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General Information:

Id:	6,481
Diseases:	Alzheimer disease - [OMIM]
Organism:	Mammalia
Publication type:	review
Reference:	Folch J et al.(2015) The role of leptin in the sporadic form of Alzheimers disease. Interactions with the adipokines amylin, ghrelin and the pituitary hormone prolactin Life Sci. 140: 19-28 [PMID: 25998028]

Interaction Information:

Comment	Leptin (Lep) is emerging as a pivotal molecule involved in both the early events and the terminal phases of Alzheimer's disease (AD).
Formal Description Interaction-ID: 61496	gene/protein LEP affects_activity of disease Alzheimer disease

Comment	In the canonical pathway, Lep acts as an anorexigenic factor via its effects on hypothalamic nucleus.
Formal Description Interaction-ID: 62062	gene/protein LEP affects_activity of tissue/cell line hypothalamic nucleus

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62066	gene/protein LEP increases_activity of process negative regulation of appetite by inhibiting neurons that produce the molecules NPY and AgRP.

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62067	gene/protein IAPP increases_activity of process negative regulation of appetite by inhibiting neurons that produce the molecules NPY and AgRP.

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62068	complex/PPI Insulin increases_activity of process negative regulation of appetite by inhibiting neurons that produce the molecules NPY and AgRP.

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62070	gene/protein LEP decreases_expression of gene/protein NPY by inhibiting neurons that produce the molecules NPY and AgRP.
Drugbank entries	Show/Hide entries for NPY
Drugbank DB02952	Alpha-Aminoisobutyric Acid not specified NPY
Drugbank DB03380	L-Tyrosinamide not specified NPY
Drugbank DB02952	Alpha-Aminoisobutyric Acid not specified NPY

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62071	gene/protein LEP decreases_quantity of gene/protein AGRP by inhibiting neurons that produce the molecules NPY and AgRP.

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62072	gene/protein IAPP decreases_expression of gene/protein NPY by inhibiting neurons that produce the molecules NPY and AgRP.
Drugbank entries	Show/Hide entries for NPY
Drugbank DB02952	Alpha-Aminoisobutyric Acid not specified NPY
Drugbank DB03380	L-Tyrosinamide not specified NPY
Drugbank DB02952	Alpha-Aminoisobutyric Acid not specified NPY

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62073	gene/protein IAPP decreases_quantity of gene/protein AGRP by inhibiting neurons that produce the molecules NPY and AgRP.

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62074	complex/PPI Insulin decreases_expression of gene/protein NPY by inhibiting neurons that produce the molecules NPY and AgRP.
Drugbank entries	Show/Hide entries for NPY
Drugbank DB02952	Alpha-Aminoisobutyric Acid not specified NPY
Drugbank DB03380	L-Tyrosinamide not specified NPY
Drugbank DB02952	Alpha-Aminoisobutyric Acid not specified NPY

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62075	complex/PPI Insulin decreases_quantity of gene/protein AGRP by inhibiting neurons that produce the molecules NPY and AgRP.

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62076	gene/protein LEP decreases_activity of tissue/cell line NPY-producing neuron

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62077	gene/protein LEP decreases_activity of tissue/cell line AGRP-producing neuron

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62078	gene/protein IAPP decreases_activity of tissue/cell line NPY-producing neuron

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62079	gene/protein IAPP decreases_activity of tissue/cell line AGRP-producing neuron

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62080	complex/PPI Insulin decreases_activity of tissue/cell line NPY-producing neuron

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62081	complex/PPI Insulin decreases_activity of tissue/cell line AGRP-producing neuron

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62082	tissue/cell line NPY-producing neuron decreases_expression of gene/protein NPY
Drugbank entries	Show/Hide entries for NPY
Drugbank DB02952	Alpha-Aminoisobutyric Acid not specified NPY
Drugbank DB03380	L-Tyrosinamide not specified NPY
Drugbank DB02952	Alpha-Aminoisobutyric Acid not specified NPY

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62083	tissue/cell line AGRP-producing neuron increases_quantity of gene/protein AGRP

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62089	gene/protein LEP increases_activity of tissue/cell line melanocortin-producing neuron in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62091	tissue/cell line melanocortin-producing neuron increases_quantity of gene/protein Melanocortin

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62092	gene/protein IAPP increases_activity of tissue/cell line melanocortin-producing neuron n the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.

Comment	Leptin, amylin and insulin decrease appetite by inhibiting neurons that produce the molecules NPY and AgRP, while stimulating melanocortin-producing neurons in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.
Formal Description Interaction-ID: 62093	complex/PPI Insulin increases_activity of tissue/cell line melanocortin-producing neuron in the arcuate-nucleus region of the hypothalamus, near the third ventricle of the brain.

