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Singh T.,University of Alabama at Birmingham | Katiyar S.K.,Birmingham Veterans Affairs Medical Center | Katiyar S.K.,University of Alabama at Birmingham
PLoS ONE | Year: 2013

Lung cancer remains a leading cause of death due to its metastasis to distant organs. We have examined the effect of honokiol, a bioactive constituent from the Magnolia plant, on human non-small cell lung cancer (NSCLC) cell migration and the molecular mechanisms underlying this effect. Using an in vitro cell migration assay, we found that treatment of A549, H1299, H460 and H226 NSCLC cells with honokiol resulted in inhibition of migration of these cells in a dose-dependent manner, which was associated with a reduction in the levels of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). Celecoxib, a COX-2 inhibitor, also inhibited cell migration. Honokiol inhibited PGE2-enhanced migration of NSCLC cells, inhibited the activation of NF-κB/p65, an upstream regulator of COX-2, in A549 and H1299 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-κB, also inhibited migration of NSCLC cells. PGE2 has been shown to activate β-catenin signaling, which contributes to cancer cell migration. Therefore, we checked the effect of honokiol on β-catenin signaling. It was observed that treatment of NSCLC cells with honokiol degraded cytosolic β-catenin, reduced nuclear accumulation of β-catenin and down-regulated matrix metalloproteinase (MMP)-2 and MMP-9, which are the down-stream targets of β-catenin and play a crucial role in cancer cell metastasis. Honokiol enhanced: (i) the levels of casein kinase-1α, glycogen synthase kinase-3β, and (ii) phosphorylation of β-catenin on critical residues Ser45, Ser33/37 and Thr41. These events play important roles in degradation or inactivation of β-catenin. Treatment of celecoxib also reduced nuclear accumulation of β-catenin in NSCLC cells. FH535, an inhibitor of Wnt/β-catenin pathway, inhibited PGE2-enhanced cell migration of A549 and H1299 cells. These results indicate that honokiol inhibits non-small cell lung cancer cells migration by targeting PGE2-mediated activation of β-catenin signaling. © 2013 Singh, Katiyar.


Donnelly J.P.,University of Alabama at Birmingham | Baddley J.W.,University of Alabama at Birmingham | Baddley J.W.,Birmingham Veterans Affairs Medical Center | Wang H.E.,University of Alabama at Birmingham
Antimicrobial Agents and Chemotherapy | Year: 2014

Inappropriate use of antibiotics for acute respiratory tract infections (ARTIs) has decreased in many outpatient settings. For patients presenting to U.S. emergency departments (EDs) with ARTIs, antibiotic utilization patterns are unclear. We conducted a retrospective cohort study of ED patients from 2001 to 2010 using data from the National Hospital Ambulatory Medical Care Survey (NHAMCS). We identified patients presenting to U.S. EDs with ARTIs and calculated rates of antibiotic utilization. Diagnoses were classified as antibiotic appropriate (otitis media, sinusitis, pharyngitis, tonsillitis, and nonviral pneumonia) or antibiotic inappropriate (nasopharyngitis, unspecified upper respiratory tract infection, bronchitis or bronchiolitis, viral pneumonia, and influenza). There were 126 million ED visits with a diagnosis of ARTI, and antibiotics were prescribed in 61%. Between 2001 and 2010, antibiotic utilization decreased for patients aged <5 presenting with antibiotic-inappropriate ARTI (rate ratio [RR], 0.94; confidence interval [CI], 0.88 to 1.00). Utilization also decreased significantly for antibiotic- inappropriate ARTI patients aged 5 to 19 years (RR, 0.89; CI, 0.85 to 0.94). Utilization remained stable for antibiotic-inappropriate ARTI among adult patients aged 20 to 64 years (RR, 0.99; CI, 0.97 to 1.01). Among adults, rates of quinolone use for ARTI increased significantly from 83 per 1,000 visits in 2001 to 2002 to 105 per 1,000 in 2009 to 2010 (RR, 1.08; CI, 1.03 to 1.14). Although significant progress has been made toward reduction of antibiotic utilization for pediatric patients with ARTI, the proportion of adult ARTI patients receiving antibiotics in U.S. EDs is inappropriately high. Institution of measures to reduce inappropriate antibiotic use in the ED setting is warranted. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Pisprasert V.,University of Alabama at Birmingham | Ingram K.H.,Kennesaw State University | Lopez-Davila M.F.,University of Alabama at Birmingham | Munoz A.J.,University of South Carolina | And 2 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-To examine the utility of commonly used insulin sensitivity indices in nondiabetic European Americans (EAs) and African Americans (AAs). RESEARCH DESIGN AND METHODS-Two-hundred forty nondiabetic participants were studied. Euglycemic-hyperinsulinemic clamp was the gold standard approach to assess glucose disposal rates (GDR) normalized by lean body mass. The homeostatic model assessment for insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) were calculated from fasting plasma glucose and insulin (FIL). Oral glucose tolerance test (OGTT) was performed to determine Matsuda index, the simple index assessing insulin sensitivity (SIisOGTT), Avignon index, and Stomvoll index. Relationships among these indices with GDR were analyzed by multiple regression. RESULTS-GDR values were similar in EA and AA subgroups; even so, AA exhibited higher FIL and were insulin-resistant compared with EA, as assessed by HOMA-IR, QUICKI, Matsuda index, SIisOGTT, Avignon index, and Stumvoll index. In the overall study population, GDR was significantly correlated with all studied insulin sensitivity indices (/r/ = 0.381-0.513); however, these indices were not superior to FIL in predicting GDR. Race and gender affected the strength of this relationship. In AA males, FIL and HOMA-IR were not correlated with GDR. In contrast, Matsuda index and SIisOGTT were significantly correlated with GDR in AA males, and Matsuda index was superior to HOMA-IR and QUICKI in AAs overall. CONCLUSIONS-Insulin sensitivity indices based on glucose and insulin levels should be used cautiously as measures of peripheral insulin sensitivity when comparing mixed gender and mixed race populations. Matsuda index and SIisOGTT are reliable in studies that include AA males. © 2013 by the American Diabetes Association.


