosing chronic pancreatitis (histologically documented), previous chronic cholecystitis (histologically confirmed), previous pericarditis, xeroftalmia, polyclonal hypergammaglobulinemia, eosinophilia. His serum IgG4 levels were significantly increased (5560 mg/dl). In regard to the above mentioned elements a systemic disease characterized by elevated serum levels of IgG4 and IgG4-positive lymphoplasmacytic infiltrative lesions in several tissues, was suspected. Immune-rheumatic diseases and infectious diseases were excluded. Steroid treatment was started achieving a significant swift response. Conclusion: Until now IgG4 related disease has been considered rare in the West and exclusive of Japanese and Korean countries, our case report leads us to reflect on the necessity to take into account this disease in patients with multisystemic involvement.

Background: Due to the continuing increase of the elderly population in the western countries, the prevalence of the main chronic diseases (obesity, type 2 diabetes and related metabolic disorders, arterial hypertension, vascular damage due to atherosclerotic process, cancer, chronic obstructive pulmonary disease, neurodegenerative diseases, chronic kidney disease, immune-mediated diseases) is increasing. There is incontrovertible evidence that regular physical activity contributes to the primary and secondary prevention of several chronic diseases and is associated with a reduced risk of premature death. Methods: In this review the most prevalent chronic pathologic conditions are discussed, how regular exercise may provide benefits for prevention and/or treatment of these diseases and are graphically described by means of various figures the main biological mechanisms through which exercise exerts its beneficial effects known to date. Results: Specific interventions aimed to implement physical activity levels of the general population are of certain efficacy both for primary and secondary prevention of the major chronic diseases and constitutes an excellent cost/effective tool to improve the health status of different categories of patients. Conclusion: Exercise represents a unique case in which a single intervention is useful against a broad range of diseases and risk factors, this knowledge should lead to an ever-increasing use of this lifestyle change.

Intracellular Ca2+ signal plays a major role in many cellular processes, such as apoptosis and epithelial to mesenchymal transition (EMT). The role of Ca2+ in apoptotic signaling has been investigated deeply over the past few decades. In recent years, it has made progress in the interactions of intracellular Ca2+ homeostasis with EMT. Besides, Bcl-2 family proteins as versatile regulators of cell apoptosis not only regulate Ca2+ signal, but also play an important role in the induction of EMT. In this review, we summarized the relations among intracellular Ca2+ concentration, apoptosis and Bcl-2 family proteins. We also discussed the functions of intracellular Ca2+ concentration and Bcl-2 family proteins in EMT. By taking into account these analyses; we proposed a hypothesis of cell death and survival controlled by calcium signal.

Cancer is one of the leading causes of mortality in the developed countries. The search for novel drug candidates is a priority goal for cancer therapy. However, the emergence of drug resistance reduces the effectiveness of new medications. The ATP binding cassette (ABC) family of proteins are efflux pumps that transport various structurally unrelated and potentially dangerous substances out of the cells. These transporters have evolved as a complex cellular defense system, for the recognition and removal of toxic agents entering the cells from their environment. Several of the ABC transporters are related to chemoresistance in cancer therapy, as the rapidly dividing malignant cells use them to protect themselves from medical interventions. Here we review the members of the ABC transporter families responsible for the multidrug resistance in anticancer therapy.

