IntroductionObesity is associated with impaired immune function and increased susceptibility to i... more IntroductionObesity is associated with impaired immune function and increased susceptibility to infection. High fat (HF) diet-induced obesity is a commonly used animal model. However, HF diet itself is known to affect immune function and infection. Thus, it is not discernable which one, HF diet or adiposity, is the major contributor to the observed impairment in immunity and susceptibility to infection in HF diet-induced obesity. We hypothesized that obesity is a major contributor to impaired immune function.Methods and resultsWeight-matched outbred female CD-1 mice (1-mo) were randomly assigned to either a HF (45%) or a low fat (LF, 10%) diet group. Ten week after feeding their respective diets, weight gain in the mice fed the HF diet varied greatly. Thus, based on the average body weight, mice in HF diet group were divided into two sub-groups: HF lean (HF-L) and HF obese (HF-O). After 25-week, mice were immunized with an influenza A/Puerto Rico/8/34 vaccine and boosted 3-week late...
Background: Epidemiological studies suggest that higher fruits and vegetables (F&V) consumption c... more Background: Epidemiological studies suggest that higher fruits and vegetables (F&V) consumption correlates with reduced risk of hepatic steatosis, yet evidence for causality and the underlying mechanisms is lacking. Objectives: We aimed to determine the causal relation between F&V consumption and improved metabolic disorders in mice fed high-fat (HF) (Experiment-1) or normal-fat (Experiment-2) diets and its underlying mechanisms. Methods: Six-week-old male C57BL/6J mice were randomly grouped and fed diets supplemented at 0%-15% (wt:wt) with a freeze-dried powder composed of 24 commonly consumed F&V (human equivalent of 0-9 servings/d) for 20 wk. In Experiment-1, mice were fed an HF (45% kcal fat) diet with 0% (HF0), 5%, 10%, or 15% (HF15) F&V or a matched lowfat control diet (10% kcal fat). In Experiment-2, mice were fed an AIN-93 diet (basal) (B, 16% kcal fat) with 0% (B0), 5%, 10%, or 15% (B15) F&V supplementation. Body weight and composition, food intake, hepatic steatosis, inflammation, ceramide levels, sphingomyelinase activity, and gut microbiota were assessed. Results: In Experiment-1, mice fed the HF15 diet had lower weight gain (17.9%), hepatic steatosis (48.4%), adipose tissue inflammation, blood (24.6%) and liver (33.9%) ceramide concentrations, and sphingomyelinase activity (38.8%) than HF0 mice (P < 0.05 for all). In Experiment-2, mice fed the B15 diet had no significant changes in weight gain but showed less hepatic steatosis (28.5%), blood and adipose tissue inflammation, and lower blood (30.0%) ceramide concentrations than B0 mice (P < 0.05 for all). These F&V effects were associated with favorable microbiota changes. Conclusions: These findings represent the first evidence for a causal role of high F&V intake in mitigating hepatic steatosis in mice. These beneficial effects may be mediated through changes in ceramide and/or gut microbiota, and suggest that higher than currently recommended servings of F&V may be needed to achieve maximum health benefits.
Summary Autoimmune diseases are a host of diseases characterized by abnormal immune response agai... more Summary Autoimmune diseases are a host of diseases characterized by abnormal immune response against normal tissues of the body. There are about 100 autoimmune diseases, and they are estimated to affect at least 3%–5% of population. While the etiology is still unclear, both genetic and environmental factors are recognized to play key roles in the disease development. Pharmaceutical therapies have substantially improved the disease control and prognosis. However, the adverse effects and high cost of the drugs limit their use. There has been an increasing interest in alternative and complementary means to improve the outcomes of conventional therapies in many autoimmune diseases. Diet as a modifiable factor has the potential to improve clinical outcomes for several major autoimmune diseases. This chapter provides a summary and analysis of both observational and experimental studies as well as perspectives on the role of nutrition in prevention and treatment of some of the most prominent autoimmune diseases.
