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ABSTRACT: Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3), a protein that modulates inflammation and clearance of glucose adducts. We used Lean and Diet-induced Obese (DIO) WT and Gal-3 KO mice to investigate the role of Gal-3 in modulation of adiposity, glucose metabolism and inflammation. Deficiency of Gal-3 lead to age-dependent development of excess adiposity and systemic inflammation, as indicated by elevated production of acute-phase proteins, number of circulating pro-inflammatory Ly6C monocytes and development of neutrophilia, microcytic anemia and thrombocytosis in 20-week-old Lean and DIO male Gal-3 KO mice. This was associated with impaired fasting glucose, heightened response to a glucose tolerance test and reduced adipose tissue expression of adiponectin, Gal-12, ATGL and PPARγ, in the presence of maintained insulin sensitivity and hepatic expression of gluconeogenic enzymes in 20-week-old Gal-3 KO mice compared to their diet-matched WT controls. Expression of PGC-1α and FGF-21 in the liver of Lean Gal-3 KO mice was comparable to that observed in DIO animals. Impaired fasting glucose and altered responsiveness to a glucose load preceded development of excess adiposity and systemic inflammation, as demonstrated in 12-week-old Gal-3 KO mice. Finally, a role for the microflora in mediating the fasting hyperglycemia, but not the excessive response to a glucose load, of 12-week-old Gal-3 KO mice was demonstrated by administration of antibiotics. In conclusion, Gal-3 is an important modulator of glucose metabolism, adiposity and inflammation.
PLoS ONE 01/2013; 8(2):e57915. · 4.09 Impact Factor
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ABSTRACT: Obesity increases severity of acute pancreatitis and risk of pancreatic cancer. Pancreatitis and obesity are associated with elevated IL-6, a cytokine involved in inflammation and tumorigenesis. We studied the role of IL-6 in the response of lean and obese mice to pancreatitis induced by IL-12 + IL-18. Lean and diet-induced obese (DIO) WT and IL-6 KO mice and ob/ob mice pretreated with anti-IL-6 antibodies were evaluated at Days 1, 7, and 15 after induction of pancreatitis. Prolonged elevation of IL-6 in serum and visceral adipose tissue was observed in DIO versus lean WT mice, whereas circulating sIL-6R declined in DIO but not lean mice with pancreatitis. The severe inflammation and lethality of DIO mice were also observed in IL-6 KO mice. However, the delayed resolution of neutrophil infiltration; sustained production of CXCL1, CXCL2, and CCL2; prolonged activation of STAT-3; and induction of MMP-7 in the pancreas, as well as heightened induction of serum amylase A of DIO mice, were blunted significantly in DIO IL-6 KO mice. In DIO mice, production of OPN and TIMP-1 was increased for a prolonged period, and this was mediated by IL-6 in the liver but not the pancreas. Results obtained in IL-6 KO mice were confirmed in ob/ob mice pretreated with anti-IL-6 antibodies. In conclusion, IL-6 does not contribute to the increased severity of pancreatitis of obese mice but participates in delayed recovery from acute inflammation and may favor development of a protumorigenic environment through prolonged activation of STAT-3, induction of MMP-7, and sustained production of chemokines.
Journal of leukocyte biology 03/2012; 91(6):957-66. · 4.99 Impact Factor
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ABSTRACT: Obesity increases severity of acute pancreatitis (AP) by unclear mechanisms. We investigated the effect of the PPAR-gamma agonist rosiglitazone (RGZ, 0.01% in the diet) on severity of AP induced by administration of IL-12+ IL-18 in male C57BL6 mice fed a low fat (LFD) or high fat diet (HFD), under the hypothesis that RGZ would reduce disease severity in HFD-fed obese animals. In both LFD and HFD mice without AP, RGZ significantly increased body weight and % fat mass, with significant upregulation of adiponectin and suppression of erythropoiesis. In HFD mice with AP, RGZ significantly increased survival and hastened recovery from pancreatic inflammation, as evaluated by significantly improved pancreatic histology, reduced saponification of visceral adipose tissue and less severe suppression of erythropoiesis at Day 7 post-AP. This was associated with significantly lower circulating and pancreas-associated levels of IL-6, Galectin-3, osteopontin and TIMP-1 in HFD + RGZ mice, particularly at Day 7 post-AP. In LFD mice with AP, RGZ significantly worsened the degree of intrapancreatic acinar and fat necrosis as well as visceral fat saponification, without affecting other parameters of disease severity or inflammation. Induction of AP lead to major suppression of adiponectin levels at Day 7 in both HFD and HFD + RGZ mice. In conclusion, RGZ prevents development of severe AP in obese mice even though it significantly increases adiposity, indicating that obesity can be dissociated from AP severity by improving the metabolic and inflammatory milieu. However, RGZ worsens selective parameters of AP severity in LFD mice.
