Parkinson disease is the second most common neurodegenerative disorder, affecting 0.1-0.2% of the... more Parkinson disease is the second most common neurodegenerative disorder, affecting 0.1-0.2% of the general population. It is a progressive debilitating disorder caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta. It is characterized by motor and non-motor symptoms. Parkinson disease can be caused by mutations in genes that encode proteins involved in the autophagic process, resulting in impaired autophagy. Indeed, autophagy has been implicated in the pathogenesis of Parkinson disease, particularly because its impairment causes the buildup of proteins. Thus, this review aims to provide an overview of Parkinson disease-related genetic mutations and their association with autophagy impairment in Parkinson disease, which can be helpful in improving the understanding of the pathogenesis of Parkinson disease, illustrating the potential therapeutic implications of agents that can enhance autophagy in Parkinson disease. Additionally, we will highlight the essential need for the development of highly sensitive and specific assays for gene-based diagnostic biomarkers. Finally, we will provide an overview on the potential gene-based therapeutic approaches for Parkinson disease, which have been most advanced and are associated with the most common targets being alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2), and glucocerebrosidase (GBA).
Diabetic nephropathy is a common complication of type I and type II diabetes, in which renal glom... more Diabetic nephropathy is a common complication of type I and type II diabetes, in which renal glomeruli are destroyed, resulting in renal damage, proteinuria, and hypertension. Apoptosis, autophagy, and necroptosis are 3 forms of programmed cell death that have been implicated in the pathogenesis of diabetic nephropathy. Apoptosis of podocytes leads to glomerular injury and podocyte depletion, which are associated with proteinuria and glomerular structural damage in diabetic nephropathy. Additionally, epithelial cells in the proximal convoluted tubules also undergo apoptosis in diabetic nephropathy, leading to tubular atrophy, which causes tubular cell depletion and the subsequent formation of atubular glomeruli in association with the loss of renal function. On the other hand, insufficiency of autophagy has been correlated with the pathogenesis of diabetic nephropathy. For instance, decreased autophagic activity has been shown in podocytes of the diabetic kidney, causing variations in podocyte function and subsequent disruption to the glomerular filtration barrier. Furthermore, attenuated autophagic activity has also been demonstrated in proximal tubular cells of the diabetic kidney, resulting in the buildup of impaired molecules and organelles, which are normally broken down by autophagy, leading to proteinuria. Moreover, necroptosis might have a key role in podocyte damage and subsequent decline in diabetic nephropathy. Thus, this article aims to review the mechanisms and effects of programmed cell death in diabetic nephropathy, including the roles of apoptosis, autophagy, and necroptosis.
Background and Aim: Muscle atrophy is common in Parkinson's disease (PD). Although myostatin ... more Background and Aim: Muscle atrophy is common in Parkinson's disease (PD). Although myostatin has been implicated in muscle atrophy, its expression in PD skeletal muscle has not been investigated. Therefore, this study aimed to elucidate the influence of PD induction and exercise training on myostatin expression in the gastrocnemius skeletal muscle. Materials and Methods: Thirty albino mice were randomly selected and separated into three groups of 10 mice each: Sedentary control, sedentary PD (SPD), and exercised PD (EPD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid were used to induce chronic parkinsonism in the PD groups. Immunohistochemistry was used to investigate the expression of myostatin and nuclear factor kappa B (NF-κB) in gastrocnemius muscles of all three groups. Results: Myostatin expression and NF-κB nuclear localization, indicative of its activation, were significantly (p<0.01) higher in gastrocnemius skeletal muscle in the SPD group than in the ...
Apoptosis, autophagy and necrosis are the three main types of programmed cell death. One or more ... more Apoptosis, autophagy and necrosis are the three main types of programmed cell death. One or more of these types of programmed cell death may take place in neurons leading to their death in various neurodegenerative disorders in humans. Purkinje neurons (PNs) are among the most highly vulnerable population of neurons to cell death in response to intrinsic hereditary diseases or extrinsic toxic, hypoxic, ischemic, and traumatic injury. In this review, we will describe the three main types of programmed cell death, including the molecular mechanisms and the sequence of events in each of them, and thus illustrating the intracellular proteins that mediate and regulate each of these types. Then, we will discuss the role of Ca 2+ in PN function and increased vulnerability to cell death. Additionally, PN death will be described in animal models, namely lurcher mutant mouse and shaker mutant rat, in order to illustrate the potential therapeutic implications of programmed cell death in PNs by reviewing the previous studies that were carried out to interfere with the programmed cell death in an attempt to rescue PNs from death.