Objectives Osteoporosis is a debilitating disease that increases with age and is characterized by... more Objectives Osteoporosis is a debilitating disease that increases with age and is characterized by increased bone fragility. However, dietary factors can influence the development of osteoporosis. For example, high fat diets (HFD) have been shown to have detrimental effects on bone density and quantity. However, the effects of HFD on bone microarchitecture have not been extensively studied. The architecture of the bone is important because it provides information regarding the quality of the bone and not just quantity. Therefore, the purpose of this study was to investigate the effects of HFD on bone microarchitecture in mice when compared to low fat diet fed mice. Methods Five-week-old mice were randomized into two different treatment groups, control and HFD (n = 6 per group). The control group were fed AIN-93 G growing rodent diet (20% protein, 65% carbohydrate (CHO), 15% fat) while the HFD group was fed a standard HFD ordered from Research Diets Inc. Cat #D12451M (20% protein, 35%...
Objectives Epidemiological studies have shown that consumption of fruits and vegetables (F&V) is ... more Objectives Epidemiological studies have shown that consumption of fruits and vegetables (F&V) is inversely associated with incidence of cardiovascular disease (CVD). However, the evidence for causality and underlying mechanisms is lacking. Our objective was to determine if increased consumption of F&V could prevent atherosclerosis and its underlying mechanisms. Methods A unique blend of the most commonly consumed 24 F&V was freeze-dried into a powder and mixed into diets. Thirty six 4-week old male LDL receptor knockout mice were randomly assigned to one of 3 diet groups (12/group): low fat (LF, 10 kcal% fat), high-fat (27 kcal% fat) with 0% F&V (HF), and HF plus 15% F&V diet (HF + FV, equivalent to 8–9 servings for humans). After 20 weeks, mice were euthanized and blood, aorta, and liver tissue were collected. Aortic atherosclerotic lesion, hepatic steatosis, plasma lipid profile and pro-inflammatory cytokine levels were measured. Results No significant differences were found in bo...
Objectives Fecal biomarkers have emerged as an important tool to assess intestinal inflammation a... more Objectives Fecal biomarkers have emerged as an important tool to assess intestinal inflammation and permeability. Commonly measured biomarkers include calprotectin (CP), myeloperoxidase (MPO), alpha-1-antitrypsin (AAT) and neopterin (NEO). We sought to develop a simple, fast and cost-effective single extraction procedure for use in determining all four biomarkers of interest. The applicability and sensitivity of this procedure for use in healthy adults was examined. Methods Sample extraction buffers and methods including sample weight, dilution, homogenization and centrifugation were all considered in the development of a single extraction procedure. An extraction buffer that included phosphate-buffered saline, phenylmethylsulfonyl fluoride, bovine serum albumin and Tween 20 was used to extract fecal samples. To assess the applicability and sensitivity of the single extraction procedure, concentrations of CP, MPO, AAT and NEO were measured using commercially available sandwich ELISA...
Objectives Dementia and cognitive decline are typical age-related neurological disorders. However... more Objectives Dementia and cognitive decline are typical age-related neurological disorders. However, obesity has been linked to premature senescence manifestations in various systems including the central nervous system. Nutritional interventions play a role in curbing obesity-associated disorders. Epidemiological studies suggest that increased consumption of fruits and vegetables (F&V) is associated with a reduced risk of cognitive impairment and dementia. The objective of this study was to investigate the causal role of F&V consumption in prevention of high fat diet-induced cognitive impairment in mice. Methods Freeze-dried powder of a mixture of 24 F&V was added into the animal diets. Male C57BL/6 J mice (6 wk) were randomly assigned to one of the three diet groups (12/group): low fat (LF, 10% kcal fat), high fat (HF, 45% kcal fat), and HF plus 15%…
Melanoma, one of the most virulent forms of human malignancy, is the primary cause of mortality f... more Melanoma, one of the most virulent forms of human malignancy, is the primary cause of mortality from cancers arising from the skin. The prognosis of metastatic melanoma remains dismal despite targeted therapeutic regimens that exploit our growing understanding of cancer immunology and genetic mutations that drive oncogenic cell signaling pathways in cancer. Epigenetic mechanisms, including DNA methylation/demethylation, histone modifications and noncoding RNAs recently have been shown to play critical roles in melanoma pathogenesis. Current evidence indicates that imbalance of DNA methylation and demethylation, dysregulation of histone modification and chromatin remodeling, and altered translational control by noncoding RNAs contribute to melanoma tumorigenesis. Here, we summarize the most recent insights relating to epigenetic markers, focusing on diagnostic potential as well as novel therapeutic approaches for more effective treatment of advanced melanoma.