PLoS ONE 01/2012; 7(7):e40944. · 4.09 Impact Factor
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Diagnostic Cytopathology 10/2011; · 1.16 Impact Factor
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Venkatesh Ponemone,
Ali Keshavarzian,
Marc I Brand,
Theodore Saclarides,
Herand Abcarian, Robert J Cabay,
Emma Fletcher,
Bianca Larsen,
Larry J Durstine,
Giamila Fantuzzi,
Raja Fayad
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ABSTRACT: Leptin and adiponectin (APN) are adipokines produced by adipocytes that participate in the modulation of immune and inflammatory responses. In Crohn's disease (CD), fat wrapping surrounding the inflamed intestine produces high levels of leptin and APN. In inflammatory bowel disease (IBD), apoptosis resistance of lamina propria T lymphocytes (LPL-T) is one of the mechanisms that maintains chronic inflammation. We addressed the mechanism by which leptin and APN regulate inflammation and apoptosis in IBD.
Immune cell infiltration, several factors expressed by adipose tissue (AT), and spontaneous release of cytokines by adipocytes were measured. The presence of APN and leptin in intestinal mucosa was detected and their effect on LPL-T apoptosis, signal transducer and activator of transcription 3 (STAT3), Suppressor of Cytokine Signaling 3 (SOCS3), Bcl-2 and Bcl-xL expression, and cytokine production was studied. In addition, the effects of globular and high-molecular-weight (HMW) APN on LPL-T cytokine production and apoptosis were studied.
Higher levels of several chemokines, cytokines, and growth factors were present in AT near active than near inactive disease. A significantly higher amount of inflammatory infiltrate was present in AT near active CD than near ulcerative colitis, controls, and near the inactive area of CD. There were no changes in the ratios of APN molecular weight in control and IBD adipocyte products. Leptin and APN inhibited anti-CD3-stimulated-LPL-T apoptosis and potentiated STAT3 phosphorylation, Bcl-2, and Bcl-xL expression in IBD and control mucosa. However, SOCS3 expression was suppressed only in IBD. Both globular and HMW APN have similar effects on LPL-T cytokine production and apoptosis. Leptin and APN enhanced interleukin (IL)-10 production by anti-CD3-stimulated LPL-T in IBD only. APN, but not leptin, increased anti-CD3-induced IL-6 levels in LPL-T only in IBD patients. IL-10 exerts its anti-inflammatory activity in the presence of SOCS3 suppression by leptin or APN.
Leptin and APN maintain the inhibition of anti-CD3-stimulated LPL-T apoptosis by enhancing Bcl-2 and Bcl-xL overexpression and promoting STAT3 phosphorylation while suppressing SOCS3.
Clinical and translational gastroenterology. 01/2010; 1:e1.
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ABSTRACT: Obesity is associated with increased severity of acute pancreatitis (AP). We recently developed a model of AP induced by administration of interleukin (IL)-12+IL-18, two cytokines that are elevated in patients with AP. In this model, severe AP develops in obese leptin-deficient ob/ob mice compared to lean littermates. In the present report, we evaluated the pancreatic response of diet-induced obesity (DIO) mice to IL-12+IL-18. Body weight loss and adipose tissue necrosis were more severe and prolonged in cytokine-injected DIO compared to lean mice. Edematous AP developed in lean mice, whereas DIO mice developed necrotizing AP. Obese DIO mice developed more severe hypocalcemia, increased liver damage and a heightened acute-phase response compared to lean mice, although leukopenia and thrombocytopenia were of comparable severity in lean and DIO mice. Serum levels of IL-6, IL-10, and IL-22 were significantly higher in DIO compared to lean mice, whereas interferon-gamma and tumor necrosis factor-alpha did not differ between the two groups. In conclusion, obesity induced by high-fat diet is associated with increased disease severity and duration in the model of AP induced by administration of IL-12+IL-18.
