Novel oral transforming growth factor-ß signaling inhibitor potently inhibits postsurgical adhesion band formation.

Here, we have investigated the therapeutic potency of EW-7197, a transforming growth factor-ß type I receptor kinase inhibitor, against postsurgical adhesion band formation. Our results showed that this pharmacological inhibitor prevented the frequency and the stability of adhesion bands in mice model. We have also shown that downregulation of proinflammatory cytokines, reduce submucosal edema, attenuation of proinflammatory cell infiltration, inhibition of oxidative stress, decrease in excessive collagen deposition, and suppression of profibrotic genes at the site of surgery are some of the mechanisms by which EW-7197 elicits its protective responses against adhesion band formation. These results clearly suggest that EW-7197 has novel therapeutic properties against postsurgical adhesion band formation with clinically translational potential of inhibiting key pathological responses of inflammation and fibrosis in postsurgery patients.

Stem cell therapy: A novel approach for myocardial infarction.

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide. Until recently, it was thought that myocardium was not able to repair itself, but studies have now shown that resident cardiac stem cells have regenerative capacity, and stem cell therapy may be a novel approach for cardiac muscle repair and regeneration. Stem cell-derived paracrine factors have been shown to regulate ventricular remodeling, inflammation, apoptosis, cardiomyocytes regeneration, and neovascularization in regions of infarcted cardiac tissue. In this review, we summarize the evidence from cellular, animal, and clinical studies supporting the potential clinical significance of stem cell therapy as a novel therapeutic approach for the treatment of MI.

CD73; a key ectonucleotidase in the development of breast cancer: Recent advances and perspectives.

Tumor cell invasion and metastasis are the definitive cause of mortality in breast cancer (BC). Hypoxia and pro-inflammatory cytokines upregulate the CD73 gene in the tumor microenvironment. Subsequently, CD73 triggers molecular and cellular signaling pathways by both enzymatic and nonenzymatic pathways, which finally leads to breast tumor progression and development. In this paper, we summarize current advances in the understanding of CD73-driven mechanisms that promote BC development and mortality. Furthermore, we evaluate the therapeutic potential of CD73 targeting in BC.

Role of adenosine signaling in the pathogenesis of breast cancer.

The plasma level of adenosine increases under ischemic and inflamed conditions in tumor microenvironment. Adenosine elicits a range of signaling pathways in tumors, resulting in either inhibition or enhancement of tumor growth depending upon different subtypes of adenosine receptors activation and type of cancer. Metabolism of adenosine-5'-triphosphate (ATP) and its derivatives including adenosine is dysregulated in the breast tumor microenvironment, supporting the role of this metabolite in the pathogenesis of breast cancer. Adenosine regulates inflammation, apoptosis, cell proliferation, and metastasis in breast cancer cells. This review summarizes the role of adenosine in the pathogenesis of breast cancer for a better understanding and hence a better management of this disease.

The diagnostic and prognostic value of copeptin in cardiovascular disease, current status, and prospective.

Copeptin is a glycosylated peptide derived from the cleavage of the precursor of arginine-vasopressin. In contrast to arginine-vasopressin, copeptin is a stable molecule and can easily be measured using a simple rapid assay. The serum concentration of copeptin is increased in several clinical conditions, including hypertension, chronic kidney disease, and, of special interest in this review, in cardiovascular diseases. The diagnostic and prognostic value of copeptin in different cardiovascular diseases (acute coronary syndrome, stable coronary artery disease, congestive heart failure, and acute ischemic stroke) has been reviewed in this article, to provide an understanding of how its measurement may be applied to improve the management of these conditions.

Prevalence of combined and noncombined dyslipidemia in an Iranian population.

