WO2017165572A1 - Augmentation du niveau d'expression de gènes liés à l'apoptose par traitement d'un sujet humain avec un nitroxyde - Google Patents

Augmentation du niveau d'expression de gènes liés à l'apoptose par traitement d'un sujet humain avec un nitroxyde Download PDF

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WO2017165572A1
WO2017165572A1 PCT/US2017/023681 US2017023681W WO2017165572A1 WO 2017165572 A1 WO2017165572 A1 WO 2017165572A1 US 2017023681 W US2017023681 W US 2017023681W WO 2017165572 A1 WO2017165572 A1 WO 2017165572A1
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disease
expression level
age
gene
human subject
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Louis Habash
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Priority claimed from US15/078,911 external-priority patent/US9545398B1/en
Priority claimed from US15/373,250 external-priority patent/US9744162B1/en
Priority claimed from US15/373,239 external-priority patent/US10231959B2/en
Application filed by Individual filed Critical Individual
Priority to CA3056059A priority Critical patent/CA3056059C/fr
Priority to JP2019500747A priority patent/JP2019509352A/ja
Publication of WO2017165572A1 publication Critical patent/WO2017165572A1/fr
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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    • C12Q2600/00—Oligonucleotides characterized by their use
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    • G—PHYSICS
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Definitions

  • the present disclosure relates generally to the field of treating diseases and more particularly to treating human subjects with decrease in gene expression (such as age- related decrease in gene expression) and diseases associated with decrease in gene expression with a mtroxide.
  • Apoptosis is a process of programmed cell death that occurs in multicellular organisms. Through apoptosis, cells commit suicide as a way to clear unwanted or damaged ceils or to prevent uncontrolled growth. Thus, apoptosis plays an essential role in tissue development and function. Dysregulation in the apoptotic pathway, for example decrease or increase in apoptosis, can lead to a number of diseases and conditions, for example, cancers, autoimmune diseases, inflammatory diseases, and infections.
  • Some embodiments disclosed herein provide methods for increasing gene expression.
  • the methods include administering to a human subject an effective amount of a nitroxide antioxidant resulting in an increased expression level of a gene (e.g., a gene associated with the apoptosis pathway).
  • the methods further comprise: identifying the human subject.
  • the human subject is over the age of 35 and has a decrease expression level of a gene (e.g., a gene associated with the apoptosis pathway).
  • the gene is selected from the group consisting of: Cd51, Perp, Unc5b, Bag5 and Bn3.
  • the human subject is over the age of 45.
  • the human subject is over the age of 55. In some embodiments, the human subject is over the age of 65. In some embodiments, the expression level of the gene in a skin tissue is increased. In some embodiments, the expression level of the gene in an adipose tissue is increased. In some embodiments, the expression level of the gene in blood is increased. In some embodiments, the expression level of the gene in a neuronal tissue is increased. In some embodiments, the nitroxide antioxidant is 4-hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 0.01- 300 mg/kg.
  • the effective amount of the nitroxide antioxidant is within a range of 0.1 -250 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 1 -200 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 2-150 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 5-125 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 7-100 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 10-75 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 5-30 mg/kg.
  • Some embodiments disclosed herein provide methods for increasing the expression level of a gene in a human subject in need thereof, comprising: administering to a human subject an effective amount of a nitroxide antioxidant, whereby the expression level of a gene (e.g., a gene associated with the apoptosis pathway) is increased.
  • the methods further comprise: identifying the human subject.
  • the human subject has a decreased expression level of the gene (e.g., a gene associated with the apoptosis pathway).
  • the gene is selected from the group consisting of: Cd51, Perp, Unc5b, Bag5 and Bri3, In some embodiments, the decreased expression level of the gene is age- related.
  • the human subject is over the age of 35. In some embodiments, the human subject is over the age of 45. In some embodiments, the human subject is over the age of 55. In some embodiments, the human subject is over the age of 65. In some embodiments, the decreased expression level of the gene is disease-related. In some embodiments, the disease is selected from the group consisting of cancer, rheumatoid/osteoid arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease, Alzeimer's disease, multiple sclerosis, atherosclerosis, cardiovascular disease, cataracts, dementia, osteoporosis, type 2 diabetes, and hypertension. In some embodiments, the disease is age-related.
  • the disease is age-related.
  • the expression level of the gene in a skin tissue is increased. In some embodiments, the expression level of the gene in an adipose tissue is increased. In some embodiments, the expression level of the gene in blood is increased. In some embodiments, the expression level of the gene in a neuronal tissue is increased.
  • the nitroxide antioxidant is 4-hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 0.01 -300 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 0.1 -250 mg/kg.
  • the effective amount of the nitroxide antioxidant is within a range of 1-200 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 2-150 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 5-125 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 7- 00 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 10-75 mg/kg. In some embodiments, the effecti ve amount of the nitroxide antioxidant is within a range of 15-30 mg/kg.
  • Some embodiments disclosed herein provide methods for reducing risk of a disease in a human subject in need thereof, comprising: administering to a human subject an effective amount of a nitroxide antioxidant, whereby the expression level of a gene (e.g., a gene associated with the apoptosis pathway) is increased.
  • the methods further comprise: identifying the human subject.
  • the human subject is over the age of 35 havmg an increased risk of a disease due to a decreased expression level of the gene (e.g., a gene associated with the apoptosis pathway).
  • the disease is selected from the group consisting of cancer, rheumatoid/osteoid arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease, Alzeimer's disease, multiple sclerosis, atherosclerosis, cardiovascular disease, cataracts, dementia, osteoporosis, type 2 diabetes, and hypertension.
  • the gene is selected from the group consisting of: Cd51, Perp, UneSb, Bag5 and Bn3.
  • the human subject is over the age of 45. In some embodiments, the human subject is over the age of 55. In some embodiments, the human subject is over the age of 65.
  • the expression level of the gene in a skin tissue is increased. In some embodiments, the expression level of the gene in an adipose tissue is increased. In some embodiments, the expression level of the gene in blood is increased. In some embodiments, the expression level of the gene in a neuronal tissue is increased.
  • the nitroxide antioxidant is 4-hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 0.01- 300 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 0.1-250 mg kg.
  • the effective amount of the nitroxide antioxidant is withm a range of 1-200 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is withm a range of 2-150 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 5-125 mg/kg. In some embodiments, the effective amount of the nitroxide antioxi dant is within a range of 7-100 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is withm a range of 10-75 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 15-30 mg/kg.
  • Some embodiments disclosed herein provide methods comprising: administering to a human subject an effective amount of a nitroxide antioxidant, whereby the expression level of a gene (e.g., a gene associated with the apoptosis pathway) is increased.
  • the methods further comprise: identifying the human subject.
  • the human subject has or is at risk of developing a cancer and is in need of an increased expression level of a gene (e.g., a gene associated with the apoptosis pathway).
  • the cancer can be selected from the group consisting of bladder cancer, colorectal cancer, hepatocellular carcinoma, prostate carcinoma, and kidney carcinoma.
  • the gene is selected from the group consisting of: Cd51, Perp, Unc5b, Bag5 and Bri3.
  • the cancer is age-related.
  • the human subject is over the age of 35. In some embodiments, the human subject is over the age of 45. In some embodiments, the human subject is over the age of 55. In some embodiments, the human subject is over the age of 65.
  • the expression level of the gene in a skin tissue is increased. In some embodiments, the expression level of the gene in an adipose tissue is increased. In some embodiments, the expression level of the gene in blood is increased. In some embodiments, the expression level of the gene in a neuronal tissue is increased.
  • the mtroxide antioxidant is 4-hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl.
  • the effective amount of the nitroxide antioxidant is within a range of 0.01- 300 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 0.1-250 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 1-200 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 2-150 mg kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 5-125 mg/kg.
  • the effective amount of the nitroxide antioxidant is within a range of 7-100 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 10-75 mg kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 15-30 mg/kg.
  • Some embodiments disclosed herein provide methods comprising: administering to a human subject an effective amount of a nitroxide antioxidant, wherein the expression level of a gene associated (e.g., a gene associated with the apoptosis pathway) is increased.
  • the methods further comprise: identifying the human subject.
  • the human subject has or is at risk of developing an autoimmune disease and is in need of an increased expression level of the gene (e.g., a gene associated with the apoptosis pathway).
  • the autoimmune disease can be selected from the group consisting of rheumatoid/osteoid arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease, multiple sclerosis, atherosclerosis, and osteoporosis.
  • the gene is selected from the group consisting of: Cd51, Perp, Unc5b, Bag5 and Bn3. In some embodiments, the gene is Cd51.
  • the autoimmune disease is age-related. In some embodiments, the human subject is over the age of 35. In some embodiments, the human subject is over the age of 45. In some embodiments, the human subject is over the age of 55.
  • the human subject is over the age of 65.
  • the expression level of the gene in a skin tissue is increased.
  • the expression level of the gene in an adipose tissue is increased.
  • the expression level of the gene in blood is increased.
  • the expression level of the gene in a neuronal tissue is increased.