Afaq F.,University of Alabama at Birmingham | Katiyar S.K.,University of Alabama at Birmingham | Katiyar S.K.,Birmingham Veterans Affairs Medical Center
Mini-Reviews in Medicinal Chemistry | Year: 2011

Polyphenols are a large family of naturally occurring plant products and are widely distributed in plant foods, such as, fruits, vegetables, nuts, flowers, bark and seeds, etc. These polyphenols contribute to the beneficial health effects of dietary products. Clinical and epidemiological studies suggest that exposure of the skin to environmental factors/pollutants, such as solar ultraviolet (UV) radiation induce harmful effects and leads to various skin diseases including the risk of melanoma and non-melanoma skin cancers. The incidence of non-melanoma skin cancer, comprising of squamous cell carcinoma and basal cell carcinoma, is a significant public health concern world-wide. Exposure of the skin to solar UV radiation results in inflammation, oxidative stress, DNA damage, dysregulation of cellular signaling pathways and immunosuppression thereby resulting in skin cancer. The regular intake of natural plant products, especially polyphenols, which are widely present in fruits, vegetables, dry legumes and beverages have gained considerable attention as protective agents against the adverse effects of UV radiation. In this article, we first discussed the impact of polyphenols on human health based on their structure-activity relationship and bioavailability. We then discussed in detail the photoprotective effects of some selected polyphenols on UV-induced skin inflammation, proliferation, immunosuppression, DNA damage and dysregulation of important cellular signaling pathways and their implications in skin cancer management. The selected polyphenols include: green tea polyphenols, pomegranate fruit extract, grape seed proanthocyanidins, resveratrol, silymarin, genistein and delphinidin. The new information on the mechanisms of action of these polyphenols supports their potential use in skin photoprotection and prevention of photocarcinogenesis in humans. © 2011 Bentham Science Publishers.


Prasad R.,University of Alabama at Birmingham | Katiyar S.K.,University of Alabama at Birmingham | Katiyar S.K.,Birmingham Veterans Affairs Medical Center
Oncotarget | Year: 2014

MiR-106b is overexpressed in various types of cancers and is associated with the regulation of the carcinogenic processes. Using RT-PCR, we have identified overexpression of miRNA-106b in various melanoma cell lines (A375, Hs294t, SKMel28, SK-Mel 119, Mel 1241, Mel 1011 and Mel 928) as compared to its expression in normal human epidermal melanocytes (NHEM). The overexpression of miR-106b in melanoma cells (A375, Hs294t) was associated with greater cell proliferation capacity than NHEM. Treatment of A375 and Hs294t cells with anti-miR-106b resulted in inhibition of cell proliferation as well as G1-phase arrest. We determined the effects of grape seed proanthocyanidins (GSPs) on the expression of miRNA-106b and its underlying molecular targets. Treatment of A375 and Hs294t cells with GSPs resulted in suppression of the levels of miRNA-106b, cytotoxicity, G1-phase arrest and reactivation of p21/WAF1/Cip1. Dietary GSPs significantly inhibited growth of A375 melanoma cell tumor xenografts in nude mice, which was associated with reduction in the levels of miRNA-106b, tumor cell proliferation and increases in the levels of p21/WAF1/Cip1 protein. These studies suggest that miRNA-106b plays a crucial role in melanoma growth and that GSPs act as an inhibitor of miR-106b thereby blocking melanoma growth in vitro and in vivo models.


