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1.  Anti-inflammatory therapeutics for the treatment of atherosclerosis 
Nature reviews. Drug discovery  2011;10(5):365-376.
Atherosclerosis is the primary cause of heart disease and stroke and is thus the underlying pathology of the leading causes of death in the western world. Although risk can be reduced by lowering lipid levels, the equally important contribution of inflammation to the development of cardiovascular disease is not adequately addressed by existing therapies. Here, we summarize the evidence supporting a role for inflammation in the pathogenesis of atherosclerosis, discuss agents that are currently in the clinic and provide a perspective on the challenges faced in the development of drugs that target vascular inflammation.
doi:10.1038/nrd3444
PMCID: PMC3947588  PMID: 21532566
2.  Sociodemographic factors in a pediatric chronic pain clinic: The roles of age, sex and minority status in pain and health characteristics 
Journal of pain management  2010;3(3):273-281.
Little is known about how sociodemographic factors relate to children’s chronic pain. This paper describes the pain, health, and sociodemographic characteristics of a cohort of children presenting to an urban tertiary chronic pain clinic and documents the role of age, sex and minority status on pain-related characteristics. A multidisciplinary, tertiary clinic specializing in pediatric chronic pain. Two hundred and nineteen patients and their parents were given questionnaire packets to fill out prior to their intake appointment which included demographic information, clinical information, Child Health Questionnaire – Parent Report, Functional Disability Index – Parent Report, Child Somatization Index – Parent Report, and a Pain Intensity Scale. Additional clinical information was obtained from patients’ medical records via chart review. This clinical sample exhibited compromised functioning in a number of domains, including school attendance, bodily pain, and health compared to normative data. Patients also exhibited high levels of functional disability. Minority children evidenced decreased sleep, increased somatization, higher levels of functional disability, and increased pain intensity compared to Caucasians. Caucasians were more likely to endorse headaches than minorities, and girls were more likely than boys to present with fibromyalgia. Younger children reported better functioning than did teens. The results indicate that sociodemographic factors are significantly associated with several pain-related characteristics in children with chronic pain. Further research must address potential mechanisms of these relationships and applications for treatment.
PMCID: PMC3113686  PMID: 21686073
Chronic pain; pediatric; clinical cohort; ethnic differences
3.  Interleukin-6 protects hepatocytes from CCl4-mediated necrosis and apoptosis in mice by reducing MMP-2 expression 
Journal of hepatology  2005;42(4):548-556.
Background/Aims
Interleukin-6 stimulates liver regeneration and promotes hepatoprotection following experimental liver injury, but underlying mechanisms have not been fully characterized. Because studies suggest matrix metalloproteinase-2 (MMP-2) may promote liver injury, we examined whether IL-6 exerted its protective effects via regulation of MMP-2.
Methods
MMP-2 was analyzed in livers of IL-6−/− and IL-6+/+ mice following CCl4 administration. IL-6−/− mice were pretreated with IL-6 and liver histology and MMP-2 expression were examined after liver injury. IL-6−/− mice were treated with an MMP-2 inhibitor and assessment of injury (histology and serum ALT levels), apoptosis by TUNEL assay, and hepatocyte proliferation by BRDU-labeling was performed. These studies were complemented by analysis of cultured stellate cells.
Results
MMP-2 mRNA, protein, and activity was increased in IL-6−/− livers. Restoration of IL-6 signaling in IL-6−/− mice rescued injury and restored MMP-2 expression to wild-type levels. Furthermore, pharmacologic inhibition of MMP-2 decreased hepatocellular injury and apoptosis in IL-6−/− mice. In cultured stellate cells, recombinant IL-6 suppressed endogenous MMP-2 mRNA and protein expression.
Conclusions
IL-6 may be hepatoprotective in acute injury through down-regulation of MMP-2. These findings suggest a role for MMP-2 in amplifying liver injury in vivo.
doi:10.1016/j.jhep.2004.11.043
PMCID: PMC2893541  PMID: 15763341
Matrix degradation; Stellate cells; Fibrosis; Liver injury; Interleukin-6; Matrix metalloproteinase-2
4.  Extremes of Clinical and Enzymatic Phenotypes in Children With Hyperinsulinism Caused by Glucokinase Activating Mutations 
Diabetes  2009;58(6):1419-1427.
