Compositions for anti-inflammatory, antioxidant effects and improved respiratory function by specific histone deacetylase inhibition

Abstract

Compositions comprising LSF compositions and treatment regiments comprising administration of LSF containing compositions are disclosed. Compositions and/or regiments may optionally include the administration of vitamins, minerals, and anti-oxidants. Methods for using these compositions and treatment regimens for treating subjects for diseases, including diseases associated with inflammation and/or oxidative stress, are provided. Various methods for use of the LSF compositions for inhibition of histone deacetylases (HDACs) in various cells, tissues, and/or conditions are also provided.

We claim: 
     
         1 . A pharmaceutical composition for treatment, suppression and/or amelioration of a condition or disease associated with inflammation or oxidative stress, wherein said composition comprises L-sulforaphane (LSF), an LSF derived and/or substituted compound, and/or an LSF analogue. 
     
     
         2 . The composition of  claim 1  wherein the LSF, LSF derived and/or substituted compound, and/or an LSF analogue is isolated, purified and/or synthesized and has the following formula: 
       
         
           
           
               
               
           
         
         and has an inhibitory effect against one or more HDAC proteins. 
       
     
     
         3 . The composition of  claim 1  wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, ORa, SRa, SORa, SO2Ra, OSO2Ra, OSO3Ra, NO2, NHRa, N(Ra)2, ═N—Ra, N(Ra)CORa, N(CORa)2, N(Ra)SO2R′, N(Ra)C(═NRa)N(Ra)Ra, CN, halogen, CORa, COORa, OCORa, OCOORa, OCONHRa, OCON(Ra)2, CONHRa, CON(Ra)2, CON(Ra)ORa, CON(Ra)SO2Ra, PO(ORa)2, PO(ORa)Ra, PO(ORa)(N(Ra)Ra) and aminoacid ester having inhibitory efficacy against the LSD1 protein; and further wherein each of the Ra groups is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, and the like; and further wherein each of the substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and/or acyl groups are C1-28 (including all ranges therein). 
     
     
         4 . The composition of  claim 3  wherein the LSF, LSF derived and/or substituted compound, and/or an LSF analogue has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The composition of  claim 1  wherein said condition or disease is pulmonary edema or exercise-induced pulmonary hemorrhage (EIPH). 
     
     
         6 . The composition of  claim 1  further comprising one or more of hydroxytyrosol, oleuropein, N-acetylcysteine, L-proline, glycine, and taurine. 
     
     
         7 . A method of treating or preventing a condition or disease associated with inflammation or oxidative stress, comprising administering to a subject in need thereof a composition comprising L-sulforaphane (LSF), an LSF derived and/or substituted compound, and/or an LSF analogue. 
     
     
         8 . The method of  claim 7  wherein the LSF, LSF derived and/or substituted compound, and/or an LSF analogue is isolated, purified and/or synthesized and has the following formula: 
       
         
           
           
               
               
           
         
         and has an inhibitory effect against one or more HDAC proteins. 
       
     
     
         9 . The method of  claim 7  wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, ORa, SRa, SORa, SO2Ra, OSO2Ra, OSO3Ra, NO2, NHRa, N(Ra)2, ═N—Ra, N(Ra)CORa, N(CORa)2, N(Ra)SO2R′, N(Ra)C(═NRa)N(Ra)Ra, CN, halogen, CORa, COORa, OCORa, OCOORa, OCONHRa, OCON(Ra)2, CONHRa, CON(Ra)2, CON(Ra)ORa, CON(Ra)SO2Ra, PO(ORa)2, PO(ORa)Ra, PO(ORa)(N(Ra)Ra) and aminoacid ester having inhibitory efficacy against the LSD1 protein; and further wherein each of the Ra groups is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, and the like; and further wherein each of the substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and/or acyl groups are C1-28 (including all ranges therein). 
     
     
         10 . The method of  claim 7  wherein the LSF, LSF derived and/or substituted compound, and/or an LSF analogue has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 7  further comprising administering to said individual one or more of hydroxytyrosol, oleuropein, N-acetylcysteine, L-proline, glycine, and taurine. 
     
     
         12 . The method of  claim 7  wherein said disease or condition is pulmonary edema or exercise-induced pulmonary hemorrhage (EIPH). 
     
     
         13 . A method for increasing or decreasing gene expression in a cell comprising contacting said cell with a composition comprising L-sulforaphane (LSF), an LSF derived and/or substituted compound, and/or an LSF analogue. 
     
     
         14 . The method of  claim 13  further comprising inhibiting one or more histone deacetylases (HDAC) in said cell. 
     
     
         15 . The method of  claim 14  wherein said HDAC is HDAC8. 
     
     
         16 . The method of  claim 14  further comprising administering comprising contacting said cell with one or more of hydroxytyrosol, oleuropein, N-acetylcysteine, L-proline, glycine, and taurine. 
     
     
         17 . The method of  claim 13  further comprising increasing lysine acetylation of a histone polypeptide in said cell. 
     
     
         18 . The method of  claim 13  wherein said increase of decrease of gene expression improves cell viability. 
     
     
         19 . A method for treating or preventing oxidative stress in an individual or cell comprising contacting said individual or cell with a with a composition comprising L-sulforaphane (LSF), an LSF derived and/or substituted compound, and/or an LSF analogue. 
     
     
         20 . The method of  claim 19  wherein the LSF, LSF derived and/or substituted compound, and/or an LSF analogue is isolated, purified and/or synthesized and has the following formula: 
       
         
           
           
               
               
           
         
         and has an inhibitory effect against one or more HDAC proteins.