BACKGROUND: Combination of dyslipidemic phenotypes, including elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), elevated plasma triglycerides (TG), and decreased low-density lipoprotein cholesterol (HDL-C) concentrations, is important because of the association of individual phenotypes with increased risk of cardiovascular disease (CVD). We investigated the prevalence of combined dyslipidemias and their effects on CVD risk in an Iranian large population. METHOD: A total of 9847 individuals were recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorders (MASHAD) cohort study. Anthropometric parameters and biochemical indices were measured in all of the subjects. Different types of combined dyslipidemias including high TG + low HDL-C, high TG + low HDL-C + high LDL-C, low HDL-C + high LDL-C, high TG + high LDL-C, and finally high TG + high LDL-C + low HDL-C were considered. Ten-year CVD risk was calculated using the QRISK2 risk algorithm and adjustments were made as suggested by the Joint British Societies' (JBS2). Logistic regression analyses were performed to determine the association between different combined dyslipidemias and categorical QRISK. RESULTS: A total of 3952 males and 5895 females were included in this current study. Among the included subjects, 83.4% had one form of dyslipidemia, and 16.6% subjects were not dyslipidemic. The mean age was 48.88 ± 7.9 and 47.02 ± 8.54 years for dyslipidemic and nondyslipidemic groups, respectively. The results showed that the frequency of dyslipidemia was 98%, 87.1%, and 90% in subjects with metabolic syndrome, CVD, and diabetes, respectively. Our results suggested that around 15.7% of study population were at 10 years CVD risk (high ≥20) and it was higher in men than women (P < .001). Moreover, risk of CVD was higher in TG↑ & HDL↓ & LDL↑ group than other groups. CONCLUSION: Prevalence of dyslipidemia was 83.4% among Iranian adults. The results showed that individuals with increased plasma TG and LDL-C, and low HDL-C levels had the highest 10 years CVD risk compared to other combined dyslipidemic phenotypes.

Role of thrombin in the pathogenesis of central nervous system inflammatory diseases.

Thrombin initiates proinflammatory signaling responses through activation of protease-activated receptors (PARs) in in vitro and in vivo systems. Proinflammatory signaling function of thrombin increases secretion of proinflammatory cytokines and chemokines, triggers vascular permeability, promotes leukocyte migration, and induces adhesion molecule expression. Thrombin as a potent signaling molecule is strongly implicated in a number of proinflammatory disorders including severe sepsis, cancer, cardiovascular disease, and of special interest in this review neurodegenerative disorders. This review summarizes the role of thrombin in the pathogenesis of central nervous system (CNS) inflammatory diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), promoting greater understanding and clinical management of these diseases. J. Cell. Physiol. 232: 482-485, 2017. © 2016 Wiley Periodicals, Inc.

Role of Wnt5a in the Pathogenesis of Inflammatory Diseases.

Wnt5a initiates pro-inflammatory responses through activation of non-canonical Wnt signaling pathway. Pro-inflammatory functions of Wnt5a trigger pro-inflammatory signaling cascades and increase secretion of pro-inflammatory cytokines and chemokines. Wnt5a as a potent signaling molecule is strongly implicated in a number of diseases including cancer, diabetes, metabolic disorders, and of special interest in this review, inflammatory diseases. This review summarizes the role of Wnt5a in the pathogenesis of inflammatory diseases including atherosclerosis, rheumatoid arthritis, psoriasis vulgaris and sepsis, promoting greater understanding, and clinical management of these diseases. J. Cell. Physiol. 232: 1611-1616, 2017. © 2016 Wiley Periodicals, Inc.

Proinflammatory signaling functions of thrombin in cancer.

Thrombin-induced activation of protease-activated receptors (PARs) represents a link between inflammation and cancer. Proinflammatory signaling functions of thrombin are associated with several inflammatory diseases including neurodegenerative, cardiovascular, and of special interest in this review cancer. Thrombin-induced inflammatory responses up-regulates expression of cytokines, adhesion molecules, angiogenic factors, and matrix-degrading proteases that facilitate tumor cells proliferation, angiogenesis, invasion, and metastasis. This review summarizes the current knowledge about the mechanisms of thrombin-mediated proinflammatory responses in cancer pathology for a better understanding and hence a better management of this disease.

Association of hematocrit with blood pressure and hypertension.