  • the nitroxide antioxidant is 4-hydroxy-2,2,6,6-tetramethylpiperidine-l -oxyl.
  • the effective amount of the nitroxide antioxidant is within a range of 0.01-300 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 0.1-250 mg/kg.
  • the effective amount of the nitroxide antioxidant is within a range of 1-200 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 2-150 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 5-125 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 7-100 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 10-75 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is withm a range of 15-30 mg/kg.
  • Some embodiments disclosed herein provide methods for a disease associated with a decreased apoptosis in a patient in need thereof, comprising: administering to a human subject an effective amount of a nitroxide antioxidant, whereby the expression level of a gene (e.g., a gene associated with the apoptosis pathway) is increased.
  • the methods further comprise: identifying the human subject.
  • the human subject has or is at risk of developing the disease associated with a decreased expression of the gene (e.g., a gene associated with the apoptosis pathway).
  • the disease can be selected from the group consisting of cancer, rheumatoid/osteoid arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease, Alzeimer's disease, multiple sclerosis, atherosclerosis, cardiovascular disease, cataracts, dementia, osteoporosis, type 2 diabetes, and hypertension.
  • the gene is selected from the group consisting of: Cd51, Perp, Unc5b, Bag5 and Bn3.
  • the human subject is over the age of 35. In some embodiments, the human subject is over the age of 45. In some embodiments, the human subject is over the age of 55. In some embodiments, the human subject is over the age of 65.
  • the expression level of the gene in a skin tissue is increased. In some embodiments, the expression level of the gene in an adipose tissue is increased. In some embodiments, the expression level of the gene in blood is increased. In some embodiments, the expression level of the gene in a neuronal tissue is increased.
  • the nitroxide antioxidant is 4-hydroxy-2,2,6,6-tetramethylpiperidine-l -oxyl. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 0.01 -300 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is withm a range of 0.1-250 mg/kg.
  • the effective amount of the nitroxide antioxidant is within a range of 1-200 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 2-150 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 5-125 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 7-100 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is withm a range of 10-75 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is withm a range of 15-30 mg/kg.
  • Some embodiments disclosed herein provide methods for treating an individual in need thereof, comprising: administering to an individual an effective amount of a nitroxide antioxidant to increase the level of expression of a gene (e.g., a gene associated with the apoptosis pathway).
  • the methods further comprise: identifying the individual.
  • the individual is over the age of 35 and is in need of an increased expression level of the gene (e.g., a gene associated with the apoptosis pathway).
  • the gene is selected from the group consisting of: Cd5i, Perp, Unc5b, Bag5 and Bri3.
  • the human subject is over the age of 45.
  • the human subject is over the age of 55. In some embodiments, the human subject is over the age of 65. In some embodiments, the human subject has a decrease expression level of the gene. In some embodiments, the individual has or is at risk of developing an age-related condition. In some embodiments, the age-related condition comprises increased senescence in a tissue. In some embodiments, the age-related condition comprises inactivation of the apoptosis pathway in a tissue. In some embodiments, the age-related condition comprises increased molecular heterogeneity. In some embodiments, the age-related condition comprises increased functional impairment in a tissue. In some embodiments, the expression level of the gene in a skin tissue is increased.
  • the expression level of the gene in an adipose tissue is increased. In some embodiments, the expression level of the gene in blood is increased. In some embodiments, the expression level of the gene in a neuronal tissue is increased.
  • the nitroxide antioxidant is 4-hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl. In some embodiments, the effective amount of the nitroxide antioxidant is withm a range of 0.01- 300 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 0.1 -250 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 1-200 mg/kg.
  • the effective amount of the nitroxide antioxidant is within a range of 2-150 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 5-125 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is withm a range of 7-100 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 10-75 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 15-30 mg/kg.
  • Some embodiments disclosed herein provide methods for treating an individual in need thereof!, comprising: administering to an individual an effective amount of a nitroxide antioxidant to increase the level of expression of the gene associated with the apoptosis pathway.
  • the methods further comprise: identifying an individual.
  • the individual has a disease-related decreased expression level of the gene (e.g., a gene associated with the apoptosis pathway).
  • the disease can be selected from the group consisting of cancer, rheumatoid/osteoid arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease, Alzeimer's disease, multiple sclerosis, atherosclerosis, cardiovascular disease, cataracts, dementia, osteoporosis, type 2 diabetes, and hypertension.
  • the gene is selected from the group consisting of: Cd51, Perp, Unc5b, Bag5 and Bri3.
  • the human subject is over the age of 35. In some embodiments, the human subject is over the age of 45. In some embodiments, the human subject is over the age of 55. In some embodiments, the human subject is over the age of 65.
  • the expression level of the gene in a skin tissue is increased. In some embodiments, the expression level of the gene in an adipose tissue is increased. In some embodiments, the expression level of the gene in blood is increased. In some embodiments, the expression level of the gene in a neuronal tissue is increased.
  • the nitroxide antioxidant is 4-hydroxy-2,2,6,6-tetramethylpiperidine-l -oxyl. In some embodiments, the effective amount of the nitroxide antioxidant is withm a range of 0.01-300 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 0.1-250 mg/kg.
  • the effective amount of the nitroxide antioxidant is withm a range of 1-200 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 2-150 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 5-125 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 7-100 mg/kg. In some embodiments, the effective amount of the nitroxide antioxidant is within a range of 10-75 mg/kg. in some embodiments, the effective amount of the nitroxide antioxidant is within a range of 15-30 mg/kg.
  • Some embodiments disclosed herein provide methods for treating an individual having or at risk of developing a condition due to aging, comprising; administering to an individual an effective amount of a nitroxide antioxidant, whereby the expression level of a gene (e.g., a gene associated with the apoptosis pathway) is increased.
  • the methods further comprise: identifying the individual.
  • the individual is over the age of 35.
  • the individual has a decreased expression level of the gene.
  • the gene is selected from the group consisting of: Cd51, Perp, Unc5b, Bag5 and Bri3.
  • the condition is an age-related condition.
  • the age-related condition comprises increased senescence in a tissue. In some embodiments, the age-related condition comprises inactivation of the apoptosis pathway in a tissue. In some embodiments, the age-related condition comprises increased molecular heterogeneity. In some embodiments, the age-related condition comprises increased functional impairment in a tissue. In some embodiments, the age-related condition is selected from the group consisting of cancer, rheumatoid/osteoid arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease, Alzeimer's disease, multiple sclerosis, atherosclerosis, cardiovascular disease, cataracts, dementia, osteoporosis, type 2 diabetes, and hypertension. In some embodiments, the human subject is over the age of 35. In some embodiments, the human subject is over the age of 45. In some embodiments, the human subject is over the age of 55. In some embodiments, the human subject is over the age of 65.
  • cancer rheumatoid/
  • the methods comprise: administering to a individual an effective amount of a nitroxide antioxidant (e.g., the nitroxide antioxidant is 4-hydroxy-2,2,6,6- tetramethylpiperidine-l-oxyl), wherein the individual has a cancer whose expression level of Unc5b is downregulated, whereby the expression level of Unc5b is increased.
  • the methods further comprise: identifying the individual.
  • the cancer is an age-related cancer. The individual can be over the age of 35 or 55.
  • the cancer can be selected from the group consisting of bladder cancer, colorectal cancer, hepatocellular carcinoma, prostate carcinoma, and kidney carcinoma.
  • the methods comprise: administering to an individual an effective amount of a nitroxide antioxidant (e.g., the nitroxide antioxidant is 4-hydroxy-2,2,6,6- tetramethylpiperidine-l -oxyl), wherein the individual has an infection, whereby the expression level of Cd51 is increased.
  • the methods further comprise: identifying the individual.
  • the infection can be a bacterial infection.
  • the infection can be caused by a gram positive bacterium, or a gram negative bacterium.
  • the infection can be caused by bacterium of the genus Mycobacterium (e.g., Mycobacterium tuberculosis).
  • the infection can be a Mycobacterium avium intracellulare infection.
  • the infection can be caused by a bacterium of the genus Corynebactetium, e.g. Corynebacterium parvum.
  • the infection can be caused by a bacterium of the genus Listeria, e.g., Listeria monocytogenes.
  • the infection can be caused by a bacterium of the genus Streptococci.
  • the infection can result in sepsis, meningitis, or a combination thereof.
  • the infection can be a fungal infection.
  • the infection can be a viral infection.
  • the individual can have a compromised immune system.
  • the compromised immune system can be age related.
  • the individual can be over the age of 35 or 55.
  • the increased expression level of Cd51 can inhibit apoptosis of immune cells.
  • the immune cells can comprise macrophages or T-cells.
  • the methods can further comprise inhibiting or delaying
  • the methods comprise: administering to an individual an effective amount of a nitroxide antioxidant (e.g., the nitroxide antioxidant is 4- hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl), wherein the individual has a neurodegenerative disease whose expression level of Bag5 is downregulated, whereby the expression level of Bag5 is increased.
  • the methods further comprise: identifying the individual.