OBJECTIVE
Heterozygous activating mutations of glucokinase have been reported to cause hypoglycemia attributable to hyperinsulinism in a limited number of families. We report three children with de novo glucokinase hyperinsulinism mutations who displayed a spectrum of clinical phenotypes corresponding to marked differences in enzyme kinetics.
RESEARCH DESIGN AND METHODS
Mutations were directly sequenced, and mutants were expressed as glutathionyl S-transferase–glucokinase fusion proteins. Kinetic analysis of the enzymes included determinations of stability, activity index, the response to glucokinase activator drug, and the effect of glucokinase regulatory protein.
RESULTS
Child 1 had an ins454A mutation, child 2 a W99L mutation, and child 3 an M197I mutation. Diazoxide treatment was effective in child 3 but ineffective in child 1 and only partially effective in child 2. Expression of the mutant glucokinase ins454A, W99L, and M197I enzymes revealed a continuum of high relative activity indexes in the three children (26, 8.9, and 3.1, respectively; wild type = 1.0). Allosteric responses to inhibition by glucokinase regulatory protein and activation by the drug RO0281675 were impaired by the ins454A but unaffected by the M197I mutation. Estimated thresholds for glucose-stimulated insulin release were more severely reduced by the ins454A than the M197I mutation and intermediate in the W99L mutation (1.1, 3.5, and 2.2 mmol/l, respectively; wild type = 5.0 mmol/l).
CONCLUSIONS
These results confirm the potency of glucokinase as the pancreatic β-cell glucose sensor, and they demonstrate that responsiveness to diazoxide varies with genotype in glucokinase hyperinsulinism resulting in hypoglycemia, which can be more difficult to control than previously believed.
doi:10.2337/db08-1792
PMCID: PMC2682682  PMID: 19336674
5.  Considerable Differences in Vaccine Immunogenicities and Efficacies Related to the Diluent Used for Aluminum Hydroxide Adjuvant▿  
We are developing an anticandidal vaccine using the recombinant N terminus of Als3p (rAls3p-N). We report that although more rAls3p-N was bound by aluminum hydroxide diluted in saline than by aluminum hydroxide diluted in phosphate-buffered saline (PBS), its immunogenicity and efficacy were superior in PBS. Thus, protein binding, by itself, may not predict the efficacy of some vaccines with aluminum adjuvants.
doi:10.1128/CVI.00427-07
PMCID: PMC2268268  PMID: 18184821
6.  Hepatoprotection via the IL-6/Stat3 pathway 
Journal of Clinical Investigation  2003;112(7):978-980.
Stat3 is a vital transcription factor that is activated downstream of the gp130 receptor, primarily via IL-6 signaling in adult liver. A new study demonstrates that Stat3 provides hepatoprotection against Fas-mediated apoptotic liver damage by two mechanisms: direct inactivation of caspases and reduction of reactive oxygen species.
doi:10.1172/JCI200319974
PMCID: PMC198534  PMID: 14523032
7.  Impaired Hepatocyte DNA Synthetic Response Posthepatectomy in Insulin-Like Growth Factor Binding Protein 1-Deficient Mice with Defects in C/EBPβ and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Regulation 
Molecular and Cellular Biology  2003;23(4):1251-1259.
After a two-thirds hepatectomy, normally quiescent liver cells are stimulated to reenter the cell cycle and proliferate to restore the original liver mass. One of the most rapidly and highly induced genes and proteins in regenerating liver is insulin-like growth factor binding protein 1 (IGFBP-1), a secreted protein that may modulate the activities of insulin-like growth factors (IGFs) or signal via IGF-independent mechanisms. To assess the functional role of IGFBP-1 in liver regeneration, mice with a targeted disruption of the IGFBP-1 gene were generated. Although IGFBP-1−/− mice demonstrated normal development, they had abnormal liver regeneration after partial hepatectomy, characterized by liver necrosis and reduced and delayed hepatocyte DNA synthesis. The abnormal regenerative response was associated with blunted activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and a reduced induction of C/EBPβ protein expression posthepatectomy. Like cell cycle abnormalities observed in hepatectomized C/EBPβ−/− mice, cyclin A and cyclin B1 expression was delayed and reduced in IGFBP-1−/− livers, whereas cyclin D1 expression was normal. Treatment of IGFBP-1−/− mice with a preoperative dose of IGFBP-1 induced MAPK/ERK activation and C/EBPβ expression, suggesting that IGFBP-1 may support liver regeneration at least in part via its effect on MAPK/ERK and C/EBPβ activities. These findings are the first demonstration of the involvement of IGFBP-1 in the regulation of in vivo mitogenic signaling pathways.
doi:10.1128/MCB.23.4.1251-1259.2003
PMCID: PMC141131  PMID: 12556485
8.  Massive hepatic apoptosis associated with TGF-β1 activation after Fas ligand treatment of IGF binding protein-1–deficient mice 
Journal of Clinical Investigation  2003;111(1):129-139.