BACKGROUND: Hypertension (HTN) is a risk factor for stroke, renal failure, and cardiovascular disease. The association between biochemical and hematological parameters with high blood pressure may provide a more precise approach to risk prediction conferred by HTN in these patients. OBJECTIVE: The aim of current study was to explore whether biochemical and hematological parameters are associated with HTN in a cohort study with a 7-year follow-up. MATERIALS AND METHODS: A total of 9808 individuals were enrolled and recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorders (MASHAD) cohort study, and biochemical and hematological factors were measured in all subjects. Univariate and multivariate logistic regression analysis were performed to determine the association of biochemical and hematological parameters with HTN. RESULTS: Several biochemical parameters including fasting plasma glucose (FBG), serum high-sensitivity C-reactive protein (hs-CRP), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and uric acid were increased in hypertensive participants. In contrast, serum high-density lipoprotein cholesterol (HDL-C) was lower in hypertensive individuals. Furthermore, we demonstrated that hematological parameters including white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), and mean corpuscular hemoglobin (MCH) were higher in the hypertensive group compared to the control group. But mean corpuscular volume (MCV), and red cell distribution width (RDW), were decreased in the hypertensive group. Furthermore, our results strongly suggested that among these parameters, hematocrit was the independent risk factor for hypertension in the population. CONCLUSION: We demonstrated the association of altered biochemical and hematological factors with hypertension supporting the value of emerging markers for early prediction of high blood pressure in prone individuals.

Effects of body electroacupuncture on plasma leptin concentrations in obese and overweight people in Iran: a randomized controlled trial.

BACKGROUND: The prevalence of obesity, a major public health problem, is increasing in many countries, including Iran. Leptin, a peptide hormone that is released from adipocytes, is a major factor in appetite regulation. Levels of plasma leptin increase with increased body fat mass (BFM). Research has found acupuncture to be effective both in weight loss and suppression of appetite. Although a few studies have reported the effect of body and ear acupuncture on leptin levels, researchers have performed few studies on the effect of body electroacupuncture in humans. OBJECTIVE: The research team examined the effects of body electroacupuncture and a low-calorie diet on plasma leptin in obese and overweight individuals with an excess (phlegm-dampness or phlegm-heat) or deficiency (spleen/stomach qi deficiency or primary qi deficiency) pattern according to Chinese medicine. DESIGN: The research team randomly assigned participants to one of two groups, intervention or control. SETTING: This study occurred in the nutritional clinic at Ghaem Hospital in Mashhad, Iran. PARTICIPANTS: Participants were individuals (N = 86) between 18 and 65 years of age with body mass indexes (BMI) between 25 and 45 kg/m2. INTERVENTION: The intervention group (n = 47) received actual electroacupuncture, and the control group (n = 47) received sham acupuncture. Both groups consumed a low-calorie diet for 6 weeks. OUTCOME MEASURES: The research team measured plasma leptin, BFM, body weight (BW), and BMI before and after treatment. RESULTS: For participants in the intervention group with both the excess and the deficiency patterns, the research team found a significant reduction in plasma leptin (24.96%, P = .001) and BFM (8.29%, P = .001). In the control group, the team found a less significant reduction in leptin and BFM. The difference between the two groups was significant for leptin (P = .03) but not for BFM (P = .8). CONCLUSIONS: While body electroacupuncture with a low-calorie diet can reduce plasma leptin concentration, the mechanism will require further clarification.

Treatment of non-healing wounds with autologous bone marrow cells, platelets, fibrin glue and collagen matrix.

BACKGROUND AIMS: Recalcitrant diabetic wounds are not responsive to the most common treatments. Bone marrow-derived stem cell transplantation is used for the healing of chronic lower extremity wounds. METHODS: We report on the treatment of eight patients with aggressive, refractory diabetic wounds. The marrow-derived cells were injected/applied topically into the wound along with platelets, fibrin glue and bone marrow-impregnated collagen matrix. RESULTS: Four weeks after treatment, the wound was completely closed in three patients and significantly reduced in the remaining five patients. CONCLUSIONS: Our study suggests that the combination of the components mentioned can be used safely in order to synergize the effect of chronic wound healing.

