scholarly journals The X-Linked Inhibitor of Apoptosis Protein Inhibitor Embelin Suppresses Inflammation and Bone Erosion in Collagen Antibody Induced Arthritis Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Anak A. S. S. K. Dharmapatni ◽  
Melissa D. Cantley ◽  
Victor Marino ◽  
Egon Perilli ◽  
Tania N. Crotti ◽  
...  
Keyword(s):  
Low Dose ◽  
Bone Erosion ◽  
Joint Inflammation ◽  
Inhibitor Of Apoptosis ◽  
High Dose ◽  
Tartrate Resistant Acid Phosphatase ◽  
Collagen Crosslinks ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Carboxy Terminal

Objective. To investigate the effect of Embelin, an inhibitor of X-Linked Inhibitor of Apoptosis Protein (XIAP), on inflammation and bone erosion in a collagen antibody induced arthritis (CAIA) in mice.Methods. Four groups of mice (n=6per group) were allocated: CAIA untreated mice, CAIA treated with Prednisolone (10 mg/kg/day), CAIA treated with low dose Embelin (30 mg/kg/day), and CAIA treated with high dose Embelin (50 mg/kg/day). Joint inflammation was evaluated using clinical paw score and histological assessments. Bone erosion was assessed using micro-CT, tartrate resistant acid phosphatase (TRAP) staining, and serum carboxy-terminal collagen crosslinks (CTX-1) ELISA. Immunohistochemistry was used to detect XIAP protein. TUNEL was performed to identify apoptotic cells.Results. Low dose, but not high dose Embelin, suppressed inflammation as reflected by lower paw scores (P<0.05) and lower histological scores for inflammation. Low dose Embelin reduced serum CTX-1 (P<0.05) and demonstrated lower histological score and TRAP counting, and slightly higher bone volume as compared to CAIA untreated mice. XIAP expression was not reduced but TUNEL positive cells were more abundant in Embelin treated CAIA mice.Conclusion. Low dose Embelin suppressed inflammation and serum CTX-1 in CAIA mice, indicating a potential use for Embelin to treat pathological bone loss.

scholarly journals Phase I/II Trial of AEG35156 X-Linked Inhibitor of Apoptosis Protein Antisense Oligonucleotide Combined With Idarubicin and Cytarabine in Patients With Relapsed or Primary Refractory Acute Myeloid Leukemia

2009 ◽  
Vol 27 (28) ◽  
pp. 4741-4746 ◽  
Author(s):  
Aaron D. Schimmer ◽  
Elihu H. Estey ◽  
Gautam Borthakur ◽  
Bing Z. Carter ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Antisense Oligonucleotide ◽  
Myeloid Leukemia ◽  
Complete Response ◽  
Inhibitor Of Apoptosis ◽  
High Dose ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Acute Myeloid

Purpose X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of caspases 3 and 9 which are overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report on a phase I/II trial of the XIAP antisense oligonucleotide AEG35156 in combination with reinduction chemotherapy. Patients and Methods Twenty-four patients with rapidly relapsed or refractory AML were treated with escalating doses of AEG35156 (12 to 250 mg/m2) as an intravenous solution over 2 hours and 32 patients were treated with the highest planned dose of 350 mg/m2 in combination with idarubicin and high-dose cytarabine reinduction chemotherapy. Correlative studies were conducted to determine the effects of AEG35156 on levels of XIAP mRNA. Results Knockdown of XIAP mRNA during treatment increased with the dose of the antisense. All patients who received 350 mg/m2 of AEG35156 had higher than 30% target knockdown with a median maximal knockdown of 90% (range, 48% to 100%). The overall response rate was higher among the patients receiving the highest dose of AEG35156. In this group, 15 (47%) of 32 patients achieved complete response (CR)/CR with incomplete platelet count recovery (CRp) compared with only one (4%) of 24 receiving 12 to 250 mg/m2 AEG35156. Among the patients receiving 350 mg/m2 of AEG35156 in combination with chemotherapy, 10 (91%) of 11 who were refractory to a single induction chemotherapy regimen achieved CR/CRp after reinduction with AEG35156 and chemotherapy. AEG35156 was well tolerated save for two cases of peripheral neuropathy in patients receiving multiple doses of AEG35156. Conclusion At the highest dose tested, AEG35156 knocks down its target and appears very effective when combined with chemotherapy in patients with AML refractory to a single induction regimen.

Turner syndrome patients with bicuspid aortic valves and renal malformations exhibit abnormal expression of X-linked inhibitor of apoptosis protein (XIAP)

2015 ◽  
Vol 28 (11-12) ◽  
Author(s):  
Ganesh S. Jevalikar ◽  
Margaret Zacharin ◽  
Mary White ◽  
Steven W. Yau ◽  
Winnie Li ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Turner Syndrome ◽  
Quantitative Polymerase Chain Reaction ◽  
Inhibitor Of Apoptosis ◽  
Aortic Valves ◽  
Inhibitor Of Apoptosis Protein ◽  
Abnormal Expression ◽  
Apoptosis Protein ◽  
Renal Malformations ◽  
Bicuspid Aortic Valves

AbstractWe analyzed mRNA expression of X-linked inhibitor of apoptosis protein (XIAP) in patients with Turner syndrome (TS) and examined its association with phenotypic features.XIAP mRNA expression levels were investigated in 98 patients with TS in total RNA extracted from blood leucocytes by real time quantitative polymerase chain reaction.Levels of XIAP mRNA were significantly lower in patients with bicuspid aortic valves (BAV; n=13) than those without (log XIAP –1.17±0.3 vs. –0.94±0.2, p=0.002). Significantly higher expression of XIAP mRNA was seen in patients with a mosaic karyotype and renal malformations (log XIAP –0.79±0.3 vs. –1.0±0.3, p=0.03). No correlations were seen between XIAP and other manifestations.Abnormal expression of XIAP may be an important underlying mechanism in the development of BAV and renal malformations in TS. However, abnormal XIAP mRNA expression, as determined from peripheral mononuclear cells, does not appear to explain all the somatic and visceral stigmata of TS.

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