Comment	NPY and AgRP stimulate eating, and melanocortins inhibit eating, via other neurons.
Formal Description Interaction-ID: 62101	gene/protein NPY increases_activity of phenotype increased eating frequency
Drugbank entries	Show/Hide entries for NPY
Drugbank DB02952	Alpha-Aminoisobutyric Acid not specified NPY
Drugbank DB03380	L-Tyrosinamide not specified NPY
Drugbank DB02952	Alpha-Aminoisobutyric Acid not specified NPY

Comment	NPY and AgRP stimulate eating, and melanocortins inhibit eating, via other neurons.
Formal Description Interaction-ID: 62102	gene/protein AGRP increases_activity of phenotype increased eating frequency

Comment	NPY and AgRP stimulate eating, and melanocortins inhibit eating, via other neurons.
Formal Description Interaction-ID: 62103	gene/protein Melanocortin increases_activity of phenotype decreased eating frequency

Comment	The gastric hormone ghrelin stimulates appetite by activating the NPY/AgRP-expressing neurons.
Formal Description Interaction-ID: 62104	gene/protein Ghrelin increases_activity of process positive regulation of appetite by activating the NPY/AgRP-expressing neurons

Comment	The gastric hormone ghrelin stimulates appetite by activating the NPY/AgRP-expressing neurons.
Formal Description Interaction-ID: 62106	gene/protein Ghrelin increases_activity of tissue/cell line NPY-producing neuron

Comment	The gastric hormone ghrelin stimulates appetite by activating the NPY/AgRP-expressing neurons.
Formal Description Interaction-ID: 62107	gene/protein Ghrelin increases_activity of tissue/cell line AGRP-producing neuron

Comment	In the hypothalamus, leptin regulates food intake, glucose homeostasis, and energy expenditure.
Formal Description Interaction-ID: 62186	gene/protein LEP affects_activity of process eating behavior in the hypothalamus

Comment	In the hypothalamus, leptin regulates food intake, glucose homeostasis, and energy expenditure.
Formal Description Interaction-ID: 62187	gene/protein LEP affects_activity of process glucose homeostasis in the hypothalamus

Comment	In the hypothalamus, leptin regulates food intake, glucose homeostasis, and energy expenditure.
Formal Description Interaction-ID: 62188	gene/protein LEP affects_activity of process energy expenditure in the hypothalamus

Comment	Obesity has been associated with changes in brain structure, cognitive deficits, dementia and AD. In agreement with this, high-fat diet (HFD)-induced obesity also causes a variety of health disorders including cognitive decline in experimental animal models .
Formal Description Interaction-ID: 62190	disease Obesity increases_activity of phenotype abnormal brain morphology

Comment	Obesity has been associated with changes in brain structure, cognitive deficits, dementia and AD. In agreement with this, high-fat diet (HFD)-induced obesity also causes a variety of health disorders including cognitive decline in experimental animal models .
Formal Description Interaction-ID: 62194	disease Obesity increases_activity of disease Dementia

Comment	Obesity significantly increases cognitive decline and AD risk, supporting the notion that AD is a degenerative metabolic disease in which brain glucose uptake and utilization are impaired.
Formal Description Interaction-ID: 62197	disease Obesity increases_activity of phenotype cognitive impairment

Comment	Obesity significantly increases cognitive decline and AD risk, supporting the notion that AD is a degenerative metabolic disease in which brain glucose uptake and utilization are impaired.
Formal Description Interaction-ID: 62200	disease Obesity increases_activity of disease Alzheimer disease

Comment	Most obese individuals show increased food intake despite high circulating Lep levels.
Formal Description Interaction-ID: 62208	disease Obesity increases_activity of phenotype increased eating frequency despite high circulating Lep levels

Comment	Most obese individuals show increased food intake despite high circulating Lep levels.
Formal Description Interaction-ID: 62209	disease Obesity increases_activity of phenotype increased circulating leptin level and increased food intake.

Comment	Pathologically low Lep levels and disruptions in orexigenic NPY hypothalamic neuron signalling were described in a mouse model (Tg2576) overexpressing Abeta, suggesting that Lep regulation may be involved.
Formal Description Interaction-ID: 62211	organism model Tg2576 mouse increases_activity of phenotype decreased circulating leptin level suggesting that Lep regulation may be involved.