Epithelial ovarian cancer (EOC) is responsible for more cancer-related deaths than any other malignancy of the female reproductive system. The standard of care for advanced EOC involves a combination of cytoreductive surgery and platinum-based chemotherapy. Although a majority of patients respond to a platinum-containing regimen, many fail to respond to first-line treatment (platinum-refractory disease) or experience disease progression within 6 months of completing treatment (platinum-resistant disease). Even in patients who initially respond to platinum-based therapy, secondary development of platinum resistance is common. Many chemotherapeutic regimens with comparable efficacy and toxicities are available, leaving the determination of optimal therapy to the physician’s discretion. There have been many efforts over the years to develop accurate predictors of outcomes in patients treated with chemotherapy to help inform treatment decisions. Predictive treatment markers are particularly relevant in a disease such as EOC, where a large number of similarly efficacious chemotherapy regimens are available. Chemosensitivity and resistance assays (CSRAs) are attractive approaches to interrogate the efficacy and complex biology of EOC. Some early predictive cellular tests, such as the early clonogenic assays, were limited by technical and logistical issues. Over time, changes in these assays have improved their prognostic and predictive value, but there is still a lack of widespread adoption due to methodological difficulties or limited clinical validation. Herein, we provide an overview of the evolution of CSRAs used to predict outcomes in patients treated with chemotherapy that have been evaluated for use in EOC, with a focus on the latest generation chemoresponse assay.

Our previous studies demonstrated that a recombinant fibronectin (FN)-derived oligopeptide that we named F20 stimulated osteoblast adhesion, proliferation, and differentiation in vitro and in vivo. In the present study, we used a synthetic oligopeptide and investigated the osteogenic potential of F20 coating on titanium discs, to stimulate superior osseointegration for dental implant surface modification. Surface characteristic analysis of titanium was performed by confocal laser scanning microscopy (CLSM) observation. Synthetic F20 was coated onto the machined or SLA titanium discs by an adsorption procedure. ST2 cells were seeded on the titanium discs. We evaluated cell adhesion with SEM and CLSM observation, cell proliferation with picogreen assay, and osteoblast differentiation with real-time PCR, ALP activity assay, immunoblot assay and ALP staining. FITC-labeled F20 coating on the discs was detected by fluorescence, showing good F20 adsorption and different coating patterns according to the surface roughness. In the SEM and CLSM observations, cells were well attached on the machined surface and greater stress fiber formation was seen on discs coated with F20 than on other discs. F20 stimulated cellular proliferation, as well as osteoblast differentiation through the extracellular signalregulated kinase (Erk) signaling pathway. These cellular responses to F20 were slightly better on the machined titanium surface than the SLA surface. These results suggest that F20 promotes osteogenesis through the Erk pathway and is a suitable biomolecule for surface modification of dental implants for improved osseointegration.

Lectins are a heterogeneous group of proteins and glycoproteins with potential role as therapeutic and diagnostic tools to combat various diseases, besides some functions on human organism. Abelmoschus esculentus (Okra), a horticultural plant of African origin, is cultivated in northeastern Brazil, and used for different medicinal purposes. This work is aimed to elucidate the action mechanisms of Abelmoschus esculentus lectin (AEL) gastro protective effect on gastropathy induced by ethanol. Fasted mice treated with Ethanol 99.9% (0.2 ml/animal, p.o.) received previously AEL (0.01, 0.1, 1.0, 10 or 50 mg/kg, i.v.), saline (5 ml/kg; i.v.) or ranitidine (80 mg/kg, p.o.) in four experimental series, in which pharmacological tools (yohimbine, naloxone, L-NAME or indomethacin), were administered with the purpose of make clear possible molecular action mechanisms. Mice were euthanized 30 min after ethanol challenge to verify the stomach damages. Establishment of gastric oxidative stress, tissue hemoglobin (Hb) content and microscopic features (H) were taken in order to characterize the AEL gastro protective effect. AEL (1 mg/kg) was capable of protect mucosa against ethanol damages in presence of two (L-NAME and indomethacin) of four antagonists/inhibitors used. The AEL effect was reversed by naloxone and yohimbine, showing the involvement of opioids and lpha-2 adrenergic receptors on gastric protective effect of this lectin. Evaluation of microscopic features, oxidative stress, and Hb levels pointed the protective effects of AEL. This activity seems to be mediated by alpha-2 adrenergic and opioid receptors activation. Nitric oxide or prostaglandins were not involved. AEL simultaneously showed antioxidant effect that is probably implicated in its intricate defensive mechanism of action.