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(12) Patent Application Publication (10) Pub. No.: US 2007/0077310 A1 Zemel Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0077310 A1 Zemel Et Al US 20070077310A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0077310 A1 Zemel et al. (43) Pub. Date: Apr. 5, 2007 (54) METHODS OF REDUCING THE Publication Classification PRODUCTION OF REACTIVE OXYGEN SPECIES AND METHODS OF SCREENING (51) Int. Cl. ORDENTIFYING COMPOUNDS AND CI2O I/26 (2006.01) COMPOSITIONS THAT REDUCE THE A 6LX 3L/355 (2006.01) PRODUCTION OF REACTIVE OXYGEN A6IR 33/42 (2006.01) SPECIES A6IR 33/10 (2006.01) (75) Inventors: Michael B. Zemel, Knoxville, TN (52) U.S. Cl. ......................... 424/602; 424/687: 514/355; (US); Xiaocun Sun, Knoxville, TN 514/458; 435/25 (US) Correspondence Address: SALWANCHIK LLOYD & SALWANCHK (57) ABSTRACT A PROFESSIONAL ASSOCATION PO BOX 142950 The Subject application provides methods of identifying GAINESVILLE, FL 32614-2950 (US) compounds, combinations of compounds, compositions, and/or combinations of compositions that are Suitable for (73) Assignee: University of Tennessee Research reducing the production of reactive oxygen species (ROS) in Foundation, Knoxville, TN an individual with the proviso that said compound, combi Appl. No.: 11/542,703 nation of compounds, composition, or combination of com (21) positions is not a dietary material containing calcium or (22) Filed: Oct. 3, 2006 dietary calcium. Also provided in the Subject application are methods of treating diseases or disorders associated with Related U.S. Application Data ROS production and methods of reducing ROS production in an individual with the proviso that said compound, (60) Provisional application No. 60/723,042, filed on Oct. combination of compounds, composition, or combination of 3, 2005. Provisional application No. 60/787,819, filed compositions is not a dietary material containing calcium or on Mar. 31, 2006. dietary calcium. Patent Application Publication Apr. 5, 2007 Sheet 1 of 38 US 2007/007731.0 A1 Z. A *(p<0.015) 250 se (p<0.01) Owild-type mice 200 Transgenic mices 150 100 O A1 50 O Baseline After Diet *(p<0.001) a 4 *(-0.01<0.01) Owild-type mice sco Transgenic mice- gld 3 - s O 2 A. Sa 1 O Baseline After Diet FIG. 2 Patent Application Publication Apr. 5, 2007 Sheet 2 of 38 US 2007/007731.0 A1 12 - * (p P O.04) - BodyE. Weightfat weight Basal diet High calcium diet FIG. 3 180 150 120 Basal diet High calcium diet FIG. 4 Patent Application Publication Apr. 5, 2007 Sheet 3 of 38 US 2007/007731.0 A1 46 2 600 (p<0.001)(p<U. PViceral fat 5 Subcutaneous fat 5 2 400 r # (p<0.001) O 200 - O A. O Basal diet High calcium diet * (p<0.012) a 2.5 O Viceral fat Subcutaneous fat isr 2 m-- o 1.5 A. A <6 1 Z. 0.5 O Basal diet High calcium diet FIG. 6 Patent Application Publication Apr. 5, 2007 Sheet 4 of 38 US 2007/007731.0 A1 (p<0.001) O Viceral fat Subcutaneous fat 2 O O Basal diet High calcium diet FIG. 7 * (p<0.001) # (p<0.001) Viceral fat Subcutaneous fat Basal diet High calcium diet FIG. 8 Patent Application Publication Apr. 5, 2007 Sheet 5 of 38 US 2007/007731.0 A1 Basal diet High calcium diet FIG. 10 Patent Application Publication Apr. 5, 2007 Sheet 6 of 38 US 2007/007731.0 A1 Viceral fat Subcutaneous fat Basal diet High calcium diet FIG. 11 D Control 600 attocopherol 500 4 OO 300 200 100 O -- -- GDP Nifedipine Patent Application Publication Apr. 5, 2007 Sheet 7 of 38 US 2007/0077310 A1 80 O Control or it tocopherol 6 O - 4 0 20 O Control H.O, Ho. Ho, GDP Nifedipine FIG. 13 D Wild type l UCP2 transfected 0.8 .S. 5 0.6 d d is 0.4 r 2s 0.2 9 S. > O Control H2O, -- -- GDP Nifedipine FIG. 14 Patent Application Publication Apr. 5, 2007 Sheet 8 of 38 US 2007/007731.0 A1 600 is 450 E s 300 es S. 150 O Control H2O2 -- otocopherol 280Ž O) S560 s s 40 C A3 20 O Control Glucose Glucose Glucose Glucose -- -- 1,25D GDP Nifedipine FIG. 16 Patent Application Publication Apr. 5, 2007 Sheet 9 of 38 US 2007/007731.0 A1 300 S 200 *cy 100 9. O Control Glucose Glucose -- dittocopherol FIG. 17 UCP2 transfected 2 O Wild-type 1 6 1 2 Control Glucose Glucose Glucose Glucose -- -- -- Nifedipine 1, 25D GDP FIG. 18 Patent Application Publication Apr. 5, 2007 Sheet 10 of 38 US 2007/0077310 A1 1 8 DUCP2 transfected 12 Control Glucose Glucose Glucose Glucose -- -- -- Nifedipine 1, 25D GDP FIG. 19 Control Glucose Glucose Glucose Glucose -H -H -H 125D GDP Nifedipine FIG. 20 Patent Application Publication Apr. 5, 2007 Sheet 11 of 38 US 2007/0077310 A1 3 & t 2 . 