BACKGROUNDWe have shown elevated levels of p53 and active caspase-3 in the heart with Parkinson d... more BACKGROUNDWe have shown elevated levels of p53 and active caspase-3 in the heart with Parkinson disease (PD). The main aim of this study is to examine the effect of treadmill training on the cardiac expression of p53 and active caspase-3 in the mouse with induced Parkinsonism. METHODS Thirty randomly selected normal albino mice were equally divided into the following 3 groups: sedentary control (SC), sedentary Parkinson diseased (SPD), and exercised Parkinson diseased (EPD). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p) were used to induce chronic Parkinson disease in the SPD and EPD animals. The expression of p53 and active caspase-3 was investigated, using immunohistochemistry, in the heart in each animal group. RESULTS Both p53 and active caspase-3 expression was significantly (p value < 0.05) reduced in the PD heart following endurance exercise training. CONCLUSION Our present data suggest that chronic exercise training reduced PD-induced upregulation ...
Background: Upregulation of Apoptotic markers (p53 and active caspase-3) is reported in diabetic ... more Background: Upregulation of Apoptotic markers (p53 and active caspase-3) is reported in diabetic nephropathy. Exercise training is reported to exert renoprotective effects in diabetes. This study correlated the effects of endurance exercise training on the renal expression of p53 and active caspase-3 in a rat model of Type 1 diabetes. Materials and methods: Thirty healthy Sprague-Dawley rats were randomly divided into the following three groups: sedentary control (SC), sedentary diabetic (SD) rats, and exercised diabetic (ED) rats. The drug alloxan was administered to SD and ED groups of rats in order to induce diabetes mellitus. Expression of p53 and active caspase-3 in the renal tissue from each of the three different groups was investigated by immunohistochemistry. Increased blood levels compared to control group of rats validated the onset of diabetes in rats from SD and ED groups. Results: Significantly (P < 0.05) higher renal p53 and active caspase-3 expression was observed in SD versus SC group. Blood glucose levels and the expression of both p53 and active caspase-3 in the diabetic renal tissue were significantly reduced following endurance exercise training. Conclusion: This study attributes the renoprotective effects of endurance exercise training in diabetes to reduction in blood glucose levels and/or suppression of proapoptotic factors in the kidney.
Parkinson’s Disease: Pathogenesis and Clinical Aspects
Parkinson' s disease is one of the most common neurodegenerative diseases in the elderly. The mot... more Parkinson' s disease is one of the most common neurodegenerative diseases in the elderly. The motor symptoms occur predominantly due to substantial dopamine depletion, caused by degeneration of the dopaminergic neurons in substantia nigra pars compacta. Apoptosis has been implicated as the main mechanism of neuronal death in Parkinson' s disease. Apoptosis is mediated by a number of initiator and executioner caspases, and occurs via the intrinsic or extrinsic pathways. Activation of initiator caspase-9 mediates the intrinsic pathway-also called the mitochondria-mediated pathway. Alternatively, activation of initiator caspase-8 mediates the extrinsic apoptotic pathway-the cell death receptor-mediated pathway. Both initiator caspases converge onto a common pathway of executioner caspases, involving caspase-3 and caspase-6. Activation of the executioner caspases leads to the morphological features characteristic of apoptosis, such as DNA cleavage and its subsequent fragmentation. Proapoptotic factors, such as Bax, have been implicated in neuronal cell death in Parkinson' s disease, and there is evidence that both the intrinsic and extrinsic apoptotic pathways may play a role. This chapter provides an overview of apoptosis and its significance in Parkinson' s disease.