Prooxidant-antioxidant balance in stroke patients and 6-month prognosis.

BACKGROUND: Oxidative stress is thought to play an important role in the pathogenesis of stroke. METHODS: In the present study, we assessed the extent of oxidative stress in the sera of 120 patients in the first 24 hours after the onset of stroke and 80 healthy control subjects using a novel assay of prooxidant-antioxidant balance (PAB) that can measure the prooxidant burden and the antioxidant capacity simultaneously in one assay, thereby giving a redox index. RESULTS: In stroke patients median serum PAB values were significantly higher than that of the control group [125.50 (103.36 - 151.80) vs 43.40 (29.77 - 77.01), p < 0.001]. However, no significant difference was observed between subgroups of patients with transient ischemic attack (TIA), cerebral infarction or cerebral hemorrhage (p > 0.05). Median Serum PAB values were not significantly different in patients with different outcomes based on their 6-month prognosis (p > 0.05). CONCLUSIONS: We conclude that serum PAB values are elevated in patients with stroke, indicating a heightened state of oxidative stress, but do not distinguish between stroke types or predict 6-month prognosis.

Serum Pro-oxidant-antioxidant Balance in Subjects with Type 2 Diabetes Mellitus.

AIM AND OBJECTIVE: Diabetes mellitus is associated with inflammation and increased oxidative stress. In the current study, we aimed to investigate the relationship between type 2 diabetes mellitus (T2DM) and serum pro-oxidant-antioxidant balance (PAB) in a large populationbased study. METHODS: In this cross-sectional study, 7888 individuals were recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorders (MASHAD) cohort study. Participants were divided into three groups based on their serum PAB values (levels < 36.4, 36.4-82.6 and > 82.6 HK). Serum PAB values were measured using a colorimetric method and enzyme-linked immune sorbent assay (ELISA). RESULTS: Serum PAB in subjects with and without diabetes was reported 76.85 ± 61.07 HK and 69.51 ± 55.50 HK. In subjects with a serum PAB > 82.6 HK the risk of T2DM was 1.2 fold higher in comparison to subjects with a serum PAB < 36.4 HK (OR: 1.26, 95% CI: 1.09 - 1.47, P-value: 0.002). This association remained significant after adjustment for confounding factors in multivariable analysis (OR: 1.19, 95% CI: 1.02 - 1.38, P-value: 0.027). CONCLUSION: Increased pro-oxidant levels may be a major complication of T2DM in our study subjects and PAB could be an indicator of higher oxidative stress in T2DM patients from northeastern Iran.

Inhibition of angiotensin II type 1 receptor by candesartan reduces tumor growth and ameliorates fibrosis in colorectal cancer.

Colorectal cancer (CRC) is an important cause of cancer-related mortality. Aberrant activation of the renin-angiotensin system (RAS) is reported to be associated with poor clinical outcomes in patients with CRC. This study was designed to explore the anti-tumor effects of the angiotensin receptor blocker Candesartan either alone or in combination with 5-FU in in vitro and in vivo models of CRC. The cytotoxic effects of Candesartan were assessed using the MTT assay in two colorectal cancer cell lines (CT-26 and SW-480). To investigate the potential regulatory role of Candesartan on tumor growth, apoptosis, and migration, the expression levels of Cyclin D1, Survivin, MMP3, MMP9, and E-cadherin mRNAs were evaluated. The oxidant/antioxidant balance was also examined by determining the levels of MDA, thiols, SOD, and CAT. We used a xenograft model of colon cancer to investigate the effects of Candesartan alone, or in combination with 5-FU, on tumor growth following histological staining (Hematoxylin & Eosin and Masson trichrome staining) and biochemical studies as well as gene expression analyses by RT-PCR and western blotting. Candesartan suppressed tumor cell proliferation and migration by modulating Cyclin D1, MMP3/9, and E-cadherin. Treatment with Candesartan either alone, or in combination with 5-FU decreased tumor size in the mouse model, and also increased the level of oxidative markers MDA and reduced CAT, SOD, and thiols. Histological evaluation showed that Candesartan increased tumor necrosis, reduced tumor density and attenuated collagen deposition reducing tumor fibrosis in tumor xenograft. Candesartan, an inhibitor of the RAS, when used in combination with 5-FU reduced tumor growth by inhibiting fibrosis and inducing ROS production, supporting further clinical studies on this therapeutic approach for treatment of CRC.