Proceedings of the National Academy of Sciences, 1999
Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involv... more Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RAR α and one of four fusion partners: PML , PLZF , NPM , and NuMA genes. To study the leukemogenic potential of the fusion genes in vivo , we generated transgenic mice with PLZF–RAR α and NPM–RAR α. PLZF–RAR α transgenic animals developed chronic myeloid leukemia-like phenotypes at an early stage of life (within 3 months in five of six mice), whereas three NPM–RAR α transgenic mice showed a spectrum of phenotypes from typical APL to chronic myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from PLZF–RAR α transgenic mice, those from NPM–RAR α transgenic mice could be induced to differentiate by all- trans -retinoic acid (ATRA). We also studied RARE binding properties and interactions between nuclear corepressor SMRT and various fusion proteins in response to ATRA. Dissociation of SMRT from different receptors was observed at ATRA conce...
Background Epidemiologic studies suggest that fruit and vegetable (F&V) consumption is inversely ... more Background Epidemiologic studies suggest that fruit and vegetable (F&V) consumption is inversely associated with incidence of cardiovascular disease (CVD). However, evidence for causality is lacking, and the underlying mechanisms are not well understood. Objectives We aimed to determine whether there is a causal relation between consuming high levels of F&V and prevention of atherosclerosis, the hallmark of CVD pathogenesis. Furthermore, the underlying mechanisms were determined. Methods Six-week-old male LDL receptor-knockout mice were randomly assigned to 3 diet groups (12 mice/group) for 20 wk: control (CON, 10% kcal fat, 0.20 g/kg cholesterol), atherogenic (Ath, 27% kcal fat, 0.55 g/kg cholesterol), and Ath supplemented with 15% F&V (Ath + FV) (equivalent to 8–9 servings/d in humans). F&V was added as a freeze-dried powder that was prepared from the 24 most commonly consumed F&Vs in the United States. Body weight, aortic atherosclerotic lesion area, hepatic steatosis area, serum...
Objectives Obesity is associated with impaired immune function. However, impact of obesity on blo... more Objectives Obesity is associated with impaired immune function. However, impact of obesity on blood T cell profile is not well studied. The objectives of this study were to investigate the effects of high fat diet (HFD)-induced obesity and long-term fruits and vegetable (FV) consumption on body composition and blood T cell profile. Methods This is partial report from an ongoing study. A total of 240 male C57BL/6J mice were randomly assigned to 4 groups: low fat control (LF-C) or high-fat control (HF-C) diet alone, or together with 15% of a unique mixture of FV (w/w, equivalent to 7–9 servings F&V/d for human) (LF-FV or HF-FV). The feeding will continue until 50% mortality is reached in one group. Body weight, body composition (using MRI), and blood T cell profile (using FACS) are monitored longitudinally at different time points. The results reported here are those assessed when mice were 7 months old. Results After 7 months of feeding, mice fed HF-C gained more weight compared to t...
The Federation of American Societies for Experimental Biology, Apr 1, 2016
Recent studies have suggested that obesity may be associated with impaired immune function as wel... more Recent studies have suggested that obesity may be associated with impaired immune function as well as the related reduction in resistance to infection. The most commonly utilized animal model for d...