Acute liver failure caused by viral hepatitis or toxic damage involves both apoptotic and necrotic pathways. IGF binding protein-1 (IGFBP-1), a hepatocyte-derived secreted protein, is required for normal liver regeneration. To determine whether IGFBP-1 could prevent liver injury that entails direct stimulation of hepatocyte apoptosis, IGFBP-1–/– mice, IGFBP-1+/+ mice, and mice pretreated with Ab’s against IGFBP-1 were treated with a normally sublethal dose of Fas agonist. IGFBP-1 deficiency was associated with massive hepatocyte apoptosis and caspase activation within 3 hours of Fas agonist treatment, which could be corrected by pretreatment with IGFBP-1. IGFBP-1–deficient livers had enhanced signaling via the integrin receptor at early times (0.5 to 1 hour) after Fas agonist treatment accompanied by elevated activated matrix metalloproteinase-9 (MMP-9), a known target of fibronectin signaling and activator of TGF-β. Within 3 hours of Fas agonist treatment, elevated expression of active TGF-β1, a hepatocyte apoptogen, was observed in IGFBP-1–deficient livers that correlated with the appearance of the apoptotic process. Both MMP-9 and TGF-β1 expression were suppressed by IGFBP-1 treatment, supporting their role in the apoptotic process. IGFBP-1–/– mice also displayed increased injury in a toxic hepatic injury model caused by CCl4. These findings indicate that IGFBP-1 functions as a critical hepatic survival factor in the liver by reducing the level of proapoptotic signals.
doi:10.1172/JCI200316712
PMCID: PMC151838  PMID: 12511596
9.  Interleukin-6-Induced STAT3 and AP-1 Amplify Hepatocyte Nuclear Factor 1-Mediated Transactivation of Hepatic Genes, an Adaptive Response to Liver Injury 
Molecular and Cellular Biology  2001;21(2):414-424.
Following hepatic injury or stress, gluconeogenic and acute-phase response genes are rapidly upregulated to restore metabolic homeostasis and limit tissue damage. Regulation of the liver-restricted insulin-like growth factor binding protein 1 (IGFBP-1) gene is dramatically altered by changes in the metabolic state and hepatectomy, and thus it provided an appropriate reporter to assess the transcriptional milieu in the liver during repair and regeneration. The cytokine interleukin-6 (IL-6) is required for liver regeneration and repair, and it transcriptionally upregulates a vast array of genes during liver growth by unknown mechanisms. Evidence for a biologic role of IL-6 in IGFBP-1 upregulation was demonstrated by increased expression of hepatic IGFBP-1 in IL-6 transgenic and following injection of IL-6 into nonfasting animals and its reduced expression in IL-6−/− livers posthepatectomy. In both hepatic and nonhepatic cells, IL-6 -mediated IGFBP-1 promoter activation was via an intact hepatocyte nuclear factor 1 (HNF-1) site and was dependent on the presence of endogenous liver factor HNF-1 and induced factors STAT3 and AP-1 (c-Fos/c-Jun). IL-6 acted through the STAT3 pathway, as dominant negative STAT3 completely blocked IL-6-mediated stimulation of the IGFBP-1 promoter via the HNF-1 site. HNF-1/c-Fos and HNF-1/STAT3 protein complexes were detected in mouse livers and in hepatic and nonhepatic cell lines overexpressing STAT3/c-Fos/HNF-1. Similar regulation was demonstrated using glucose-6-phosphatase and α-fibrinogen promoters, indicating that HNF-1/IL-6/STAT3/AP-1-mediated transactivation of hepatic gene expression is a general phenomenon after liver injury. These results demonstrate that the two classes of transcription factors, growth induced (STAT3 and AP-1) and tissue specific (HNF-1), can interact as an adaptive response to liver injury to amplify expression of hepatic genes important for the homeostatic response during organ repair.
doi:10.1128/MCB.21.2.414-424.2001
PMCID: PMC86585  PMID: 11134330

Results 1-9 (9)