Therapeutic potential of active components of saffron in post-surgical adhesion band formation.

BACKGROUND: Abdominal adhesions are common and often develop after abdominal surgery. There are currently no useful targeted pharmacotherapies for adhesive disease. Saffron and its active constituents, Crocin and Crocetin, are wildly used in traditional medicine for alleviating the severity of inflammatory or malignant disease. PURPOSE: The aim of this study was to investigate the therapeutic potential of the pharmacological active component of saffron in attenuating the formation of post-operative adhesion bands using different administration methods in a murine model. MATERIAL METHOD: saffron extract (100 mg/kg), Crocin (100 mg/kg), and Crocetin (100 mg/kg) were administered intraperitoneally and by gavage in various groups of male Wistar rat post-surgery. Also three groups were first treated intra-peritoneally by saffron extract, Crocin, and Crocetin (100 mg/kg) for 10 days and then had surgery. At the end of the experiments, animals sacrificed for biological assessment. RESULT: A hydro-alcoholic extract of saffron and crocin but not crocetin potently reduced the adhesion band frequency in treatment and pre-treatment groups in the mice given intra-peritoneal (i.p) injections. Following the saffron or crocin administration, histological evaluation and quantitative analysis represented less inflammatory cell infiltration and less collagen composition, compared to control group. Moreover, the oxidative stress was significantly reduced in treatment groups. CONCLUSION: These findings suggest that a hydro-alcoholic extract of saffron or its active compound, crocin, is a potentially novel therapeutic strategy for the prevention of adhesions formation and might be used as beneficial anti-inflammatory or anti-fibrosis agents in clinical trials. TAXONOMY: Abdominal surgeries/post-surgical adhesions.

Rigosertib potently protects against colitis-associated intestinal fibrosis and inflammation by regulating PI3K/AKT and NF-κB signaling pathways.

AIMS: Rigosertib (RGS) is a PI3K inhibitor that exerts protective effects against tumor progression and cancer-related inflammation. This study was aimed to explore the regulatory effects of RGS on proliferative, pro-fibrotic and inflammatory factors in DSS- induced colitis mice model. MATERIALS AND METHODS: The present study integrates systems and molecular biology approaches to investigate the therapeutic potency of RGS in an experimental model of colitis specifically examining its effects on the PI3K/AKT and NF-κB signaling pathways. KEY FINDINGS: Analysis of time-resolved proteome profiling showed that PI3K-AKT inhibitors regulate expression of many proteins in all stages of inflammation, fibrogenesis and extracellular matrix remodeling. Consistent with our in-silico findings, RGS improved colitis disease activity as assessed by changes in body weight, degree of stool consistency, rectal bleeding and prolapse. RGS also reduced oxidative stress markers and colon histopathological score by decreasing inflammatory responses in colon tissues. Moreover, expression of pro-fibrotic and pro-inflammatory factors including Acta 2, Col 1a1, Col 1a2, IL-1ß, TNF-α, INF-γ, and MCP-1 were suppressed in the mice treated with RGS compared to the control group. The protective effects of RGS were mediated by inactivation of PI3K/AKT and NF-kB signaling pathways. SIGNIFICANCE: This study clearly demonstrates the anti-proliferative, anti-inflammatory and anti-fibrotic effects of RGS in colitis that may have implications for the treatment of colitis and colitis-associated cancer.

Prooxidant-antioxidant balance as a new risk factor in patients with angiographically defined coronary artery disease.