  • the neurodegenerative disease can be Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or a combination thereof.
  • the neurodegenerative disease can result in spinal ataxis, spinocerebellar degenerations, or a combination thereof.
  • the neurodegenerative disease can be an age-related neurodegenerative disease.
  • the individual can be over the age of 35 or 55.
  • the individual can be over the age of 55.
  • the expression level of Bag5 can be increased in a neuronal tissue.
  • the methods further comprise: inhibiting or delaying development of the neurodegenerative disease. DETAILED DESCRIPTION
  • the term "expression” means the detection of a gene product that is expressed or produced by a nucleic acid molecule by standard molecular biology methods, which gene product refers to e.g. an unspliced RNA, an mRNA, a splice variant mRNA, a polypeptide, a post-translationally modified polypeptide, a splice variant polypeptide etc., and specifically products made using an RNA gene product as a template, e.g. cDNA of the RNA.
  • differential expression of a gene means that the expression of the gene is at a higher level (“increased expression”) or lower level (“decreased expression”) in a human subject suffering from a disease, for example cancers and autoimmune diseases, relative to its expression in a normal or control subject.
  • Differential expression includes both quantitative, as well as qualitative, differences in the temporal or cellular expression pattern in a gene or its expression products among, for example, normal and diseased cells, or among cells which have undergone different disease events or disease stages.
  • increasing the expression level of a gene means causing the expression of the gene to increase by treating the human subject with a compound, for example a nitroxide antioxidant, such that the expression level of the gene after treatment is higher than the expression level of the gene before treatment in the human subject.
  • a compound for example a nitroxide antioxidant
  • the present disclosure relates to methods of treating age-related alteration in gene expression. It has been shown that the expression level of a number of genes, such as ones playing important roles in cell growth and apoptosis regulation, is decreased or downregulated in aging human beings (Glass et al. Genome Biology 2013, 14:R75, the content of which is hereb - incorporated by reference in its entirety). Gene expression changes also play important roles in aging and serve as biomarkers of physiological decline and disease conditions, such as Alzheimer's disease. Decreased gene expression levels, due to accumulation of DNA damages, were observed in the human brain (Lu et al. Nature 429, 883-891 (24 June 2004), the content of which is hereby incorporated by reference in its entirety).
  • a human subject having an age-related decrease or downregulation in gene expression levels such as those genes associated with the apoptosis pathway.
  • the human subject can be identified based on the human subject's age, gene expression level, family history, health conditions, medical history, habits, or a combination thereof.
  • the expression level of a gene (such as Cd51, Perp, Unc5b, Bag5 or Bri3) in a human subject is considered to be downregulated if the decrease in the expression level of that gene is statistically significant compared to that of a control or a reference.
  • the control or reference can be, for example, a normal healthy population, a population at large, a collection of individuals of the same age or condition or sex, or the same human subject at a different time (e.g., at an earlier time of life when the human subject does not have the disease or condition that results in the downregulation).
  • a normal healthy population or a population at large can be a population having the same or similar gender, age, and/or race, compared to the human subject.
  • the expression level of the gene in the control or reference can be the mean or median expression level of the gene in control subjects in the control or reference subjects in the reference. The decrease in expression level can be statistically significant if the probability of the observed difference occurring not by chance, the confidence level, is greater than a threshold.
  • the threshold can be, or be about, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or a number or a range between any two of these values.
  • the decrease in expression level can be, or be about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or a number or a range between any two of these values.
  • the decrease in expression level can be at least 0.1%, 0.2%, 0.3%, 0.4%, 0,5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more.
  • the human subject may have an age that is, is about, is over 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 years old.
  • the human subject is identified based on the human subject's expression profiles of one or more genes associated with the apoptosis pathway.
  • Non- limiting exemplary methods for determining the human subject's expression profiles include: amplification techniques such as PCR and RT-PCR (including quantitative variants), hybridization techniques such as in situ hybridization, microarrays, blots, and others, and high throughput sequencing techniques like Next Generation Sequencing (lllumma, Roche Sequencer, Life Technologies SOLIDTM), Single Molecule Real Time Sequencing (Pacific Biosciences), True Single Molecule Sequencing (Helicos), or sequencing methods using no light emitting technologies but other physical methods to detect the sequencing reaction or the sequencing product, like Ion Torrent (Life Technologies).
  • Non-limiting exemplary methods for determining the human subject's expression profiles include: binding techniques such as ELISA, immunohistochemistry, microarray and functional techniques such as enzymatic assays.
  • administering to the human subject the effective amount of the nitroxide antioxidant results in an increased expression level of a gene, for example a gene associated with the apoptosis pathway. Therefore, some embodiments disclosed herein provide methods for treating an individual in need thereof, comprising administering to an individual an effective amount of a nitroxide antioxidant to increase the level of expression of a gene (e.g., a gene associated with the apoptosis pathway). In some embodiments, the methods further comprise: identifying the individual. In some embodiments, the individual has a disease- related decreased expression level of the gene (e.g., a gene associated with the apoptosis pathway).
  • Some embodiments disclosed herein provide methods for treating an individual in need thereof, comprising administering to an individual an effective amount of a nitroxide antioxidant to increase the level of expression of a gene (e.g., a gene associated with the apoptosis pathway).
  • the methods further comprise; identifying the individual.
  • the individual is in need of an increased expression level of the gene (e.g., a gene associated with the apoptosis pathway).
  • Non-limiting examples of diseases associated with altered level of apoptosis include cancer; breast cancer; lung cancer; kidney cancer; cancers of the ovary and uterus; cancer of the central nervous system; cancers of the head and neck; melanoma; lymphomas; leukemia; neurological disorders; Alzheimer's disease; Parkinson's disease; Huntington's disease; amyotrophic lateral sclerosis; stroke; cardiovascular disorders; ischemia; heart failure; infectious diseases; bacterial infections; viral infections; autoimmune diseases; systemic lupus erythematosus; autoimmune lymphoproliferative syndrome; rheumatoid arthritis; and thyroiditis.
  • Non-limiting exemplary genes involved in the apoptosis pathway include those involved in the extrinsic apoptosis pathway (FAS, FASLG, TNFRSFIOA, TNFRSFIOB, TNFRSFT OC, TNFRSF10D, TNFRSFl IB, TNFSFIO, TNFRSF1A, TNF, FADD, CFLAR), those in the Caspases family (CASP1, CASP2, CASP3, CASP4, CASP5, CASP6, CASP7, CASP8, CASP9, CASP10, CASP14), those in the LAPs family (NAIP, BIRC2, BIRC3, XI ⁇ P.
  • BIRC5, BIRC6, BIRC7 those involved in the mitochondrial/intrinsic apoptosis pathway (Bcl-2 family: BCL2, MCLl, BCL2L1, BCL2L2, BCL2A1, BCL2L10, BAX, BAK1, BOK, BID, BCL2L11, BMF, BAD, BIK, I IRK.
  • PMAIPl BNIP3, BNIP3L, BCL2L14, BBC3, BCL2L12, and BCL2L13; and other proteins: APA 1 , CYCS, DIABLO, HTRA2, AIFMl , and ENDOG).
  • the gene associated with the apoptosis pathway can be Cd51, Perp, Une5b, Bag5 or Bri3.
  • the treatment can result in increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof.
  • the increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof can increase the level of apoptosis.
  • the increased level of apoptosis can result in a decrease in or disappearance of signs and symptoms of a disease associated with decreased apoptosis, including the curing of the disease associated with decreased apoptosis.
  • the increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof can decrease the level of apoptosis.
  • the decreased level of apoptosis can result in a decrease in or disappearance of signs and symptoms of the disease associated with increased apoptosis, including the curing of the disease associated with increased apoptosis.
  • Cd51 is also known as apoptosis inhibitor of macrophage (AIM), Spa, and apoptosis inhibitor 6. Higher Cd51 levels have been observed in younger people, especially in women (Yamazaki et al., PLoS One. (2014) 9(10):el09123, the content of which is incorporated by reference in its entirety). Thus, estrogen can be involved in the increase in circulating Cd51 levels. Consequently, up-regulation of Cd5i by, for example, a nitroxide antioxidant can prevent and counteract age-related diseases caused by lower Cd51 levels.
  • Cd51 participates in macrophage homeostasis, including macrophage survival by inhibiting apoptosis.
  • Macrophages play a major role in host innate defense. They can be found in tissues, for example, that function in the filtration of blood or lymph fluids, including liver, spleen, lung, and lymph nodes. Macrophages recognize, internalize, and destroy endogenous and foreign substances that may be harmful. Inflammation is a major mechanism to protect organisms from damage in responding to pathogen infection and tissue injur ⁇ '.
  • Cd51 is an immune regulator that inhibits immune cell apoptosis at the inflammatory sites and functions as a modulator in immune response.
  • Cd51 has been shown to be involved in pattern recognition of bacteria and in the modulation of monocyte inflammatory responses (Sarrias et al, J. Biol. Chem. (2005) 280:35391 -35398, the content of which is incorporated by reference in its entirety).