Obesity 09/2009; 18(3):476-81. · 4.28 Impact Factor
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ABSTRACT: We investigated the effect of adiponectin (APN) deficiency in the CD4(+)CD45RB(high) transfer model of colitis. Recombination activating gene (Rag)-1 knockout (KO) and Rag-1 APN KO mice receiving CD4(+)CD45RB(high) cells developed colitis of comparable severity. Colonic mRNA expression of IL-6 and IL-17 was lower in Rag-1 APN KO mice compared to Rag-1 KO mice. Rag-1 APN KO and Rag-1 KO mice released comparable amounts of IL-6 from colon cultures, whereas release of IL-17 was higher in Rag-1 APN KO compared to Rag-1 KO mice. Expression of TNFalpha mRNA was comparable in Rag-1 KO and Rag-1 APN KO mice, but protein release was lower in Rag-1 APN KO mice compared to Rag-1 KO mice. Levels of IFNgamma and IL-10 at mRNA and protein were comparable in Rag-1 KO and Rag-1 APN KO mice. Higher mRNA expression of VCAM-1 was observed in the colon of healthy APN KO compared to WT mice, while induction of colitis resulted in a comparable increase in VCAM-1 expression in Rag-1 KO and Rag-1 APN KO mice. In conclusion, although APN regulates expression of cytokines and adhesion molecules in the colon, this does not result in alteration of overall colitis severity in the CD4(+)CD45RB(high) transfer model.
Cytokine 07/2009; 47(2):119-25. · 3.02 Impact Factor
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ABSTRACT: Discordant results of cervical biopsy histology after a cytologic diagnosis of high-grade squamous intraepithelial lesion (HSIL) are often attributed to sampling variation. The purpose of the current study was to determine whether deeper levels and ancillary staining (p16(Ink4a) and ProExC) reduce the discordant rate.
A total of 246 cases of HSIL were retrieved from the computerized database from 2005 and 2006. Of these cases, 151 were followed by cervical biopsy. There was cytologic-histologic correlation in 87 cases, as defined by the presence of high-grade (2 or 3) cervical intraepithelial neoplasia (HGCIN). For each discordant biopsy (n = 64), 2 deeper levels for hematoxylin and eosin (H&E) were taken at 30-micro and 90-micro depths, and 4 sections for p16(Ink4a) and ProExC staining were taken at a 60-micro depth. All cytologic and histologic material from these 64 cases was reviewed by 3 cytopathologists. In 2 cases, the original HSIL diagnoses were downgraded and the cases censored from the study.
Fifty-seven of the 62 discordant cases had sufficient tissue for deeper levels and ancillary staining. Two of 57 cases were reclassified to HGCIN. In both of these cases, reclassification was suggested by results of immunostains; however, the H&E sections were necessary for definitive interpretation of the immunostain results.
In the current study, deeper levels and ancillary staining with p16(Ink4a) and ProExC did not significantly reduce the discordance rate. Although there are many known causes of sampling variation, including factors related to colposcopic technique, regression of infection, and insufficient histologic sectioning, sampling variation remains a valid justification of noncorrelation in women with HSIL followed up by cervical biopsy alone.
Cancer 03/2009; 117(3):157-66. · 4.77 Impact Factor
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ABSTRACT: The goal of this study was to investigate the role of the adipokine adiponectin (APN) in development of spontaneous colitis in IL-10 knockout (KO) mice. To this aim, we generated double IL-10 APN KO mice and compared their disease development to that of single IL-10 KO mice. Both IL-10 KO and double IL-10 APN KO mice spontaneously developed colitis of comparable severity. No significant differences in inflammatory infiltrate or crypt elongation were observed in colonic tissue obtained from IL-10 KO and double IL-10 APN KO mice at either 12 or 20 wk of age. A comparable increase in circulating levels of serum amyloid A and IFN-gamma was observed in IL-10 KO and double IL-10 APN KO mice as disease progressed. In vitro stimulation of lymphocytes from mesenteric lymph nodes with anti-CD3 and anti-CD28 induced a significantly higher production of IL-17 and TNF-alpha in IL-10 KO and double IL-10 APN KO mice compared with their healthy littermates. No significant differences in cytokine production from lymphocytes or colonic mRNA expression of cytokines were observed between IL-10 KO and double IL-10 APN KO mice. Both IL-10 KO and double IL-10 APN KO mice had a similar decrease in body weight and bone mass compared with their respective healthy littermates. Finally, APN deficiency did not lead to development of insulin resistance, either in APN KO or double IL-10 APN KO mice. In conclusion, lack of APN does not play a significant role in the pathogenesis of spontaneous colonic inflammation in the IL-10 KO model.