Active caspase-3-mediated apoptosis has been implicated in the pathogenesis of harmaline-induced ... more Active caspase-3-mediated apoptosis has been implicated in the pathogenesis of harmaline-induced tremor. The aim of this study is to illustrate the impact of tremor induction on the expression of factors mediating the cell surface death receptor–dependent apoptosis. A total of 20 normal Wistar rats were randomly selected and equally divided into control and experimental groups. Tremor was induced in the experimental group by injecting the rats with a single dose of harmaline (50 mg/kg). After that, cerebellar tissues were evaluated by immunohistochemistry to examine the expression of tumor necrosis factor α (TNF-α) and active caspase-8 in the 2 groups of animals. TNF-α and active caspase-8 expression was significantly higher in cerebella from experimental rats compared with that in those from the control rats ( P value
Background: Apoptosis plays a key role in the pathogenesis of Parkinson disease (PD). Active casp... more Background: Apoptosis plays a key role in the pathogenesis of Parkinson disease (PD). Active caspase-3, which is a proapoptotic factor, has been shown to reduce cardiac contractility, causing cardiac dysfunction in many pathological diseases. Reduced cardiac contractility and cardiac autonomic dysfunction have been reported in PD patients and PD mice treated with MPTP. The aim of this study was to show the impact of PD induction on the expression of the apoptotic mediators p53 and active caspase-3 in the heart. Material/Methods: Equal control and PD groups were formed by 20 randomly selected normal albino mice. We used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg) and probenecid (250 mg/kg) (MPTP/p) to induce chronic Parkinsonism in the PD group. Immunohistochemistry was performed to investigate the expression of p53, active caspase-3, and b-adrenergic receptor in hearts from the 2 animal groups. Results: P53 and active caspase-3 expression was significantly higher in PD hearts than in the control hearts (p value <0.01). b-adrenergic receptor expression was significantly lower in PD hearts than in control hearts (p value <0.01). Conclusions: Our results show an association of PD with p53 and active caspase-3 overexpression and b-adrenergic receptor underexpression in the heart, potentially promoting the cardiac autonomic dysfunction frequently observed in PD.
Parkinson disease is the second most common neurodegenerative disorder, affecting 0.1-0.2% of the... more Parkinson disease is the second most common neurodegenerative disorder, affecting 0.1-0.2% of the general population. It is a progressive debilitating disorder caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta. It is characterized by motor and non-motor symptoms. Parkinson disease can be caused by mutations in genes that encode proteins involved in the autophagic process, resulting in impaired autophagy. Indeed, autophagy has been implicated in the pathogenesis of Parkinson disease, particularly because its impairment causes the buildup of proteins. Thus, this review aims to provide an overview of Parkinson disease-related genetic mutations and their association with autophagy impairment in Parkinson disease, which can be helpful in improving the understanding of the pathogenesis of Parkinson disease, illustrating the potential therapeutic implications of agents that can enhance autophagy in Parkinson disease. Additionally, we will highlight the essential need for the development of highly sensitive and specific assays for gene-based diagnostic biomarkers. Finally, we will provide an overview on the potential gene-based therapeutic approaches for Parkinson disease, which have been most advanced and are associated with the most common targets being alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2), and glucocerebrosidase (GBA).
Diabetic nephropathy is a common complication of type I and type II diabetes, in which renal glom... more Diabetic nephropathy is a common complication of type I and type II diabetes, in which renal glomeruli are destroyed, resulting in renal damage, proteinuria, and hypertension. Apoptosis, autophagy, and necroptosis are 3 forms of programmed cell death that have been implicated in the pathogenesis of diabetic nephropathy. Apoptosis of podocytes leads to glomerular injury and podocyte depletion, which are associated with proteinuria and glomerular structural damage in diabetic nephropathy. Additionally, epithelial cells in the proximal convoluted tubules also undergo apoptosis in diabetic nephropathy, leading to tubular atrophy, which causes tubular cell depletion and the subsequent formation of atubular glomeruli in association with the loss of renal function. On the other hand, insufficiency of autophagy has been correlated with the pathogenesis of diabetic nephropathy. For instance, decreased autophagic activity has been shown in podocytes of the diabetic kidney, causing variations in podocyte function and subsequent disruption to the glomerular filtration barrier. Furthermore, attenuated autophagic activity has also been demonstrated in proximal tubular cells of the diabetic kidney, resulting in the buildup of impaired molecules and organelles, which are normally broken down by autophagy, leading to proteinuria. Moreover, necroptosis might have a key role in podocyte damage and subsequent decline in diabetic nephropathy. Thus, this article aims to review the mechanisms and effects of programmed cell death in diabetic nephropathy, including the roles of apoptosis, autophagy, and necroptosis.