  • Cd51 has been shown to potentiate the antimicrobial response against Mycobacterium tuberculosis by enhancing autophagy (Sanjurjo et al., LoS One. (2013) 8(1 l):e79670, the content of which is incorporated by reference in its entirety).
  • Cd51 has been shown inhibit apoptosis of T cells and natural killer T (NKT) cells from Corynebacterium parvum-mduced liver granulomas (Kuwata et al, Comp. Hepatol. (2004) 3, Suppl. 1 :S44, the content of which is incorporated by reference in its entirety).
  • Cd51 has been shown to prevent apoptosis of CD4 + CD8 ⁇ (CD4/CD8) double-positive thymocytes induced by dexarnethasone and ⁇ -irradiation awaiting maturation in the thymus (Miyazaki et al, J. Exp. Med. (1999) 189:413- 422, the content of which is incorporated by reference in its entirety).
  • Cd51 has been shown to support the survival and the phagocytic activity of macrophages in liver inflammatory (hepatitis) lesions (Haruta et al., J. Biol. Chem. (2001) 276:22910-22914, the content of which is incorporated by reference in its entirety). Cd51 has been shown to be responsible for the resistance to infection with the intracellular bacteria Listeria monocytogenes and macrophage survival and bacterial clearance in L. monocytogenes infection (Joseph et al Cell (2004) 119:299-309, the content of which is incorporated by reference in its entirety).
  • Cd51 has been shown to mediate protection of macrophages from the apoptotic effects of oxidized lipids, including oxidized low density lipoprotein (oxLDL). Cd51 has been shown to facilitate cellular adhesion, promotion of lipid accumulation through enhanced CD36-mediated uptake of oxLDL, and macrophage survival within atherosclerotic lesions (Arai et al., Cell Metab. (2005) 1 :201-213; Amezaga et al, J. Leukoc. Biol. (2014) 95(3): 509-20, the contents of which are incorporated by reference in their entireties).
  • oxLDL oxidized low density lipoprotein
  • up-regulation of Cd51 inhibits immune cell apoptosis and strengthens innate immune response, for example, at lesion sites.
  • increasing the expression level of Cd51 can be used to treat a human subject with an age-related disease caused by a decreased expression level of Cd51, a human subject having a decreased expression of Cd51, or any combination thereof.
  • Perp is an important mediator of stratified epithelial development, cell adhesion, and apoptosis through desmosomal activities. Perp has been shown to be a p53 transcriptional target pro-apoptotic gene expressed in high levels during apoptosis (Ihrie et al, Current Biology (2003) 13(22): 1985-1990; Nowak et al,, Cell Death and Differentiation (2005) 12(1): 52-64, the contents of which are incorporated by reference in their entireties).
  • Perp has been shown to contribute to radiation-induced apoptosis in CD4 ' CD8 + thymocytes which undergo p53-dependent apoptotic response (Ihrie et al,, Current Biology (2003) 13(22): 1985- 1990; Lowe et al.. Nature (1993) 362(6423): 847-849, the contents of which are incorporated by reference in their entireties).
  • Perp induction has been linked to p53 -dependent apoptosis, and Perp has been shown to be an effector of p53-dependent apoptosis (Attardi et al, Genes Dev. (2000) 14(6):704-18, the content of which is incorporated by reference in its entirety).
  • Perp has been observed to lead to an enhanced activity of the second mitochondria-derived activator of caspase (Smac) cascade (Chen et al, Cancer Biol. Ther. (201 1) 12(12): 1114-9, the content of which is incorporated by reference in its entirety).
  • Smac promotes caspases-9 activation.
  • Caspase-9 is an initiator caspase, and is activated and required during apoptosis.
  • increasing the expression level of Perp can increase apoptosis in a human subject with an insufficient level of apoptosis, possibly caused by a decreased expression of Perp.
  • Increasing the expression level of Perp can increase the expression level of Perp in a human subject who needs an increased expression level of Perp, for example, a human subject having a disease-related decreased expression level of Perp.
  • Perp has been shown to be required for Salmonella-induced inflammation (Hallstrom et al, Cell Microbiol. (2015) 17(6):843-59, the content of which is incorporated by reference in its entirety). Perp has been linked to human longevity (Flachsbart et al., Mutat. Res. (2010) 694(1-2): 13-9, the content of which is incorporated by reference in its entirety). Thus, increasing the expression level of Perp can be used to treat a human subject with an age-related disease caused by a decreased expression level of Perp, a human subject having a decreased expression of Perp, or any combination thereof.
  • Perp is a putative tumor suppressor gene and is downregulated in metastasizing cells, mammaiy carcinoma cells, and tumor tissues (Hildebrandt et al, Anticancer Res. (2000) 20(5A):2801-9, the content of which is incorporated by reference in its entirety). Downregulation of Perp has been reported in tumors of the ovary, uterus and breast, and in cutaneous melanoma, pancreas and mammary carcinoma cell lines, compared with the respective normal tissues and non-metastasizing cell lines. Loss of heterozygosity for Perp has been shown in ceil lines derived from melanoma, breast, pancreas, cervical, prostate and colon carcinoma.
  • Perp has been shown to be significantly downregulated in aggressive monosomy-3 type primary uveal melanoma (UM) tumors, compared to less aggressive disomy-3 type (Davies et al., J. Cell .Moi. Med. (2009) 13: 1995-2007; Paraoan et al, Exp. Eye, Res. (2006) 83(4):91 1 -9, the contents of which are incorporated by reference in their entireties).
  • Perp expression has been shown to stabilize active p53, thus p53-regulated apoptosis, via modulation of p53-MDM2 interaction in uveal melanoma cells (Davies et al.. Ceil Death and Disease (201 1 ) 2:el36, the content of which is incorporated by reference in its entirety).
  • Perp is a tumor suppressor of skin cancer.
  • the lack of Perp has been shown to impair cell adhesion as a result of aberrant desmosome assembly, thereby diminishing tumor development (Marques et al. Cancer Res. (2005) 65:655 -6, the content of which is incorporated by reference in its entirety).
  • SCC Squamous cell carcinoma
  • Perp has been reported to be downregulated during SCC progression, and Perp deficiency has been reported to promote SCC (Beaudry et al., PLoS Genet. (2010) 6(10): el001168, the content of which is incorporated by reference in its entirety).
  • the loss of Perp expression has been reported to correlate with the progression of oral cavity SCC with increased local relapse (Kong et al., Oral Surg. Oral Med. Oral Pathol. Oral Radiol. (2013) 115(1):95-103, the content of which is incorporated by reference in its entirety).
  • increasing the expression level of Perp can be used to treat a human subject with cancer such as SCC or oral cavity SCC,
  • Perp has been shown to be a target of the p53 -related transcription factor, p63, involved in maintaining epithelial integrity by promoting desmosomal cell-cell adhesion (Ihrie et al,, Cell (2005) 120(6): 843-56, the content of which is incorporated by reference in its entirety). Lack of Perp can result in postnatal lethality accompanied by dramatic blisters throughout their stratified epithelia, including the oral mucosa and skin, possibly because of a reduction in desmosome number and compromised desmosome complex formation. Thus, Perp is a critical component of the desmosome in the skin and other stratified epithelia.
  • Loss of Perp has been shown to enhance the phenotypic effects of pemphigus vulgaris, an autoimmune bullous disease in which autoantibodies against proteins of the desmosomal adhesion complex perturb desmosomal function, leading to intercellular adhesion defects in the oral mucosa and skin (Nguyen et al, J. Invest. Dermatol. (2009) 129(7): 1710-8, the content of which is incorporated by reference in its entirety).
  • an autoimmune disease such as rheumatoid arthritis.
  • Unc5b is also known as Unc5h2. Down-regulation of Unc5b has been shown to significantly inhibit apoptosis (He et al., Mol. Biol. Cell. (2011) 22(11): 1943 ⁇ 54, the content of which is incorporated by reference in its entirely). Thus, increasing the expression level of Unc5b can increase apoptosis in a human subject with an insufficient level of apoptosis, possibly caused by a decreased expression of Unc5b. Increasing the expression level of Unc5b can increase the expression level of Unc5b in a human subject who needs an increased expression level of Unc5b, for example, a human subject having a disease- related decrease in the expression level of Unc5b.
  • Unc5b has been shown to be downregulated in multiple cancers, including colorectal, breast, ovary, uterus, stomach, lung, and kidney cancers (Thiebault et al, Proc. Natl. Acad. Sci. U.S.A. (2003) 100(7):4173-8, the content of which is incorporated by reference in its entirety). Unc5b has been shown to mediate p53-dependent apoptosis through death-associated protein kinase (DAP-kinase) (Llambi et al., EMBO J. (2005) 24(6): 1192-201 ; Arakawa, Cell Death Differ.
  • DAP-kinase death-associated protein kinase
  • Unc5b expression has been observed in bladder cancer cells (Liu et al., BMC Cancer. (2014) 14: 93, the content of which is incorporated by reference in its entirety). Decreased Unc5b expression has been shown in prostate carcinoma cells (Kong et al., Tumour Biol.
