34 research outputs found
Meeting at the Crossroad between Obesity and Hepatic Carcinogenesis:Unique Pathophysiological Pathways Raise Expectations for Innovative Therapeutic Approaches
Coxsackievirus and adenovirus receptor expression in human endometrial adenocarcinoma: possible clinical implications
The coxsackievirus and adenovirus receptor (CAR) is a crucial receptor for the entry of both coxsackie B viruses and adenoviruses into host cells. CAR expression on tumor cells was reported to be associated with their sensitivity to adenoviral infection, while it was considered as a surrogate marker for monitoring and/or predicting the outcome of adenovirus-mediated gene therapy. The aim of the present study was to evaluate the clinical significance of CAR expression in endometrial adenocarcinoma. CAR expression was assessed immunohistochemically in tumoral samples of 41 endometrial adenocarcinoma patients and was statistically analyzed in relation to various clinicopathological parameters, tumor proliferative capacity and patient survival. CAR positivity was noted in 23 out of 41 (56%) endometrial adenocarcinoma cases, while high CAR expression in 8 out of 23 (35%) positive ones. CAR intensity of immunostaining was classified as mild in 11 (48%), moderate in 10 (43%) and intense in 2 (9%) out of the 23 positive cases. CAR positivity was significantly associated with tumor histological grade (p = 0.036), as well differentiated tumors more frequently demonstrating no CAR expression. CAR staining intensity was significantly associated with tumor histological type (p = 0.016), as tumors possessing squamous elements presented more frequently intense CAR immunostaining. High CAR expression showed a trend to be correlated with increased tumor proliferative capacity (p = 0.057). Patients with tumors presenting moderate or intense CAR staining intensity were characterized by longer survival times than those with mild one; however, this difference did not reach statistical significance. These data reveal, for the first time, the expression of CAR in clinical material obtained from patients with endometrial adenocarcinoma in relation to important clinicopathological parameters for their management. As CAR appears to modulate the proliferation and characteristics of cancer cells, its expression could be considered of possible clinical importance for future (gene) therapy applications
Antithrombotic and Antiatherosclerotic Properties of Olive Oil and Olive Pomace Polar Extracts in Rabbits
Olive oil polar lipid (OOPL) extract has been reported to inhibit atherosclerosis development on rabbits. Olive pomace polar lipid (PPL) extract inhibits PAF activity in vitro and the most potent antagonist has been identified as a glycerylether-sn-2-acetyl glycolipid with common structural characteristics with the respective potent antagonist of OOPL. The aim of this study was to investigate the effect of PPL on early atherosclerosis development on rabbits and to compare it with the antiatherosclerotic effect of OOPL. OOPL and PPL inhibition potency, towards both PAF action and PAF binding, was tested in vitro on washed rabbit platelets. Consequently, rabbits were divided into three groups (A, B, and C). All groups were fed atherogenic diet for 22 days. Atherogenic diets in groups B and C were enriched with OOPL and PPL, respectively. At the end of the experimental time, rabbits were euthanized and aortic samples were examined histopathologically. OOPL and PPL inhibited PAF-induced aggregation, as well as specific PAF binding, with PPL being more potent. Free and bound PAF levels and PAF-AH activity were significantly elevated at the end of the experimental time. Plasma total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides levels were also found increased. Groups B and C exhibited significantly increased
values of EC50 compared to group A. Histopathological examination revealed that the development of early atherosclerosis lesions in groups B and C were significantly inhibited compared to group A. Significant differences were noted in the early atherosclerosis lesions between groups B and C, thus indicating that PPL exhibit its anti-atherosclerotic activity by blocking PAF receptor. Specific PAF antagonists with similar in vitro and in vivo bioactivity to those that have been previously reported in OOPL exist in PPL
Guanylyl cyclase activation reverses resistive breathing–induced lung injury and inflammation
Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure–volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC–cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases
Guanylyl Cyclase Activation Reverses Resistive Breathing–Induced Lung Injury and Inflammation
An assessment of serum leptin levels in patients with chronic viral hepatitis: a prospective study
<p>Abstract</p> <p>Background</p> <p>The role of leptin in the course of liver disease due to chronic viral hepatitis (CVH) remains controversial. Our aims were to investigate the relationship between serum leptin concentrations and the severity of liver disease in a cohort of subjects with HBeAg negative chronic hepatitis B (CHB) and C (CHC) and to analyze the effect of body composition, the leptin system and insulin resistance together with viral factors on virologic response to antiviral treatment.</p> <p>Methods</p> <p>We studied 50 (36 men) consecutive patients suffering from biopsy-proven CVH due to HBV (n = 25) or HCV (n = 25) infection. Thirty-two (17 men) healthy volunteers served as controls. Levels of serum leptin and insulin were determined by immunoassays at baseline and at the end of the treatment.</p> <p>Results</p> <p>A significant association between serum leptin levels and the stage of hepatic fibrosis was noted; patients with cirrhosis presented higher serum leptin levels compared to those with lower fibrosis stage [CHB patients (17436 pg/ml vs 6028.5 pg/ml, p = 0.03), CHC patients (18014 pg/ml vs 4385 pg/ml, p = 0.05]. An inverse correlation between lower leptin levels and response to lamivudine monotherapy was noted in patients with CHB; those with a virologic response presented lower serum leptin levels (5334 vs 13111.5 pg/ml; p-value = 0.003) than non-responders. In genotype 1 CHC patients, insulin resistance played a significant role in the response to antiviral therapy.</p> <p>Conclusion</p> <p>Our data clearly suggest that cirrhosis due to CHB or CHC is associated with higher leptin levels. Increased serum leptin levels represent a negative prognostic factor for response to lamivudine monotherapy in patients with CHB. In CHC patients insulin resistance strongly influences the response to antiviral treatment in patients infected with genotype 1.</p