Background and Aim: Muscle atrophy is common in Parkinson's disease (PD). Although myostatin ... more Background and Aim: Muscle atrophy is common in Parkinson's disease (PD). Although myostatin has been implicated in muscle atrophy, its expression in PD skeletal muscle has not been investigated. Therefore, this study aimed to elucidate the influence of PD induction and exercise training on myostatin expression in the gastrocnemius skeletal muscle. Materials and Methods: Thirty albino mice were randomly selected and separated into three groups of 10 mice each: Sedentary control, sedentary PD (SPD), and exercised PD (EPD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid were used to induce chronic parkinsonism in the PD groups. Immunohistochemistry was used to investigate the expression of myostatin and nuclear factor kappa B (NF-κB) in gastrocnemius muscles of all three groups. Results: Myostatin expression and NF-κB nuclear localization, indicative of its activation, were significantly (p<0.01) higher in gastrocnemius skeletal muscle in the SPD group than in the ...
Apoptosis, autophagy and necrosis are the three main types of programmed cell death. One or more ... more Apoptosis, autophagy and necrosis are the three main types of programmed cell death. One or more of these types of programmed cell death may take place in neurons leading to their death in various neurodegenerative disorders in humans. Purkinje neurons (PNs) are among the most highly vulnerable population of neurons to cell death in response to intrinsic hereditary diseases or extrinsic toxic, hypoxic, ischemic, and traumatic injury. In this review, we will describe the three main types of programmed cell death, including the molecular mechanisms and the sequence of events in each of them, and thus illustrating the intracellular proteins that mediate and regulate each of these types. Then, we will discuss the role of Ca 2+ in PN function and increased vulnerability to cell death. Additionally, PN death will be described in animal models, namely lurcher mutant mouse and shaker mutant rat, in order to illustrate the potential therapeutic implications of programmed cell death in PNs by reviewing the previous studies that were carried out to interfere with the programmed cell death in an attempt to rescue PNs from death.
BACKGROUNDWe have shown elevated levels of p53 and active caspase-3 in the heart with Parkinson d... more BACKGROUNDWe have shown elevated levels of p53 and active caspase-3 in the heart with Parkinson disease (PD). The main aim of this study is to examine the effect of treadmill training on the cardiac expression of p53 and active caspase-3 in the mouse with induced Parkinsonism. METHODS Thirty randomly selected normal albino mice were equally divided into the following 3 groups: sedentary control (SC), sedentary Parkinson diseased (SPD), and exercised Parkinson diseased (EPD). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p) were used to induce chronic Parkinson disease in the SPD and EPD animals. The expression of p53 and active caspase-3 was investigated, using immunohistochemistry, in the heart in each animal group. RESULTS Both p53 and active caspase-3 expression was significantly (p value < 0.05) reduced in the PD heart following endurance exercise training. CONCLUSION Our present data suggest that chronic exercise training reduced PD-induced upregulation ...