  • Unc5b emerged more in bladder cancer cells with lower degrees of malignancy than those with higher degrees of malignancy: Unc5b expression in bladder cancer cells was significantly reduced compared to normal bladder cells, and low Unc5b expression was an independent risk factor for postoperative recurrence in patients with different stages and grades bladder cancer (Liu et al, Tumour Biol. (2013) 34(4):2099-108, the content of which is incorporated by reference in its entirety).
  • UneSb mRNA has been shown to be down- expressed m bladder cancer tissues.
  • Unc5b has been shown to be downregulated in kidney carcinoma (Zhan et al, Tumour Biol. (2013) 34(3): 1759-66, the content of which is incorporated by reference in its entirety).
  • Bag5 has been shown to function as the nucleotide exchange factor of Hsp70 for the enhancement of protein refolding (Arakawa et al. Structure (2010) 18(3):309-19, the content of which is incorporated by reference in its entirety). Bag5 has been shown to directly interacted with mutations in PTEN-induced kinase 1 (PINKl), and regulated PINKl degradation via ubiquitin proteasome system (UPS) (Wang et al, PLoS One. (2014) 9(l):e86276, the content of which is incorporated by reference in its entirety). Loss of the stability of PINKl may contribute to sporadic Parkinson's disease (PD).
  • PD sporadic Parkinson's disease
  • Bag5 has been reported to protect mitochondria against MPP+- and rotenone-induced oxidative stress. Thus, increasing the expression level of Bag5 can be used to treat a human subject with an age-related disease caused by a decreased expression level of Bag5, a human subject having a decreased expression of Bag5, or any combination thereof.
  • Bag5 has been reported to be linked to non-Hodgkin lymphoma (Kelly et al.. Cancer Epidemiol. Biomarkers. Prev. (2010) 19(1 1 ):2847-2858, the content of which is incorporated by reference in its entirety). Thus, increasing the expression level of Bag5 can be used to treat a human subject with cancer such as non-Hodgkin lymphoma.
  • Bri3 has been shown to exhibit the ability to stabilize the microtubule network and attenuate the microtubule-destabilizing activity of SCGIO (Gong et al, BMB Rep. (2008) 41(4):287-93, the content of which is incorporated by reference in its entirety).
  • SCGIO SCGIO
  • Bri3 has also been reported to be down-regulated with colorectal cancer progression (Bandres et al, Oncology Reports (2007) 1.7(5): 1089- 1094, the content of which is incorporated by reference in its entirety).
  • increasing the expression level of Bri3 can be used to treat a human subject with cancer.
  • Some embodiments disclosed herein provide methods for counteracting decrease in gene expression (e.g., age-related decrease in gene expression) or treating a disease (e.g., an age-related disease), comprising administering to a human subject an effective amount of a nitroxide antioxidant.
  • the methods further comprise: identifying the human subject (e.g., a human subject over the age of 35).
  • the human subject has a decreased expression level of one or more genes (e.g., genes associated with the apoptosis pathway or an age-related disease).
  • the methods comprise determining the expression level of one or more genes (e.g., genes associated with the apoptosis pathway).
  • a decreased expression level of one or more genes associated with the apoptosis pathway can be inferred from the human subject's age, family history, health conditions, medical history, habits, or a combination thereof.
  • the methods disclosed herein may be used to treat a human subject shows no symptoms of an age-related disease, but is at risk of having an age- related disease.
  • Exemplary risk factors for an age-related disease include, but are not limited to, age, family history, health conditions, medical history, habits, or a combination thereof.
  • risk factors for an age-related disease comprise a decreased expression level of one or more genes associated with the apoptosis pathway.
  • administering to the human subject an effective amount of the nitroxide antioxidant results in an increased expression level of a gene, for example a gene associated with the apoptosis pathway.
  • the gene associated with the apoptosis pathway can be Cd51, Perp, Unc5b, Bag5 or Bri3.
  • the treatment of the human subject with the effective amount of the nitroxide antioxidant can result in an increased expression level of the gene.
  • the treatment can result in increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof.
  • the increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof can increase the level of apoptosis.
  • the increased level of apoptosis can result in a decrease in or disappearance of signs and symptoms of an age-related disease associated with decreased apoptosis, including the curing of the age-related disease.
  • the increased expression levels of Cd51, Perp, UncSb, Bag5, Bri3, or any combination thereof can decrease the level of apoptosis.
  • the decreased level of apoptosis can rreessuulltt i inn aa ddeeccrreeaassee iinn oorr ddiissaappppeeaarraannccee ooff ssiiggnnss a anndd ssyymmppttoommss ooff tthhee aaggee--rreellaatteedd ddiisseeaassee aassssoocciiaatteedd wwiitthh iinnccrreeaasseedd aappooppttoossiiss,, iinncclluuddiinngg tthhee ccuurriinngg ooff tthhee ddiisseeaassee aasssoocciiaatteedd wwiitthh aggee
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  • Some embodiments disclosed herein provide methods for increasing the expression level of a gene in a human subject in need thereof, comprising administering to a human subject an effective amount of a nitroxide antioxidant. In some embodiments, the methods further comprise: identifying the human subject. In some embodiments, the human subject has a decreased expression level of a gene (e.g., a gene associated with the apoptosis pathway). Some embodiments disclosed herein provide methods for treating a disease associated with a decreased apoptosis in a patient in need thereof, comprising administering to a human subject an effective amount of a nitroxide antioxidant. In some embodiments, the methods further comprise: identifying the human subject.
  • the human subject has a decreased expression level of a gene (e.g., a gene associated with the apoptosis pathway).
  • the decreased expression level may be age-related, or disease related.
  • the disease may be cancer, rheumatoid/osteoid arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease, Alzeimer's disease, multiple sclerosis, atherosclerosis, cardiovascular disease, cataracts, dementia, osteoporosis, type 2 diabetes, hypertension, or any combination thereof.
  • the methods further comprise: identifying the human subject.
  • the human subject is over the age of 35 and is in need of an increased expression level of the gene (e.g., a gene associated with the apoptosis pathway).
  • the methods comprise determining the expression level of one or more genes associated with the apoptosis pathway. However, this may not be necessary in some instances, such as where a decreased expression level of one or more genes associated with the apoptosis pathway can be inferred from the human subject's age, family history, health conditions, medical history, habits, or a combination thereof.
  • the methods disclosed herein may be used to treat a human subject shows no symptoms of a disease associated with a decreased apoptosis, but is at risk of having a disease associated with a decreased apoptosis.
  • exemplary risk factors for a disease associated with a decreased apoptosis include, but are not limited to, age, family history, health conditions, medical history, habits, or a combination thereof.
  • administering to the human subject an effective amount of the nitroxide antioxidant results in an increased expression level of a gene, for example a gene associated with the apoptosis pathway.
  • the gene associated with the apoptosis pathway can be Cd51, Perp, Unc5b, Bag5 or Bri3.
  • the treatment of the human subject with the effective amount of the nitroxide antioxidant can result in an increased expression level of the gene.
  • the treatment can increase the expression levels of Cd51, Perp, Unc5b, Bag5, Bn3, or any combination thereof.
  • the increased expression of the gene counteracts the decrease in the expression level of the gene.
  • Some embodiments disclosed herein provide methods for treating cancer in a human subject in need thereof, comprising administering to a human subject an effective amount of a nitroxide antioxidant. In some embodiments, the methods further comprise: identifying the human subject. In some embodiments, the human subject has a cancer and is in need of an increased expression level of a gene associated with the apoptosis pathway or a gene selected from a group consisting of Cd51, Perp, Unc5b, Bag5 or Bri3. In some embodiments, the methods disclosed herein may be used to treat a human subject shows no symptoms of cancer, but is at risk of having cancer.
  • risk factors for cancer include, but are not limited to, age, family histoiy, health conditions, medical history, habits, or a combination thereof.
  • risk factors for cancer comprise a decreased expression level of one or more genes associated with the apoptosis pathway.
  • Non-limiting examples of the methods for identifying a human subject having a cancer include colonoscopy; sigmoidoscopy; and high-sensitivity fecal occult blood tests.
  • methods for identifying a human subject having a cancer include low-dose helical computed tomography; mammography; and pap test and human papillomavirus (HPV) testing.
  • methods for identifying a human subject having a cancer include alpha-fetoprotein blood test; breast magnetic resonance imaging (MRI); CA-125 test; clinical breast exams and regular breast self-exams; prostate-specific antigen (PSA) testing; skin exams; transvaginal ultrasound; and virtual colonoscopy.
  • MRI breast magnetic resonance imaging
  • PSA prostate-specific antigen
  • methods for identifying a human subject having a cancer include barium enema; biopsy; bone marrow aspiration and biopsy; bone scan; breast MRI for early detection of breast cancer; breast MRI; colonoscopy; computed tomography (CT) scan; digital rectal exam (DRE); blood and platelets testing; bone marrow testing; umbilical cord blood testing; electrocardiogram (EKG) and echocardiogram; endoscopic techniques; fecal occult blood tests; magnetic resonance imaging (MRI); mammography; multi gated acquisition (MUGA) scan; Papanicolaou (pap) test; positron emission tomography and computed tomography (PET-CT) scan; sigmoidoscopy; tumor marker tests; ultrasound; upper endoscopy.