AJP Gastrointestinal and Liver Physiology 01/2009; 296(2):G382-7. · 3.43 Impact Factor
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ABSTRACT: Leptin-deficient ob/ob mice are resistant to dextran sulfate sodium (DSS)-induced colitis and Concanavalin A (Con A)-induced hepatitis. However, the signal transduction pathways involved have not been identified. The present study investigated the effect of leptin-induced STAT3 signaling in the DSS and Con A models. Mice carrying a leptin receptor (LEPR) gene mutant for Y1138 (s/s mice), with abrogated leptin-induced STAT3 signaling, were compared with wild-type (WT) and LEPR-deficient db/db mice. Administration of DSS to s/s mice resulted in a clinical score and colon shortening of intermediate severity compared with disease induced in WT and db/db mice-the latter group having the lowest disease severity. A comparable degree of inflammatory infiltrate and epithelial damage was observed in the colon of WT and s/s mice, and these parameters were reduced in db/db mice. Levels of IFN-gamma, IL-6, IL-10, and TNF-alpha were comparable in the colon of s/s and db/db mice, and a similar trend was observed for CXCL2. s/s and WT mice developed severe liver disease in response to Con A, whereas db/db mice were protected. However, Con A-induced serum IL-6 and TNF-alpha levels in s/s mice mimicked levels observed in db/db rather than WT mice. In conclusion, lack of leptin-induced STAT3 signaling is associated with reduced cytokine production following DSS and Con A administration, but it appears to sensitize mice to the effects of proinflammatory mediators.
Journal of leukocyte biology 01/2009; 85(3):491-6. · 4.99 Impact Factor
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DDS Robert J. Cabay MD,
PhD Suman Setty MD,
DMSc Joel L. Schwartz DMD,
Mike Yao MD,
Mary Lou Schmidt MD,
MSc Sara C. Gordon DDS, Robert J. Cabay,
Suman Setty,
Joel L. Schwartz,
Mike Yao,
Mary Lou Schmidt,
Sara C. Gordon
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ABSTRACT: Teratomas, most often diagnosed in younger patients, represent the most frequently identified subtype of pediatric germ cell tumors. It is very uncommon for teratomas to present in the head and neck region and demonstrate malignant transformation. We present a case of squamous cell carcinoma arising in an alpha-fetoprotein-producing cystic teratoma of the mandible in a 2-year-old female that is, to the best of our knowledge, the first such published report. The patient was treated with surgical excision along with chemotherapy and has remained disease-free 2 years after the conclusion of therapy. Pediatr Blood Cancer 2009;52:130–132. © 2008 Wiley-Liss, Inc.
Pediatric Blood & Cancer 12/2008; 52(1):130 - 132. · 1.89 Impact Factor
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ABSTRACT: Fine-needle aspiration biopsy can be utilized effectively in the diagnosis of many bone lesions. Often, these lesions are suspected to be foci of metastatic disease based on clinical and/or radiographic findings. On occasion, microscopic examination of the aspirate yields a diagnosis of a primary neoplasm of chondroid origin. We discuss the cytologic features observed in crush preparations of the most frequently seen primary chondroid tumors of bone and how these lesions can be differentiated from each other and from metastatic lesions.
Diagnostic Cytopathology 11/2008; 36(10):758-61. · 1.16 Impact Factor
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Diagnostic Cytopathology 11/2008; 37(3):191. · 1.16 Impact Factor
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ABSTRACT: Teratomas, most often diagnosed in younger patients, represent the most frequently identified subtype of pediatric germ cell tumors. It is very uncommon for teratomas to present in the head and neck region and demonstrate malignant transformation. We present a case of squamous cell carcinoma arising in an alpha-fetoprotein-producing cystic teratoma of the mandible in a 2-year-old female that is, to the best of our knowledge, the first such published report. The patient was treated with surgical excision along with chemotherapy and has remained disease-free 2 years after the conclusion of therapy.
Pediatric Blood & Cancer 10/2008; 52(1):130-2. · 1.89 Impact Factor
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ABSTRACT: OBJECTIVE; To describe the role that primary care physicians can play in early recognition of oral and oropharyngeal squamous cell carcinomas (OOSCCs) and to review the risk factors for OOSCCs, the nature of oral premalignant lesions, and the technique and aids for clinical examination.
MEDLINE and CANCERLIT literature searches were conducted using the following terms: oral cancer and risk factors, pre-malignant oral lesions, clinical evaluation of abnormal oral lesions, and cancer screening. Additional articles were identified from key references within articles. The articles contained level I, II, and III evidence and included controlled trials and systematic reviews.