Accumulation of damaged proteins is causally related to many age-related diseases. The ubiquitin-... more Accumulation of damaged proteins is causally related to many age-related diseases. The ubiquitin-proteasome pathway (UPP) plays a role in selective degradation of damaged proteins, whereas molecular chaperones, such as heat shock proteins, are involved in refolding denatured proteins. This work demonstrates for the first time that the UPP and molecular chaperones work in a competitive manner and that the fates of denatured proteins are determined by the relative activities of the UPP and molecular chaperones. Enhanced UPP activity suppresses the refolding of denatured proteins whereas elevated chaperone activity inhibits the degradation of denatured proteins. CHIP, a co-chaperone with E3 activity, plays a pivotal role in determining the fates of the damaged proteins. The delicate balance between UPP-mediated degradation and refolding of denatured proteins is governed by relative levels of CHIP and other molecular chaperones. Isopeptidases, the enzymes that reverse the actions of CHIP, also play an important role in determining the fate of denatured proteins. Key words: CHIP • heat shock proteins • isopeptidase • luciferase growing body of evidence indicates that accumulation of damaged or abnormal proteins is associated with various age-related diseases (1-3). Examples of such diseases include Parkinson's disease, Huntington's disease, Alzheimer's disease, cataract and age-related macular degeneration. Accumulation of damaged or abnormal proteins may arise from enhanced generation, or arise from deficiencies in repair or removal of these abnormal proteins. It is estimated that more than 30% of newly synthesized cellular proteins are degraded due to failure of proper folding (4). Even when proteins are normally folded into tertiary structures, there is spontaneous denaturation and generation of partially folded or unfolded proteins. In addition, environmental stress such as heat, oxidation and ultraviolet radiation, could generate denatured or damaged proteins. Unfolded or partially folded proteins are unstable, they tend to aggregate A
IntroductionObesity is associated with impaired immune function and increased susceptibility to i... more IntroductionObesity is associated with impaired immune function and increased susceptibility to infection. High fat (HF) diet-induced obesity is a commonly used animal model. However, HF diet itself is known to affect immune function and infection. Thus, it is not discernable which one, HF diet or adiposity, is the major contributor to the observed impairment in immunity and susceptibility to infection in HF diet-induced obesity. We hypothesized that obesity is a major contributor to impaired immune function.Methods and resultsWeight-matched outbred female CD-1 mice (1-mo) were randomly assigned to either a HF (45%) or a low fat (LF, 10%) diet group. Ten week after feeding their respective diets, weight gain in the mice fed the HF diet varied greatly. Thus, based on the average body weight, mice in HF diet group were divided into two sub-groups: HF lean (HF-L) and HF obese (HF-O). After 25-week, mice were immunized with an influenza A/Puerto Rico/8/34 vaccine and boosted 3-week late...