  • methods for identifying a human subject having a cancer include DNA sequencing; detecting presence of single nucleotide polymorphism (SNTP); and detecting the presence of certain protein markers.
  • administering to the human subject an effective amount of the nitroxide antioxidant results in an increased expression level of a gene, for example a gene associated with the apoptosis pathway.
  • the gene associated with the apoptosis pathway can be Cd51, Perp, Unc5b, Bag5 or Bri3.
  • the treatment of the human subject with the effective amount of the nitroxide antioxidant can result in an increased expression of the gene.
  • the treatment can result in increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof.
  • the increased expression level of the gene can increase the level of apoptosis.
  • the increased level of apoptosis can result in a decrease in or disappearance of signs and symptoms of the cancer, including the curing of the cancer.
  • Non-limiting examples of cancer include bladder and other urothelial cancers; breast cancer; cervical cancer; colorectal cancer; endometrial cancer; endometrial cancer; esophageal cancer; liver (hepatocellular) cancer; lung cancer; neuroblastoma cancer; oral cavity and oropharyngeal cancer; ovarian, fallopian tube, and primary peritoneal cancer; prostate cancer; skin cancer; stomach (gastric) cancer; and testicular cancer.
  • Non-limiting examples of cancer include acute lymphoblastic leukemia, adult; acute myeloid leukemia, adult; adrenocortical carcinoma; aids-related lymphoma; anal cancer; bile duct cancer; bladder cancer; brain tumors, adult; breast cancer; breast cancer and pregnancy; breast cancer, male; carcinoid tumors, gastrointestinal; carcinoma of unknown primary; cervical cancer; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative neoplasms; ens lymphoma, primary; colon cancer; endometrial cancer; esophageal cancer; extragonadal germ cell tumors; fallopian tube cancer; gallbladder cancer; gastric cancer; gastrointestinal carcinoid tumors; gastrointestinal stromal tumors; germ cell tumors, extragonadal; germ cell tumors, ovarian; gestational trophoblastic disease; hairy cell leukemia; hepatocellular (liver) cancer, adult primary
  • non-limiting examples of cancer include, but are not limited to, hematologic and solid tumor types such as acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer (including estrogen-receptor positive breast cancer), bronchogenic carcinoma, Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chrome myelocytic (granulocytic) leukemia, chrome myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngio
  • Non-limiting examples of the cancer include acute lymphoblastic leukemia, childhood; acute myeloid leukemia/other myeloid malignancies, childhood; adrenocortical carcinoma, childhood; astrocytomas, childhood; atypical teratoid/rhabdoid tumor, childhood central nervous system; basal cell carcinoma, childhood; bladder cancer, childhood; bone, malignant fibrous histiocytoma of and osteosarcoma; brain and spinal cord tumors overview, childhood; brain stem glioma, childhood; (brain tumor), childhood astrocytomas; (brain tumor), childhood central nervous system atypical teratoid/rhabdoid tumor; (brain tumor), childhood central nervous system embryonal tumors; (brain tumor), childhood central nervous system germ cell tumors; (brain tumor), childhood craniopharyngioma; (brain tumor), childhood ependymoma; breast cancer, childhood; bronchial tumors, childhood; carcinoid tumors, childhood;
  • Non-limiting examples of cancer include embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric atypical teratoid/rhabdoid tumor of the central nervous system, pediatric biphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing's family of tumors such as primitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorable histology Wilm's tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma- derived myelocytomatosis, pediatric pre-B-cell cancers (such as leukemia), pediatric osteosarcoma, pediatric
  • Some embodiments disclosed herein provide methods for treating an autoimmune disease in a human subject in need thereof, comprising administering to the human subject an effective amount of a nitroxide antioxidant. In some embodiments, the methods further comprise: identifying the human subject. In some embodiments, the human subject has a neural degenerative disease and is in need of an increased expression level of a gene associated with the apoptosis pathway or selected from a group consisting of Cd51, Perp, Unc5b, Bag5 or Bri3. In some embodiments, the methods disclosed herein may be used to treat a human subject shows no symptoms of an autoimmune disease, but is at risk of having an autoimmune disease.
  • risk factors for an autoimmune disease include, but are not limited to, age, family- history, health conditions, medical history, habits, or a combination thereof.
  • risk factors for an autoimmune disease comprise a decreased expression level of one or more genes, such as Cd51, Perp, Unc5b, Bag5 or Bn3.
  • the method comprises administering to the human subject an effective amount of the nitroxide antioxidant results in an increased expression level of a gene, for example a gene such as Cd51, Perp, Unc5b, Bag5 or Bn3.
  • a gene such as Cd51, Perp, Unc5b, Bag5 or Bn3.
  • the treatment of the human subject with the effective amount of the nitroxide antioxidant can result in an increased expression level of the gene.
  • the treatment can result in increased expression levels of Cd51, Perp, Unc5b, Bag5, Bn3, or any combination thereof.
  • the increased level of gene can result in a decrease in or disappearance of signs and symptoms of the autoimmune disease, including the curing of the autoimmune disease.
  • the increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof can increase the level of apoptosis.
  • the increased level of apoptosis can result in a decrease in or disappearance of signs and symptoms of the autoimmune disease, including the curing of the autoimmune disease.
  • the increased expression levels of Cd51, Perp, UncSb, Bag5, Bri3, or any combination thereof can decrease the level of apoptosis.
  • the decreased level of apoptosis can result in a decrease in or disappearance of signs and symptoms of the autoimmune disease, including the curing of the autoimmune disease.
  • Non-limiting examples of autoimmune diseases include rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes meilitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch- Schonlein purpura, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, se
  • Non-limiting examples of autoimmune diseases include acquired immunodeficiency disease syndrome (AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory diseases, and thrombocytopenia, acute or chronic immune disease associated with organ transplantation, Addison's disease, allergic diseases, alopecia, alopecia areata, atheromatous disease/arteriosclerosis, atherosclerosis, arthritis (including osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis and reactive arthritis), autoimmune bullous disease, abetalipoprotemia, acquired immunodeficiency- related diseases, acute immune disease associated with organ transplantation, acquired acrocyanosis, acute and chronic parasitic or infectious processes, acute pancreatitis, acute renal failure, acute rheumatic fever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats, adult (acute) respiratory distress syndrome, AIDS dementia complex, alcoholic cirrhosis, alcohol-induced liver injury, alcohol-
  • Some embodiments disclosed herein provide methods for treating an infection in a human subject in need thereof, comprising administering to a human subject an effective amount of a nitroxide antioxidant. In some embodiments, the methods further comprise: identifying the human subject. In some embodiments, the human subject has an infection and is in need of an increased expression level of a gene associated with the apoptosis pathway or selected from a group consisting of Cd51, Perp, Unc5b, Bag5 or Bri3. In some embodiments, the methods disclosed herein may be used to treat a human subject shows no symptoms of an infection, but is at risk of having an infection. Exemplar ⁇ ' risk factors for an infection include, but are not limited to, age, family history, health conditions, medical history, habits, or a combination thereof. In some embodiments, risk factors for an mfection comprise a decreased expression level of one or more genes, such as Cd5L Perp, UncSb, Bag5 or Bri3.
  • the method comprises administering to the human subject an effective amount of the nitroxide antioxidant results in an increased expression level of a gene, for example a gene such as Cd5L Perp, Unc5b, Bag5 or Bn3.
  • a gene such as Cd5L Perp, Unc5b, Bag5 or Bn3.
  • the treatment of the human subject with the effective amount of the nitroxide antioxidant can result in an increased expression level of the gene.
  • the treatment can result in increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof.
  • the increased level of gene can result in a decrease in or disappearance of signs and symptoms of the infection, including the curing of the infection.
  • the increased expression levels of Cd51, Perp, UncSb, Bag5, Bri3, or any combination thereof! can increase the level of apoptosis.
  • the increased level of apoptosis can result in a decrease in or disappearance of signs and symptoms of the infection, including the curing of the infection.
  • the increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof can decrease the level of apoptosis.
  • the decreased level of apoptosis can result in a decrease in or disappearance of signs and symptoms of the infecti on, including the curing of the infection.
  • the infection is a bacterial infection, such as a gram positive bacterium or a gram negative bacterium.
  • the infection is caused by a bacterium of the genus Mycobacterium.
  • the bacterium can be Mycobacterium tuberculosis.
  • the infection can a Mycobacterium avium intracelluiare infection.
  • the infection is caused by a bacterium of the genus Corynebaclerium.
  • the bacterium can be Coiyne bacterium parvum.
  • the infection is caused by a bacterium of the genus Listeria.
  • the bacterium can be Listeria monocytogenes.