Background: Upregulation of Apoptotic markers (p53 and active caspase-3) is reported in diabetic ... more Background: Upregulation of Apoptotic markers (p53 and active caspase-3) is reported in diabetic nephropathy. Exercise training is reported to exert renoprotective effects in diabetes. This study correlated the effects of endurance exercise training on the renal expression of p53 and active caspase-3 in a rat model of Type 1 diabetes. Materials and methods: Thirty healthy Sprague-Dawley rats were randomly divided into the following three groups: sedentary control (SC), sedentary diabetic (SD) rats, and exercised diabetic (ED) rats. The drug alloxan was administered to SD and ED groups of rats in order to induce diabetes mellitus. Expression of p53 and active caspase-3 in the renal tissue from each of the three different groups was investigated by immunohistochemistry. Increased blood levels compared to control group of rats validated the onset of diabetes in rats from SD and ED groups. Results: Significantly (P < 0.05) higher renal p53 and active caspase-3 expression was observed in SD versus SC group. Blood glucose levels and the expression of both p53 and active caspase-3 in the diabetic renal tissue were significantly reduced following endurance exercise training. Conclusion: This study attributes the renoprotective effects of endurance exercise training in diabetes to reduction in blood glucose levels and/or suppression of proapoptotic factors in the kidney.
Parkinson’s Disease: Pathogenesis and Clinical Aspects
Parkinson' s disease is one of the most common neurodegenerative diseases in the elderly. The mot... more Parkinson' s disease is one of the most common neurodegenerative diseases in the elderly. The motor symptoms occur predominantly due to substantial dopamine depletion, caused by degeneration of the dopaminergic neurons in substantia nigra pars compacta. Apoptosis has been implicated as the main mechanism of neuronal death in Parkinson' s disease. Apoptosis is mediated by a number of initiator and executioner caspases, and occurs via the intrinsic or extrinsic pathways. Activation of initiator caspase-9 mediates the intrinsic pathway-also called the mitochondria-mediated pathway. Alternatively, activation of initiator caspase-8 mediates the extrinsic apoptotic pathway-the cell death receptor-mediated pathway. Both initiator caspases converge onto a common pathway of executioner caspases, involving caspase-3 and caspase-6. Activation of the executioner caspases leads to the morphological features characteristic of apoptosis, such as DNA cleavage and its subsequent fragmentation. Proapoptotic factors, such as Bax, have been implicated in neuronal cell death in Parkinson' s disease, and there is evidence that both the intrinsic and extrinsic apoptotic pathways may play a role. This chapter provides an overview of apoptosis and its significance in Parkinson' s disease.
Active caspase-3-mediated apoptosis has been implicated in the pathogenesis of harmaline-induced ... more Active caspase-3-mediated apoptosis has been implicated in the pathogenesis of harmaline-induced tremor. The aim of this study is to illustrate the impact of tremor induction on the expression of factors mediating the cell surface death receptor–dependent apoptosis. A total of 20 normal Wistar rats were randomly selected and equally divided into control and experimental groups. Tremor was induced in the experimental group by injecting the rats with a single dose of harmaline (50 mg/kg). After that, cerebellar tissues were evaluated by immunohistochemistry to examine the expression of tumor necrosis factor α (TNF-α) and active caspase-8 in the 2 groups of animals. TNF-α and active caspase-8 expression was significantly higher in cerebella from experimental rats compared with that in those from the control rats ( P value
Background: Apoptosis plays a key role in the pathogenesis of Parkinson disease (PD). Active casp... more Background: Apoptosis plays a key role in the pathogenesis of Parkinson disease (PD). Active caspase-3, which is a proapoptotic factor, has been shown to reduce cardiac contractility, causing cardiac dysfunction in many pathological diseases. Reduced cardiac contractility and cardiac autonomic dysfunction have been reported in PD patients and PD mice treated with MPTP. The aim of this study was to show the impact of PD induction on the expression of the apoptotic mediators p53 and active caspase-3 in the heart. Material/Methods: Equal control and PD groups were formed by 20 randomly selected normal albino mice. We used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg) and probenecid (250 mg/kg) (MPTP/p) to induce chronic Parkinsonism in the PD group. Immunohistochemistry was performed to investigate the expression of p53, active caspase-3, and b-adrenergic receptor in hearts from the 2 animal groups. Results: P53 and active caspase-3 expression was significantly higher in PD hearts than in the control hearts (p value <0.01). b-adrenergic receptor expression was significantly lower in PD hearts than in control hearts (p value <0.01). Conclusions: Our results show an association of PD with p53 and active caspase-3 overexpression and b-adrenergic receptor underexpression in the heart, potentially promoting the cardiac autonomic dysfunction frequently observed in PD.
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