Background: Epidemiological studies suggest that higher fruits and vegetables (F&V) consumption c... more Background: Epidemiological studies suggest that higher fruits and vegetables (F&V) consumption correlates with reduced risk of hepatic steatosis, yet evidence for causality and the underlying mechanisms is lacking. Objectives: We aimed to determine the causal relation between F&V consumption and improved metabolic disorders in mice fed high-fat (HF) (Experiment-1) or normal-fat (Experiment-2) diets and its underlying mechanisms. Methods: Six-week-old male C57BL/6J mice were randomly grouped and fed diets supplemented at 0%-15% (wt:wt) with a freeze-dried powder composed of 24 commonly consumed F&V (human equivalent of 0-9 servings/d) for 20 wk. In Experiment-1, mice were fed an HF (45% kcal fat) diet with 0% (HF0), 5%, 10%, or 15% (HF15) F&V or a matched lowfat control diet (10% kcal fat). In Experiment-2, mice were fed an AIN-93 diet (basal) (B, 16% kcal fat) with 0% (B0), 5%, 10%, or 15% (B15) F&V supplementation. Body weight and composition, food intake, hepatic steatosis, inflammation, ceramide levels, sphingomyelinase activity, and gut microbiota were assessed. Results: In Experiment-1, mice fed the HF15 diet had lower weight gain (17.9%), hepatic steatosis (48.4%), adipose tissue inflammation, blood (24.6%) and liver (33.9%) ceramide concentrations, and sphingomyelinase activity (38.8%) than HF0 mice (P < 0.05 for all). In Experiment-2, mice fed the B15 diet had no significant changes in weight gain but showed less hepatic steatosis (28.5%), blood and adipose tissue inflammation, and lower blood (30.0%) ceramide concentrations than B0 mice (P < 0.05 for all). These F&V effects were associated with favorable microbiota changes. Conclusions: These findings represent the first evidence for a causal role of high F&V intake in mitigating hepatic steatosis in mice. These beneficial effects may be mediated through changes in ceramide and/or gut microbiota, and suggest that higher than currently recommended servings of F&V may be needed to achieve maximum health benefits.
Summary Autoimmune diseases are a host of diseases characterized by abnormal immune response agai... more Summary Autoimmune diseases are a host of diseases characterized by abnormal immune response against normal tissues of the body. There are about 100 autoimmune diseases, and they are estimated to affect at least 3%–5% of population. While the etiology is still unclear, both genetic and environmental factors are recognized to play key roles in the disease development. Pharmaceutical therapies have substantially improved the disease control and prognosis. However, the adverse effects and high cost of the drugs limit their use. There has been an increasing interest in alternative and complementary means to improve the outcomes of conventional therapies in many autoimmune diseases. Diet as a modifiable factor has the potential to improve clinical outcomes for several major autoimmune diseases. This chapter provides a summary and analysis of both observational and experimental studies as well as perspectives on the role of nutrition in prevention and treatment of some of the most prominent autoimmune diseases.
Objectives Osteoporosis is a debilitating disease that increases with age and is characterized by... more Objectives Osteoporosis is a debilitating disease that increases with age and is characterized by increased bone fragility. However, dietary factors can influence the development of osteoporosis. For example, high fat diets (HFD) have been shown to have detrimental effects on bone density and quantity. However, the effects of HFD on bone microarchitecture have not been extensively studied. The architecture of the bone is important because it provides information regarding the quality of the bone and not just quantity. Therefore, the purpose of this study was to investigate the effects of HFD on bone microarchitecture in mice when compared to low fat diet fed mice. Methods Five-week-old mice were randomized into two different treatment groups, control and HFD (n = 6 per group). The control group were fed AIN-93 G growing rodent diet (20% protein, 65% carbohydrate (CHO), 15% fat) while the HFD group was fed a standard HFD ordered from Research Diets Inc. Cat #D12451M (20% protein, 35%...
Objectives Epidemiological studies have shown that consumption of fruits and vegetables (F&V) is ... more Objectives Epidemiological studies have shown that consumption of fruits and vegetables (F&V) is inversely associated with incidence of cardiovascular disease (CVD). However, the evidence for causality and underlying mechanisms is lacking. Our objective was to determine if increased consumption of F&V could prevent atherosclerosis and its underlying mechanisms. Methods A unique blend of the most commonly consumed 24 F&V was freeze-dried into a powder and mixed into diets. Thirty six 4-week old male LDL receptor knockout mice were randomly assigned to one of 3 diet groups (12/group): low fat (LF, 10 kcal% fat), high-fat (27 kcal% fat) with 0% F&V (HF), and HF plus 15% F&V diet (HF + FV, equivalent to 8–9 servings for humans). After 20 weeks, mice were euthanized and blood, aorta, and liver tissue were collected. Aortic atherosclerotic lesion, hepatic steatosis, plasma lipid profile and pro-inflammatory cytokine levels were measured. Results No significant differences were found in bo...