Katiyar S.K.,University of Alabama at Birmingham | Katiyar S.K.,Birmingham Veterans Affairs Medical Center | Athar M.,University of Alabama at Birmingham
Cancer Prevention Research | Year: 2013

A wide variety of phytochemicals, mostly flavonoids or polyphenolics, have been shown to possess anticarcinogenic activities. Among these are the grape seed proanthocyanidins (GSPs), which are the active ingredients of grape seed extract (GSE). Substantial in vitro and preclinical in vivo studies have shown the chemopreventive efficacy of GSPs against various forms of cancers in different tumor models. In this issue of the journal, Derry and colleagues show that administration of GSE in the diet reduces azoxymethaneinduced colon carcinogenesis in an A/J mouse model. The results of this innovative and comprehensive study indicate that inhibition of azoxymethane-induced colon cancer by dietary GSE is mediated through the induction of apoptosis that is associated with alterations in microRNA (miRNA) and cytokine expression profiles as well as β-catenin signaling. Notably, the demonstration that miRNA expression is affected by dietary GSE suggests a novel underlying mechanism for the chemopreventive action of GSE in colon cancer and, potentially, other cancers. © 2013 American Association for Cancer.


Hage F.G.,University of Alabama at Birmingham | Hage F.G.,Birmingham Veterans Affairs Medical Center
Journal of Human Hypertension | Year: 2014

C-reactive protein (CRP), the prototypical acute-phase reactant, is one of the most widely known biomarkers of cardiovascular disease. Circulating levels of CRP are clinically used to predict the occurrence of cardiovascular events and to aide in the selection of therapies based on more accurate risk assessment in individuals who are at intermediate risk. This paper reviews the role of CRP in hypertension. In hypertensive individuals, CRP levels associate with vascular stiffness, atherosclerosis and the development of end-organ damage and cardiovascular events. Data suggest that some anti-hypertensive medications may lower CRP levels in a manner independent of their effect on blood pressure. In individuals who are normotensive at baseline, CRP levels have been shown in multiple cohorts to foretell the development of hypertension on follow-up. Whether genetic variability that influences circulating levels of CRP independent of environmental and behavioral factors can also be used in a similar manner to predict the change in blood pressure and development of hypertension is controversial. In addition to its role as a biomarker, experimental studies have unraveled an active direct participation of CRP in the development of endothelial dysfunction, vascular stiffness and elevated blood pressure. CRP has also been implicated as a mediator of vascular remodeling in response to injury and cardiac remodeling in response to pressure overload. Emerging data may reveal novel vascular inflammatory pathways and identify new targets for treatment of vascular pathology. © 2014 Macmillan Publishers Limited All rights reserved.


Singh T.,University of Alabama at Birmingham | Katiyar S.K.,University of Alabama at Birmingham | Katiyar S.K.,Birmingham Veterans Affairs Medical Center
PLoS ONE | Year: 2011