Heat Shock Protein-27, -60 and -90 expression in gastric cancer: association with clinicopathological variables and patient survival
<p>Abstract</p> <p>Background</p> <p>Heat shock proteins (HSPs) are ubiquitous, highly conserved proteins across all the species and play essential roles in maintaining protein stability within the cells under normal conditions, while preventing stress-induced cellular damage. HSPs were also overexpressed in various types of cancer, being associated with tumor cell proliferation, differentiation and apoptosis. The aim of the present study was to evaluate the clinical significance of HSP -27, -60, and -90 expression in gastric carcinoma.</p> <p>Methods</p> <p>HSP -27, -60, and -90 proteins expression was assessed immunohistochemically in tumoral samples of 66 gastric adenocarcinoma patients and was statistically analyzed in relation to various clinicopathological characteristics, tumor proliferative capacity and patients' survival.</p> <p>Results</p> <p>HSP-27, -60, -90 proteins were abundantly expressed in gastric adenocarcinoma cases examined. HSP-27 expression was significantly associated with tumor size (pT, P = 0.026), the presence of organ metastases (pM, P = 0.046) and pStage (P = 0.041), while HSP-27 staining intensity with nodal status (pN, P = 0.042). HSP-60 expression was significantly associated with patients' sex (P = 0.011), while HSP-60 staining intensity with patients' age (P = 0.027) and tumor histopathological grade (P = 0.031). HSP-90 expression was not associated with any of the clinicopathological parameters examined; however, HSP-90 staining intensity was significantly associated with tumor size (pT, P = 0.020). High HSP-90 expression was significantly associated with longer overall survival times in univariate analysis (log-rank test, P = 0.033), being also identified as an independent prognostic factor in multivariate analysis (P = 0.026).</p> <p>Conclusion</p> <p>HSP-27, -60, and -90 were associated with certain clinicopathological parameters which are crucial for the management of gastric adenocarcinoma patient. HSP-90 expression may also be an independent prognostic indicator in gastric adenocarcinoma patients.</p
Pregnane X receptor and human malignancy
Pregnane X Receptor (PXR) is a member of
the nuclear receptor superfamily, expressed in liver,
intestine and other tissues. PXR exerts transcriptional
regulation by binding to its DNA response elements as
an heterodimer with Retinoid X Receptor (RXR). This
nuclear receptor is implicated in the homeostasis of
numerous endobiotics, such as glucose, lipids, steroids
and bile acids. Additionally, the activation of PXR
induces expression of drug metabolizing enzymes
(DMEs) and transporters, including multidrug resistance
protein 1 (MDR1), leading to regulation of xenobiotic
metabolism and drug-drug interactions. New roles for
PXR have been established in inflammatory bowel
disease, bone homeostasis, liver steatosis, antifibrogenesis
and oxidative stress. PXR has, additionally, a
multifactorial impact on cancer, either by directly
affecting cell proliferation and apoptosis or by inducing
chemotherapy resistance, in colon, breast, prostate, and
endometrial cancer, and in osteosarcoma. PXR
polymorphisms may also have clinical significance in
certain types of cancer and their treatment. Further
studies are needed in order to clarify the mechanisms
involved in PXR-regulated carcinogenesis. PXR downregulation
could be considered as a novel therapeutic
approach to overcome chemoresistance, while future
research should be mainly focused on modulating PXR
status in order to increase chemotherapy effectiveness
and finally improve cancer patient prognosis
Receptor-binding cancer antigen expressed on SiSo cells (RCAS1), a novel biomarker in the diagnosis and prognosis of human neoplasia
The receptor-binding cancer antigen
expressed on SiSo cells (RCAS1) is a novel tumorassociated
antigen that induces cell-cycle arrest and/or
apoptosis in RCAS1 receptor-bearing human cells.
Current evidence has revealed enhanced RCAS1
expression in the tumor malignant stage of several
organs, which may play a crucial role in tumor
progression by enabling cancer cells to evade immune
surveillance. In the last few years, tissue RCAS1 protein
expression and circulating levels in biofluids have
further been the focus of extensive research as a
diagnostic and prognostic marker in several human
malignancies. The present article aimed to review the
available data so far concerning the clinical significance
of RCAS1 in human neoplasia. Reviewing of English
literature revealed that tissue RCAS1 expression was
associated with important clinicopathological parameters
for patients' management and prognosis, being
considered as an informative biomarker in several types
of human malignancy. In addition, the current evidence
supported a crucial role for RCAS1 in tumor immune
escape, which renders this receptor a promising target
for future (gene) therapeutic approaches. However, the clinical application of circulating RCAS1 concentrations
in biofluids as a marker in the management and
prognosis of tumor malignancies needs to be further
explored, since the data so far are still extremely limited
Role of OPG-RANKL-RANK axis on the vasculature
Vascular calcification, a degenerative process
considered in the past to be a passive procedure, has now
been suggested to be related to ossification. Many
proteins responsible for bone formation have been
identified on the arterial wall. The OPG/RANKL/RANK
axis, responsible for ossification and bone
mineralization, seems to play a major role in vasculature
and atherosclerosis. Mice lacking OPG gene present
osteoporosis and arterial calcification, while
overexpression of OPG gene leads to osteopetrosis. In
the present review the latest knowledge related to the
effects of the OPG/RANKL/RANK axis on vasculature,
including atherosclerosis, will be analyzed. The clinical
significance of circulating OPG and RANKL levels in
vascular diseases will also be referred