Most OOSCCs are in advanced stages at diagnosis, and treatment does not improve survival rates. Early recognition and diagnosis of OOSCCs might improve patient survival and reduce treatment-related morbidity. Comprehensive head and neck examinations should be part of all medical and dental examinations. The head and neck should be inspected and palpated to evaluate for OOSCCs, particularly in high-risk patients and when symptoms are identified. A neck mass or mouth lesion combined with regional pain might suggest a malignant or premalignant process.
Primary care physicians are well suited to providing head and neck examinations, and to screening for the presence of suspicious oral lesions. Referral for biopsy might be indicated, depending on the experience of examining physicians.
Canadian family physician Medecin de famille canadien 07/2008; 54(6):870-5. · 1.19 Impact Factor
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ABSTRACT: Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short- and long-term leptin replacement therapy. Short-term leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.
Proceedings of the National Academy of Sciences 07/2008; 105(23):8085-90. · 9.68 Impact Factor
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ABSTRACT: Proliferative verrucous leukoplakia (PVL) is a distinct clinical form of oral leukoplakia defined by its progressive clinical course, changing clinical and histopathologic features, and potential to develop into cancer. PVL behaves in a more aggressive and relentless manner than the more innocuous white oral lesions that it can resemble clinically. We present three cases of PVL that progressed to carcinoma and discuss the histopathologic findings that may either hinder or assist in the diagnosis.
Journal of Oral Pathology and Medicine 06/2007; 36(5):315-8. · 1.63 Impact Factor
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ABSTRACT: Proliferative verrucous leukoplakia (PVL) is a distinct clinical form of oral leukoplakia defined by its progressive clinical course, changing clinical and histopathological features, and potential to develop into cancer. PVL behaves in a more aggressive and relentless manner than the more innocuous white oral lesions that it can resemble clinically.
A PubMed search was conducted which identified studies that examined patients with PVL and reported data meeting inclusion criteria.
PVL is seen much more frequently in females and most often diagnosed after the sixth decade of life. Tobacco use is not strongly linked to the presence of PVL (63% of patients did not use tobacco products). Most (74%) of the patients with PVL progressed to oral carcinoma.
PVL is a persistent and progressive oral lesion that requires very close follow-up along with early and aggressive treatment to increase the chances of a favorable outcome.
Journal of Oral Pathology and Medicine 06/2007; 36(5):255-61. · 1.63 Impact Factor
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ABSTRACT: Oral care providers must be aware of the impact of bleeding disorders on the management of dental patients. Initial recognition of a bleeding disorder, which may indicate the presence of a systemic pathologic process, may occur in dental practice. Furthermore, prophylactic, restorative and surgical dental care of patients with bleeding disorders is best accomplished by practitioners who are knowledgeable about the pathology, complications and treatment options associated with these conditions. The purpose of this paper is to review common bleeding disorders and their effects on the delivery of oral health care.
Journal (Canadian Dental Association) 03/2007; 73(1):77-83. · 1.00 Impact Factor
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ABSTRACT: Adiponectin (APN) is an adipokine that regulates insulin sensitivity and is anti-inflammatory in atherosclerosis. The goal of this study was to investigate the role of APN in intestinal inflammation.
APN knockout (KO) mice and their wild-type (WT) littermates received dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) to induce intestinal inflammation. Clinical and histologic scores and proliferation of epithelial cells were assessed. Cytokines and APN levels were measured. Expression of APN and heparin binding epidermal growth factor (HB-EGF) was analyzed by immunohistochemistry. Expression of APN and its receptors, HB-EGF, and basic fibroblast growth factor (bFGF) messenger RNA was assessed by reverse-transcription polymerase chain reaction. Association of serum APN with HB-EGF and bFGF was studied by coimmunoprecipitation.
APN KO mice are protected from chemically induced colitis; administration of APN restores inflammation. APN is expressed in the colon, luminal APN associates with colonic epithelial cells. In vitro, APN increases production of proinflammatory cytokines from colonic tissue. Expression of colonic APN overlaps with that of bFGF and HB-EGF, which play a protective role in colitis. Circulating APN binds to bFGF and HB-EGF, likely inhibiting their protective activity. Inhibition of EGF receptor signaling, which is required for biologic activity of HB-EGF, restores inflammation in APN KO mice.
APN deficiency is associated with protection from chemically induced colitis. APN exerts proinflammatory activities in the colon by inducing production of proinflammatory cytokines and inhibiting bioactivity of protective growth factors. Thus, in colitis, APN exerts an opposite role compared with atherosclerosis.
Gastroenterology 02/2007; 132(2):601-14. · 11.68 Impact Factor