Objectives Fecal biomarkers have emerged as an important tool to assess intestinal inflammation a... more Objectives Fecal biomarkers have emerged as an important tool to assess intestinal inflammation and permeability. Commonly measured biomarkers include calprotectin (CP), myeloperoxidase (MPO), alpha-1-antitrypsin (AAT) and neopterin (NEO). We sought to develop a simple, fast and cost-effective single extraction procedure for use in determining all four biomarkers of interest. The applicability and sensitivity of this procedure for use in healthy adults was examined. Methods Sample extraction buffers and methods including sample weight, dilution, homogenization and centrifugation were all considered in the development of a single extraction procedure. An extraction buffer that included phosphate-buffered saline, phenylmethylsulfonyl fluoride, bovine serum albumin and Tween 20 was used to extract fecal samples. To assess the applicability and sensitivity of the single extraction procedure, concentrations of CP, MPO, AAT and NEO were measured using commercially available sandwich ELISA...
Objectives Dementia and cognitive decline are typical age-related neurological disorders. However... more Objectives Dementia and cognitive decline are typical age-related neurological disorders. However, obesity has been linked to premature senescence manifestations in various systems including the central nervous system. Nutritional interventions play a role in curbing obesity-associated disorders. Epidemiological studies suggest that increased consumption of fruits and vegetables (F&V) is associated with a reduced risk of cognitive impairment and dementia. The objective of this study was to investigate the causal role of F&V consumption in prevention of high fat diet-induced cognitive impairment in mice. Methods Freeze-dried powder of a mixture of 24 F&V was added into the animal diets. Male C57BL/6 J mice (6 wk) were randomly assigned to one of the three diet groups (12/group): low fat (LF, 10% kcal fat), high fat (HF, 45% kcal fat), and HF plus 15%…
Melanoma, one of the most virulent forms of human malignancy, is the primary cause of mortality f... more Melanoma, one of the most virulent forms of human malignancy, is the primary cause of mortality from cancers arising from the skin. The prognosis of metastatic melanoma remains dismal despite targeted therapeutic regimens that exploit our growing understanding of cancer immunology and genetic mutations that drive oncogenic cell signaling pathways in cancer. Epigenetic mechanisms, including DNA methylation/demethylation, histone modifications and noncoding RNAs recently have been shown to play critical roles in melanoma pathogenesis. Current evidence indicates that imbalance of DNA methylation and demethylation, dysregulation of histone modification and chromatin remodeling, and altered translational control by noncoding RNAs contribute to melanoma tumorigenesis. Here, we summarize the most recent insights relating to epigenetic markers, focusing on diagnostic potential as well as novel therapeutic approaches for more effective treatment of advanced melanoma.
Proceedings of the National Academy of Sciences, 1999
Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involv... more Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RAR α and one of four fusion partners: PML , PLZF , NPM , and NuMA genes. To study the leukemogenic potential of the fusion genes in vivo , we generated transgenic mice with PLZF–RAR α and NPM–RAR α. PLZF–RAR α transgenic animals developed chronic myeloid leukemia-like phenotypes at an early stage of life (within 3 months in five of six mice), whereas three NPM–RAR α transgenic mice showed a spectrum of phenotypes from typical APL to chronic myeloid leukemia relatively late in life (from 12 to 15 months). In contrast to bone marrow cells from PLZF–RAR α transgenic mice, those from NPM–RAR α transgenic mice could be induced to differentiate by all- trans -retinoic acid (ATRA). We also studied RARE binding properties and interactions between nuclear corepressor SMRT and various fusion proteins in response to ATRA. Dissociation of SMRT from different receptors was observed at ATRA conce...