OBJECTIVES: Determination of the prooxidant-antioxidant balance (PAB) in patients with angiographically defined coronary artery disease (CAD+) by a modified PAB assay and presentation of PAB value as a novel cardiovascular risk factor. DESIGN AND METHODS: For 61 patients with CAD+ and 63 healthy volunteers, the PAB were measured and its correlation was determined with anthropological and clinical parameters. RESULTS: A significant increase of the PAB value was observed in patients in comparison to control group. A correlation, which is not quite significant, was noted between angiographic finding (number of diseased vessel) and the PAB values in patients. A significant positive correlation was established between the PAB value and systolic blood pressure, diastolic blood pressure, smoking, fasting blood sugar and serum urea concentration; and a significant negative correlation was established between PAB value and serum creatinine and bilirubin. CONCLUSIONS: This study shows that the PAB value may be considered as a cardiovascular risk factor. Further clinical research is needed to substantiate the potency of the PAB value as a cardiovascular risk factor.

Serum level of gamma-glutamyl transferase as a biomarker for predicting stenosis severity in patients with coronary artery disease.

BACKGROUND: Gamma glutamyl transferase (GGT) is associated with pathogenesis of various diseases such as coronary artery disease (CAD). GGT activity displays an essential role in the catabolism of glutathione which is reported as a major antioxidant. The aim of this study was to explore the association of GGT activity with obstruction severity of artery in 500 CAD patients. RESULTS: Our finding showed a significant association between serum GGT activity and CAD patients. In particular, the level of GGT in patients who had ≥50% obstruction was higher, compared to healthy and patients with less than 50% obstruction in their coronary arteries (the level of GGT in patients with at least one (1 SVD), two (2VD), three (3VD) coronary artery obstruction were 55.6±9.7, 71.7±12.7 and 84.7±13.4, while these values in patients with negative angio or control group were 28±10 and 17±4.6). Furthermore, the activity of this marker was associated with increased the risk of CAD (Odd ratio of GGT in 3VD group: 2, 95%CI: 1.8-2.3), which was also related with HDL-C. Of note, the level of GGT was enhanced progressively with increasing the obstruction severity of arteries. CONCLUSION: We demonstrate the prognostic value of serum level of GGT as a biomarker for predicting obstruction severity in patients with CAD.

Crocus sativus a natural food coloring and flavoring has potent anti-tumor properties.

BACKGROUND: Saffron, the dried stigmas of Crocus sativus L., is a highly valued agricultural product that is used mainly as a food coloring and flavoring agent. Three main secondary metabolites of Crocus sativus including crocin, picrocrocin, and safranal are responsible for the color, the bitter taste and for the odor and aroma, respectively. As a component of traditional medicine, saffron has been utilized as a medicinal herb for treating various ailments including cramps, asthma, liver disease, menstruation disorders, pain, and in the pathogenesis of cancer. HYPOTHESIS/PURPOSE: To summarize the recent published data on the chemo-preventive properties of Crocus sativus in cancer treatment. STUDY DESIGN: We conducted a non-systematic review of the literature. METHODS: A search of English-language literature was performed using Scopus, EMBASE and PubMed. We applied no restriction in time. Articles were searched using the keywords "Lung", "breast", "skin", "prostate", "leukemia", "cancer", "neoplasm", "tumor", "malignancy", "saffron", "crocus sativus", "crocin", "crocetin", "picrocrocin", and "safranal". RESULTS: Saffron has been reported to exert anti-tumor and anti-cancer effects in various types of cancer including lung cancer, breast cancer, leukemia, skin cancer and prostate cancer. This appears to be via various mechanisms including: the induction of apoptosis, arresting cell cycle progression, suppressing expression of matrix metalloproteinase, modulatory effects on some phase II detoxifying enzymes and decreasing expression of inflammatory molecules are potential mechanisms of saffron-induced anticancer effects. CONCLUSION: Saffron possesses potent anti-tumor properties and represents an efficacious and safe treatment.