Melanoma is the most serious type of skin disease and a leading cause of death from skin disease due to its highly metastatic ability. To develop more effective chemopreventive agents for the prevention of melanoma, we have determined the effect of green tea catechins on the invasive potential of human melanoma cells and the molecular mechanisms underlying these effects using A375 (BRAF-mutated) and Hs294t (Non-BRAF-mutated) melanoma cell lines as an in vitro model. Employing cell invasion assays, we found that the inhibitory effects of green tea catechins on the cell migration were in the order of (-)-epigallocatechin-3-gallate (EGCG)>(-)-epigallocatechin>(-)-epicatechin-3-gallate>(-)-gallocatechin>(-)-epicatechin. Treatment of A375 and Hs294t cells with EGCG resulted in a dose-dependent inhibition of cell migration or invasion of these cells, which was associated with a reduction in the levels of cyclooxygenase (COX)-2, prostaglandin (PG) E 2 and PGE 2 receptors (EP2 and EP4). Treatment of cells with celecoxib, a COX-2 inhibitor, also inhibited melanoma cell migration. EGCG inhibits 12-O-tetradecanoylphorbol-13-acetate-, an inducer of COX-2, and PGE 2-induced cell migration of cells. EGCG decreased EP2 agonist (butaprost)- and EP4 agonist (Cay10580)-induced cell migration ability. Moreover, EGCG inhibited the activation of NF-κB/p65, an upstream regulator of COX-2, in A375 melanoma cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-κB, also inhibited cell migration. Inhibition of melanoma cell migration by EGCG was associated with transition of mesenchymal stage to epithelial stage, which resulted in an increase in the levels of epithelial biomarkers (E-cadherin, cytokeratin and desmoglein 2) and a reduction in the levels of mesenchymal biomarkers (vimentin, fibronectin and N-cadherin) in A375 melanoma cells. Together, these results indicate that EGCG, a major green tea catechin, has the ability to inhibit melanoma cell invasion/migration, an essential step of metastasis, by targeting the endogenous expression of COX-2, PGE 2 receptors and epithelial-to-mesenchymal transition. © 2011 Singh, Katiyar.


Prasad R.,University of Alabama at Birmingham | Katiyar S.K.,University of Alabama at Birmingham | Katiyar S.K.,Birmingham Veterans Affairs Medical Center
Cancer Letters | Year: 2013

Here we explore the effect of grape seed proanthocyanidins (GSPs) on pancreatic cancer cell migration and the molecular mechanisms underlying these effects. Treatment of human pancreatic cancer cell lines Miapaca-2, PANC-1 and AsPC-1 with GSPs resulted in inhibition of cell migration (19-82%, P< 0.01-0.001), which was associated with decreased phosphorylation of ERK1/2 and inactivation of NF-κB. Treatment of cells with UO126, an inhibitor of MEK, and caffeic acid phenethyl ester, an inhibitor of NF-κB, also inhibited the migration of cells (40-80%, P< 0.01-0.001). Inhibition of cell migration by GSPs was associated with reversal of the epithelial-to-mesenchymal transition. This was associated with upregulation of E-cadherin and desmoglein-2 and down-regulation of fibronectin, N-cadherin and vimentin. © 2012 Elsevier Ireland Ltd.


Prasad R.,University of Alabama at Birmingham | Katiyar S.K.,Birmingham Veterans Affairs Medical Center | Katiyar S.K.,University of Alabama at Birmingham
PLoS ONE | Year: 2012

Despite advances in surgical and medical therapies, approximate 50% survival rate of head and neck squamous cell carcinoma (HNSCC) has had marginal improvement in the last 30 years. Therefore, alternative strategies are required for the management of HNSCC. Here, we report the chemotherapeutic effect of proanthocyanidins on HNSCC cells using in vitro and in vivo models. Treatment of human HNSCC cell lines from different sub-sites, such as oral cavity (SCC1), larynx (SCC5), tongue (OSC19) and pharynx (FaDu), with grape seed proanthocyanidins (GSPs) reduced their cell viability and induced cell death in a dose- and time-dependent manner. GSPs induced inhibition of cell viability was associated with: (i) G1-phase arrest, (ii) inhibition of expressions of cyclins (cyclin D1 and Cyclin D2) and cyclin-dependent kinases (Cdk), (iii) increased expression of the Cdk inhibitory proteins (Cip1/p21, Kip1/p27), enhanced binding of Cdk inhibitors to Cdks, and downregulation of E2F transcription factor. GSPs significantly (P<0.05-0.001) increased apoptosis of SCC1 and OSC19 cells with induction of Bax, reduced expression of Bcl-2, and activation of caspase-3. GSPs also reduced the expression of epidermal growth factor receptor (EGFR), and treatment of SCC1 cells with erlotinib, an EGFR-targeting small molecule tyrosine kinase inhibitor, significantly (P<0.05-0.001) reduced cell viability and increased cell death. Dietary administration of GSPs (0.5%, w/w) in supplementation with AIN76A control diet inhibited the growth of SCC1 tumor xenografts in athymic nude mice, which was associated with: (i) inhibition of cell proliferation, (ii) induction of apoptosis of tumor xenograft cells, (iii) decreased expression of cyclins and Cdks, (iv) decreased expression of EGFR, and (v) increased expression of Cip1/p21 and Kip1/p27 proteins and their increased binding to Cdks in tumor xenograft samples. Together, these results suggest that GSPs may be a promising candidate for head and neck squamous cell carcinoma therapy. © 2012 Prasad, Katiyar.

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