3. 1 O Control Glucose Glucose Glucose Glucose -- -- -- Nifedipine 1, 25D GDP FIG 21 Subcutaneous fat Visceral fat FIG.22A Patent Application Publication Apr. 5, 2007 Sheet 12 of 38 US 2007/0077310 A1 Basal diet High-Ca diet Basal diet High-Ca diet Subcutaneous fat Visceralfat FIG. 22B Basal diet High-Cadiet -N-1 Visceral fat FIG. 23A Patent Application Publication Apr. 5, 2007 Sheet 13 of 38 US 2007/007731.0 A1 1.6 b 3 1.2 s 0.8 O . t O Basal diet High-Ca diet N-N-1 Visceral fat 2.5 2 b 5 àis ,1 a O Basal diet High-Cadiet Y-N-1 Soleus muscle FIG. 23C Patent Application Publication Apr. 5, 2007 Sheet 14 of 38 US 2007/007731.0 A1 ; Control 1, 25 (OHDD, Nifedipine 1, 25(OH).D. -- Nifedipine FIG. 24A Control 1, 25(OH)D. Nifedipine 1, 25 (OH). D. re Nifedipine FIG. 24B Basal diet High-Ca Diet FIG. 24C Patent Application Publication Apr. 5, 2007 Sheet 15 of 38 US 2007/007731.0 A1 0.3 O C tr ol l, 2 5( O H), D N ifedipine 1,25(OH),D, r Nifedipine FIG. 25A Control l, 25(OH),D, Nifedipine 1,25(OH),D, -- Nifedipine FIG. 2SB Patent Application Publication Apr. 5, 2007 Sheet 16 of 38 US 2007/007731.0 A1 i Control l, 25(OH), D, Nifedipine l, 25(OH),D, -- Nifedipine FIG. 25C O Control 1, 25OH).D. Nifedipine 1,25OHDDs -- Nifedipine FIG. 25D Patent Application Publication Apr. 5, 2007 Sheet 17 of 38 US 2007/007731.0 A1 1.2 0.9 3 0.6 S NaC s H 0.3 O Control attocopherol HO, HO, -- attocopherol C y 9 e S. es Control attocopherol HO HO, attocopherol FIG. 26B Patent Application Publication Apr. 5, 2007 Sheet 18 of 38 US 2007/007,731.0 A1 1. 0.8 0.6 CO S '? 0.4 s 0.2 O Control attocopherol HO HO -H otocopherol (A) so l d Control Calcitriol Calcitriol Nifedipine -- Nifedipine FIG. 27A Patent Application Publication Apr. 5, 2007 Sheet 19 of 38 US 2007/007731.0 A1 0.6 So 0.4 s'? | | | || 8" | | | | | | | | O ... Control Calcitriol Calcitriol Nifedipine Nifedipine FIG. 27B Control Calcitriol Calcitriol Nifedipine FIG. 28A Patent Application Publication Apr. 5, 2007 Sheet 20 of 38 US 2007/007731.0 A1 Control Calcitriol Calcitriol Nifedipine FIG. 28B OControl Co-Culture Control Calcitriol Calcitriol Calcitriol He s Nifedipine DNP FIG. 29 Patent Application Publication Apr. 5, 2007 Sheet 21 of 38 US 2007/007731.0 A1 Control 3 Co-Culture 8 2 n 2 O Control Calcitriol Calcitriol Calcitrio H Nifedipine DNP FIG. 30 Patent Application Publication Apr. 5, 2007 Sheet 22 of 38 US 2007/007731.0 A1 Control on 3 Co-Culture OO S 2 1 O Control Calcitriol Calcitriol Calcitriol -- H. Nifedipine DNP FIG. 31 1 2 3 4 5 6 7 8 910 Control FIG. 32A Patent Application Publication Apr. 5, 2007 Sheet 23 of 38 US 2007/007731.0 A1 -.' . v , . , -, real-e-r-e- Calcitrio-teated FIG. 32B 1 2 M-CSF (NFS) fy IL-12 Schematic diagram of antibody array FIG. 32C Patent Application Publication Apr. 5, 2007 Sheet 24 of 38 US 2007/007731.0 A1 8C: s It Wis s b & S as c y NW s 3.c s (S 3. S Q1 & s W sa c C. S S Sto co to Sr S 2 V Asued Patent Application Publication Apr. 5, 2007 Sheet 25 of 38 US 2007/007731.0 A1 1 2 3 4 5 S 7 8 9 10 E Control FIG. 33A Calcitrio-treated FIG. 33B Patent Application Publication Apr. 5, 2007 Sheet 26 of 38 US 2007/007731.0 A1 Schematic diagram of antibody array FIG. 33C Patent Application Publication Apr. 5, 2007 Sheet 27 of 38 US 2007/007731.0 A1 8CS3 | 8 W It QoisS s 'f & S 3. s N W s & s é (Sf NS S W 8 as g c g Patent Application Publication Apr. 5, 2007 Sheet 28 of 38 US 2007/007731.0 A1 Control Co-Culture Control Calcitrio Calcitrio Calcitrio se Nifedipine DNP . FIG. 34 O Control Co-Culture Control Calcitriol Calcitrio Calcitriol s an Nifedipine DNP FIG. 35 Patent Application Publication Apr. 5, 2007 Sheet 29 of 38 US 2007/007731.0 A1 O Control Co-Culture 4 O - Control Calcitrio Calcitrio Calcitrio as o Nifedipine DNP FIG. 36 P = 0.012 basal vs. calcium. p = 0.285 basal vs. milk p = 0.005 calcium vs. milk. p = 0.018 Basal High-Ca Milk FIG. 37 Patent Application Publication Apr. 5, 2007 Sheet 30 of 38 US 2007/007731.0 A1 P = 0.002 basal vs. calcium p = 0.038 basal vs.
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