  • the infection is caused by a bacterium of the genus Streptococci. In some embodiments, the infection results in sepsis or in meningitis. In some embodiments, the infection is a fungal infection or a viral infection. In some embodiments, the individual has a compromised immune system.
  • the compromised immune system can be age related. The individual can be over the age of 35 or 35.
  • the increased expression level of Cd51 inhibits apoptosis of immune cells.
  • the immune cells can comprise macrophages or T-cells. In some embodiments, the method inhibiting or delaying development of the infection.
  • Some embodiments disclosed herein provide methods for treating a neural degenerative disease in a human subject in need thereof, comprising administering to a human subject an effective amount of a nitroxide antioxidant. In some embodiments, the methods further comprise: identifying a human subject. In some embodiments, the human subject has a neural degenerative disease and is in need of an increased expression level of a gene associated with the apoptosis pathway or selected from a group consisting of Cd51, Perp, Unc5b, Bag5 or Bri3. In some embodiments, the methods disclosed herein may be used to treat a human subject shows no symptoms of a neural degenerative disease, but is at risk of having a neural degenerative disease.
  • risk factors for a neural degenerative disease include, but are not limited to, age, family history, health conditions, medical history, habits, or a combination thereof.
  • risk factors for a neural degenerative disease comprise a decreased expression level of one or more genes, such as CdS!, Perp, Unc5b, Bag5 or Bri3.
  • the method comprises administering to the human subject an effective amount of the nitroxide antioxidant results in an increased expression level of a gene, for example a gene such as Cd51, Perp, Unc5b, Bag5 or Bri3.
  • a gene for example a gene such as Cd51, Perp, Unc5b, Bag5 or Bri3.
  • the treatment of the human subject with the effective amount of the nitroxide antioxidant can result in an increased expression level of the gene.
  • the treatment can result in increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof.
  • the increased level of gene can result in a decrease in or disappearance of signs and symptoms of the neural degenerative disease, including the curing of the neural degenerative disease.
  • the increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof can increase the level of apoptosis.
  • the increased level of apoptosis can result in a decrease in or disappearance of signs and symptoms of the neural degenerative disease, including the curing of the neural degenerative disease.
  • the increased expression levels of Cd51, Perp, Unc5b, Bag5, Bri3, or any combination thereof can decrease the level of apoptosis.
  • the decreased level of apoptosis can result in a decrease in or disappearance of signs and symptoms of the neural degenerative disease, including the curing of the neural degenerative disease.
  • the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis or a combination thereof.
  • the neurodegenerative disease can result in spinal ataxis, spinocerebellar degenerations, or any combination thereof.
  • the neurodegenerative disease cab be an age-related neurodegenerative disease.
  • the individual can be over the age of 35 or 50.
  • the expression level of Bag5 can be increased in a neuronal tissue.
  • the method further comprises inhibiting or delaying development of the neurodegenerative disease.
  • Non-limiting examples of the nitroxide antioxidant include 2-ethyl-2,5,5 ⁇ trimethyl-3-oxazolidine-l-oxyl (OXANO), 2,2,6,6-tetramethylpiperidine-l-oxyl (TEMPO), 4- hydroxy-2,2,6,6-tetramethy lpiperidine- 1 -oxyl (TEMPO L), 4-amino-2,2,6,6-tetramethy 1- 1 - piperidinyloxy (Tempamine), 3-Aminomethyl-PR.OXYL, 3-Cyano-PROXYL, 3-Carbamoyl- PROXYL, 3 ⁇ Carhoxy ⁇ PROXYL, and 4-Oxo-TEMPO.
  • OXANO 2-ethyl-2,5,5 ⁇ trimethyl-3-oxazolidine-l-oxyl
  • TEMPO 2,2,6,6-tetramethylpiperidine-l-oxyl
  • TEMPO L 4- hydroxy-2,2,6,6-tetramethy
  • TEMPO can also be substituted, typically in the 4 position, for example, 4-amino, 4-(2-bromoacetamido), 4-(ethoxyfluorophosphonyloxy), 4-hydroxy, 4-(2-iodoacetamido), 4-isothiocyanato, 4-maleimido, 4-(4-nitrobenzoyloxyl), 4- phosphonooxy, and the like.
  • nitroxide compound can be selected from the following formulas:
  • X is selected from O— and OH
  • R is selected from COOH, CONH, CN, and
  • X is selected from O— and OH
  • Ri is selected from C3 ⁇ 4 and spirocyclohexyl
  • R 2 is selected from C 2 H 5 and spirocyclohexyl
  • X is selected from O— and OH and R is selected from CONH:
  • X is selected from O— and OH and R is selected from H, OH, and NH 2 .
  • Suitable mtroxide compounds can also be found in Proctor, U.S. Pat. No. 5,352,442, and Mitchell et al., U.S. Pat. No. 5,462,946, both of which are hereby incorporated by reference in their entireties.
  • the nitroxide antioxidant, non-toxic salts thereof, acid addition salts thereof or hydrates thereof may be administered systemically or locally, usually by oral or parenteral administration.
  • the doses to be administered can be determined depending upon, for example, age, body weight symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment. In the human adult, the dose per person at a time can be generally from about 0.01 to about 1000 mg, by oral administration, up to several times per day.
  • Specific examples of particular amounts contemplated via oral administration include about 0.02, 0.03, 0.04, 0.05, 0.10, 0.15, 0.20, 0,25, 0.30, 0,35, 0.40, 0,45, 0.50, 0,55, 0.60, 0.65, 0.70, 0,75, 0.80, 0.85, 0,90, 0,95, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90
  • the dose per person at a time can be generally from about 0.01 to about 300 mg/kg via parenteral adrnimstration (preferably intravenous administration), from one to four or more times per day.
  • specific examples of particular amounts contemplated include about 0.02, 0.03, 0,04, 0.05, 0, 10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 26
  • Continuous intravenous administration can also contemplated for from 1 to 24 hours per day to achieve a target concentration from about 0,01 mg/L to about 100 mg/L
  • Non- limiting examples of particular amounts contemplated via this route include about 0.02, 0.03, 0.04, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,
  • the nitroxide antioxidant can be administered in the form of, for example, solid compositions, liquid compositions or other compositions for oral administration, injections, liniments or suppositories for parenteral administration.
  • Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders and granules.
  • Capsules include hard capsules and soft capsules.
  • Tempol may be admixed with an excipient (e.g. lactose, mannitol, glucose, microcrystalline cellulose, starch), combining agents (hydroxypropyl cellulose, polyvinyl pyrrolidone or magnesium metasilicate aluminate), disintegrating agents (e.g. cellulose calcium glycolate), lubricating agents (e.g. magnesium stearate), stabilizing agents, agents to assist dissolution (e.g. glutamic acid or aspartic acid), or the like.
  • an excipient e.g. lactose, mannitol, glucose, microcrystalline cellulose, starch
  • combining agents hydroxypropyl cellulose, polyvinyl pyrrolidone or magnesium metasilicate aluminate
  • disintegrating agents e.g. cellulose calcium
  • the agents may, if desired, be coated with coating agents (e.g. sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. Further, coating may include containment within capsules of absorbable materials such as gelatin.
  • coating agents e.g. sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate
  • coating may include containment within capsules of absorbable materials such as gelatin.
  • Liquid compositions for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs.
  • the nitroxide antioxidant is dissolved, suspended or emulsified in a commonly used diluent (e.g. purified water, ethanol or mixture thereof).
  • a commonly used diluent e.g. purified water, ethanol or mixture thereof.
  • such liquid compositions may also comprise wetting agents or suspending agents, emulsifying agents, sweetening agents, flavoring agents, perfuming agents, preserving agents, buffer agents, or the like.
  • injections for parenteral administration include solutions, suspensions, emulsions and solids which are dissolved or suspended.
  • the nitroxide antioxidant can be dissolved, suspended and emulsified in a solvent.
  • the solvents include, for example, distilled water for injection, physiological salt solution, vegetable oil, propylene glycol, polyethylene glycol, alcohol such as ethanol, or a mixture thereof.
  • the injections can also include stabilizing agents, agents to assist dissolution (e.g. glutamic acid, aspartic acid or POLYSORBATE80 ' M ), suspending agents, emulsifying agents, soothing agents, buffer agents, preserving agents, etc. They can be sterilized in the final process or manufactured and prepared by sterile procedure. They can also be manufactured in the form of sterile solid compositions, such as a freeze-dried composition, and they may be sterilized or dissolved immediately before use in sterile distilled water for injection or some other solvent.
  • compositions for parenteral administration include liquids for external use, and ointment, endermic liniments, inhale, spray, suppositories for rectal administration and pessaries for vaginal administration which comprise the nixtroxide antioxidant and are administered by methods known in the art.
  • Spray compositions can comprise additional substances other than diluents: e.g. stabilizing agents (e.g. sodium sulfite hydride), isotonic buffers (e.g. sodium chloride, sodium citrate or citric acid).