Background Epidemiologic studies suggest that fruit and vegetable (F&V) consumption is inversely ... more Background Epidemiologic studies suggest that fruit and vegetable (F&V) consumption is inversely associated with incidence of cardiovascular disease (CVD). However, evidence for causality is lacking, and the underlying mechanisms are not well understood. Objectives We aimed to determine whether there is a causal relation between consuming high levels of F&V and prevention of atherosclerosis, the hallmark of CVD pathogenesis. Furthermore, the underlying mechanisms were determined. Methods Six-week-old male LDL receptor-knockout mice were randomly assigned to 3 diet groups (12 mice/group) for 20 wk: control (CON, 10% kcal fat, 0.20 g/kg cholesterol), atherogenic (Ath, 27% kcal fat, 0.55 g/kg cholesterol), and Ath supplemented with 15% F&V (Ath + FV) (equivalent to 8–9 servings/d in humans). F&V was added as a freeze-dried powder that was prepared from the 24 most commonly consumed F&Vs in the United States. Body weight, aortic atherosclerotic lesion area, hepatic steatosis area, serum...
Objectives Obesity is associated with impaired immune function. However, impact of obesity on blo... more Objectives Obesity is associated with impaired immune function. However, impact of obesity on blood T cell profile is not well studied. The objectives of this study were to investigate the effects of high fat diet (HFD)-induced obesity and long-term fruits and vegetable (FV) consumption on body composition and blood T cell profile. Methods This is partial report from an ongoing study. A total of 240 male C57BL/6J mice were randomly assigned to 4 groups: low fat control (LF-C) or high-fat control (HF-C) diet alone, or together with 15% of a unique mixture of FV (w/w, equivalent to 7–9 servings F&V/d for human) (LF-FV or HF-FV). The feeding will continue until 50% mortality is reached in one group. Body weight, body composition (using MRI), and blood T cell profile (using FACS) are monitored longitudinally at different time points. The results reported here are those assessed when mice were 7 months old. Results After 7 months of feeding, mice fed HF-C gained more weight compared to t...
The Federation of American Societies for Experimental Biology, Apr 1, 2016
Recent studies have suggested that obesity may be associated with impaired immune function as wel... more Recent studies have suggested that obesity may be associated with impaired immune function as well as the related reduction in resistance to infection. The most commonly utilized animal model for d...
Accumulation of damaged proteins is causally related to many age-related diseases. The ubiquitin-... more Accumulation of damaged proteins is causally related to many age-related diseases. The ubiquitin-proteasome pathway (UPP) plays a role in selective degradation of damaged proteins, whereas molecular chaperones, such as heat shock proteins, are involved in refolding denatured proteins. This work demonstrates for the first time that the UPP and molecular chaperones work in a competitive manner and that the fates of denatured proteins are determined by the relative activities of the UPP and molecular chaperones. Enhanced UPP activity suppresses the refolding of denatured proteins whereas elevated chaperone activity inhibits the degradation of denatured proteins. CHIP, a co-chaperone with E3 activity, plays a pivotal role in determining the fates of the damaged proteins. The delicate balance between UPP-mediated degradation and refolding of denatured proteins is governed by relative levels of CHIP and other molecular chaperones. Isopeptidases, the enzymes that reverse the actions of CHIP, also play an important role in determining the fate of denatured proteins. Key words: CHIP • heat shock proteins • isopeptidase • luciferase growing body of evidence indicates that accumulation of damaged or abnormal proteins is associated with various age-related diseases (1-3). Examples of such diseases include Parkinson's disease, Huntington's disease, Alzheimer's disease, cataract and age-related macular degeneration. Accumulation of damaged or abnormal proteins may arise from enhanced generation, or arise from deficiencies in repair or removal of these abnormal proteins. It is estimated that more than 30% of newly synthesized cellular proteins are degraded due to failure of proper folding (4). Even when proteins are normally folded into tertiary structures, there is spontaneous denaturation and generation of partially folded or unfolded proteins. In addition, environmental stress such as heat, oxidation and ultraviolet radiation, could generate denatured or damaged proteins. Unfolded or partially folded proteins are unstable, they tend to aggregate A
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