  • stabilizing agents e.g. sodium sulfite hydride
  • isotonic buffers e.g. sodium chloride, sodium citrate or citric acid.
  • a small aerosol particle size useful for effective distribution of the medicament can be obtained by employing self-propelling compositions containing the drugs in micronized form dispersed in a propellant composition. Effective dispersion of the finely divided drug particles can be accomplished with the use of very small quantities of a suspending agent, present as a coating on the micronized drug particles. Evaporation of the propellant from the aerosol particles after spraying from the aerosol container leaves finely divided drug particles coated with a fine film of the suspending agent.
  • the average particle size can be less than about 5 microns.
  • the propellant composition may employ, as the suspending agent, a fatty alcohol such as oleyl alcohol.
  • the minimum quantity of suspending agent can be approximately 0.1 to 0.2 percent by weight of the total composition.
  • the amount of suspending agent can be less than about 4 percent by weight of the total composition to maintain an upper particle size limit of less than 10 microns or 5 microns.
  • Propellants that may be employed include hydrofluoroalkane propellants and chlorofluorocarbon propellants. Dry powder inhalation may also be employed.
  • Tempol was administered to experimental mice at a dose of 5 mg/g of food from 14 months to 31 months after birth. Mice receiving the same food without the addition of Tempol were used as a negative control. At the age of 31 months, the experimental animals were sacrificed and the hearts were surgically removed. The expression of a broad spectrum of genes in the cardiac tissue was assessed using chip-based microarray technology. Such chips are well known in the art and are widely used to assess gene expression. The experimental results showed that five genes associated with the apoptosis pathway, Cd51, Perp, Unc5b, Bag5 and Bri3, exhibited statistically significant increase in expression. This result is shown in Table 1.
  • a 70-kilogram human subject over the age of 65 is identified for decreased expression level of CdS!, Perp, Unc5b, Bag5 or Bri3.
  • the human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24- hour period: for example, three 500-mg doses at eight-hour intervals.
  • the serum level of Cd51, Perp, Unc5b, Bag5 or Bri3 is increased.
  • Example 3 Treating age-related decrease in gene expression.
  • a human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days.
  • the human subject is a 70-kilogram human subject over the age of 65 with a decreased expression level of Cd51, Perp, UncSb, Bag5 or Bn3.
  • the human subject can be identified.
  • the dose may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd5i, Perp, Unc5b, Bag5 or Bri3, is increased.
  • Example 4 Treating a human subject with decreased gene expression.
  • a 70-kilogram human subject is identified for decreased expression level of CdS!, Perp, UncSb, Bag5 or Bri3.
  • the human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd51, Perp, UncSb, Bag5 or Bri3, is increased.
  • Example 5 Treating a human subject, with decreased gene expression.
  • a human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days.
  • the human subject is a 70-kilogram human subject with a decreased expression level of Cd51, Perp, UncSb, Bag5 or Bri3.
  • the human subject can be identified.
  • the dose may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd51, Perp, UncSb, BagS or Bri3, is increased.
  • Example 6 Treating a human subject with age-related disease.
  • a 70-kilogram human subject over the age of 65 and having a cardiovascular disease (or another age-related disease) is identified for decreased expression level of Cd51, Perp, UncSb, Bag5 or Bri3.
  • the human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd51, Perp, Unc5b, Bag5 or Bri3, is increased.
  • Example 7 Treating a human subject with age-related disease.
  • a human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days.
  • the human subject is a 70-kilogram human subject over the age of 65 and having a cardiovascular disease (or another age-related disease) with a decreased expression level of Cd51, Perp, Unc5b, Bag5 or Bri3.
  • the human subject can be identified.
  • the dose may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd51, Perp, Unc5b, Bag5 or Bri3, is increased.
  • Example 8 Treating a human subject at risk of developing cancer.
  • a 70-kilogram human subject at risk of developing colorectal cancer is identified for decreased expression level of Cd51, Perp, UncSb, Bag5 or Bri3.
  • the human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd51, Perp, UncSb, Bag5 or Bri3, is increased.
  • Example 9 Treating a human subject at risk of developing cancer.
  • a human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days.
  • the human subject can be a 70-kilogram human subject at risk of developing colorectal cancer (or another cancer) with a decreased expression level of CdS!, Perp, UncSb, Bag5 or Bri3.
  • the human subject can be identified. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24- hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd51, Perp, UncSb, BagS or Bri3, is increased.
  • Example 10 Treating a human subject at risk of developing an autoimmune disease.
  • a 70-kilogram human subject at risk of developing rheumatoid arthritis is identified for decreased expression level of Cd51, Perp, Unc5b, Bag5 or Bri3.
  • the human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd51, Perp, Unc5b, Bag5 or Bri3, is increased.
  • Example 11 Treating a human subject at risk of developing an autoimmune disease.
  • a human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days.
  • the human subject is a 70-kilogram human subject at risk of developing rheumatoid arthritis (or another autoimmune disease) with a decreased expression level of Cd51, Perp, Unc5b, Bag5 or Bri3.
  • the human subject can be identified. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24- hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd51, Perp, Unc5b, Bag5 or Bri3, is increased.
  • Example 2 Treating a human subject at risk of developing a condition due to aging.
  • a 70-kilogram human subject of 45 years old at risk of developing a condition due to aging is identified.
  • the human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals.
  • the serum level of Cd51, Perp, Unc5b, Bag5 or Bri3 is increased.
  • Example 13 Treating a human subject at risk of developing a condition due to aging.
  • a human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days.
  • the human subject can be a 70-kilogram human subject of 45 years old at risk of developing a condition due to aging.
  • the human subject can be identified. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd51, Perp, Unc5b, Bag5 or Bri3, is increased.
  • Example 14 Treating a human subject having an infection.
  • a 70-kilogram human subject with an infection caused by Mycobacterium tuberculosis (or another bacteria, a fungus, a virus, or a parasite) is identified.
  • the human subject is administered a dose of 1500 mg of Tempo! (or a nitroxide antioxidant) per day for 180 days. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals.
  • the serum level of Cd51, Perp, Unc5b, Bag5 or Bn3 is increased.
  • Example 15 Treating a human subject having an infection.
  • a human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days.
  • the human subject can be a 70-kilogram human subject with an infection caused by Mycobacterium tuberculosis (or another bacteria, a fungus, a virus, or a parasite).
  • the human subject can be identified. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd51, Perp, UncSb, Bag5 or BriS, is increased.
  • Example 16 Treating a human subject at risk of developing a neurodegenerative disease.
  • a 70-kilogram human subject at risk of developing Parkinsons disease (or another neurodegenerative disease) is identified (e.g., the human subject may have decreased expression level of Cd51, Perp, UncSb, Bag5 or Bri3.
  • the human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24- hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment the serum level of Cd51, Perp, UncSb, Bag5 or Bri3, is increased.
  • Example 17 Treating a human subject at risk of developing a neurodegenerative disease.
  • a human subject is administered a dose of 1500 mg of Tempol (or a nitroxide antioxidant) per day for 180 days.
  • the human subject can be a 70-kilogram human subject at risk of developing Parkinson's disease (or another neurodegenerative disease).
  • the human subject may have decreased expression level of Cd51, Perp, Unc5b, Bag5 or Bri3.
  • the human subject can be identified. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the serum level of Cd51, Perp, Unc5b, Bag5 or Bri3, is increased.

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Abstract

L'invention concerne des procédés pour contrer la diminution liée à l'âge de l'expression génique ou traiter des maladies liées à l'âge, par exemple des cancers et des maladies auto-immunes, causées par des niveaux d'expression réduits d'un gène associé à la voie d'apoptose, à l'aide d'un nitroxyde. L'invention concerne en outre des procédés pour traiter un sujet humain ayant besoin d'un taux d'expression accru d'un gène associé à la voie d'apoptose à l'aide d'un nitroxyde.
PCT/US2017/023681 2016-03-23 2017-03-22 Augmentation du niveau d'expression de gènes liés à l'apoptose par traitement d'un sujet humain avec un nitroxyde Ceased WO2017165572A1 (fr)

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CA3056059A CA3056059C (fr) 2016-03-23 2017-03-22 Augmentation du niveau d'expression de genes lies a l'apoptose par traitement d'un sujet humain avec un nitroxyde
JP2019500747A JP2019509352A (ja) 2016-03-23 2017-03-22 ヒトの被験物質をニトロキシドで処理することによってａｐｏｐｔｏｓｉｓ関連遺伝子の発現レベルを増加させる

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US15/078,911 US9545398B1 (en) 2016-03-23 2016-03-23 Increasing expression level of apoptosis-related genes by treating a human subject with a nitroxide
US15/078,911 2016-03-23
US15/373,250 US9744162B1 (en) 2016-03-23 2016-12-08 Increasing expression level of apoptosis-related genes by treating a human subject with a nitroxide
US15/373,250 2016-12-08
US15/373,239 2016-12-08
US15/373,239 US10231959B2 (en) 2016-03-23 2016-12-08 Increasing expression level of apoptosis-related genes by treating a human subject with a nitroxide

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