Comment	In the periphery, the fat mass participates in the regulation of glucose and insulin metabolism through the release of hormones in a bidirectional feedback loop, a mechanism called the adipoinsular axis. This axis links adipose tissue and pancreatic beta-cells via leptin and insulin, respectively. Dysregulation of the axis may contribute to obesity and the development of hyperinsulinaemia associated with diabetes.
Formal Description Interaction-ID: 62241	tissue/cell line adipose tissue affects_activity of process adipoinsular axis via leptin and insulin, respectively

Comment	In the periphery, the fat mass participates in the regulation of glucose and insulin metabolism through the release of hormones in a bidirectional feedback loop, a mechanism called the adipoinsular axis. This axis links adipose tissue and pancreatic beta-cells via leptin and insulin, respectively. Dysregulation of the axis may contribute to obesity and the development of hyperinsulinaemia associated with diabetes.
Formal Description Interaction-ID: 62243	process adipoinsular axis affects_activity of tissue/cell line pancreatic beta cell via leptin and insulin, respectively

Comment	In the periphery, the fat mass participates in the regulation of glucose and insulin metabolism through the release of hormones in a bidirectional feedback loop, a mechanism called the adipoinsular axis. This axis links adipose tissue and pancreatic beta-cells via leptin and insulin, respectively.
Formal Description Interaction-ID: 62244	tissue/cell line adipose tissue affects_activity of process glucose metabolic process through the adipoinsular axis

Comment	In the periphery, the fat mass participates in the regulation of glucose and insulin metabolism through the release of hormones in a bidirectional feedback loop, a mechanism called the adipoinsular axis. This axis links adipose tissue and pancreatic beta-cells via leptin and insulin, respectively.
Formal Description Interaction-ID: 62245	tissue/cell line adipose tissue affects_activity of process insulin metabolic process through the adipoinsular axis

Comment	In the periphery, the fat mass participates in the regulation of glucose and insulin metabolism through the release of hormones in a bidirectional feedback loop, a mechanism called the adipoinsular axis. This axis links adipose tissue and pancreatic beta-cells via leptin and insulin, respectively.
Formal Description Interaction-ID: 62247	drug/chemical compound Glucose affects_quantity of complex/PPI Insulin

Comment	In the periphery, the fat mass participates in the regulation of glucose and insulin metabolism through the release of hormones in a bidirectional feedback loop, a mechanism called the adipoinsular axis. This axis links adipose tissue and pancreatic beta-cells via leptin and insulin, respectively.
Formal Description Interaction-ID: 62248	gene/protein LEP affects_quantity of complex/PPI Insulin

Comment	In the periphery, the fat mass participates in the regulation of glucose and insulin metabolism through the release of hormones in a bidirectional feedback loop, a mechanism called the adipoinsular axis. This axis links adipose tissue and pancreatic beta-cells via leptin and insulin, respectively.
Formal Description Interaction-ID: 62250	tissue/cell line adipose tissue affects_activity of process leptin metabolic process

Comment	In the periphery, the fat mass participates in the regulation of glucose and insulin metabolism through the release of hormones in a bidirectional feedback loop, a mechanism called the adipoinsular axis. This axis links adipose tissue and pancreatic beta-cells via leptin and insulin, respectively.
Formal Description Interaction-ID: 62252	tissue/cell line pancreatic beta cell increases_quantity of complex/PPI Insulin

Comment	In the periphery, the fat mass participates in the regulation of glucose and insulin metabolism through the release of hormones in a bidirectional feedback loop, a mechanism called the adipoinsular axis. This axis links adipose tissue and pancreatic beta-cells via leptin and insulin, respectively.
Formal Description Interaction-ID: 62254	tissue/cell line adipose tissue increases_quantity of gene/protein LEP

Comment	As insulin directly stimulates Lep release by adipose tissue, Lep feeds back to reduce both insulin secretion and insulin gene expression in beta-cells by modulation of K+ ATP channels and activation of cyclic nucleotide phosphodiesterase 3B and subsequent suppression of cAMP levels.
Formal Description Interaction-ID: 62255	complex/PPI Insulin increases_quantity of gene/protein LEP by adipose tissue

Comment	As insulin directly stimulates Lep release by adipose tissue, Lep feeds back to reduce both insulin secretion and insulin gene expression in beta-cells by modulation of K+ ATP channels and activation of cyclic nucleotide phosphodiesterase 3B and subsequent suppression of cAMP levels. The suppressive effect of Lep on insulin production is not only mediated by direct actions via Lep receptors (LepR) on beta-cells, but also by the autonomic nervous system (ANS). Lep-dependent ANS regulation of body weight is largely achieved via a negative afferent loop involving the hypothalamus.
Formal Description Interaction-ID: 62259	gene/protein LEP decreases_quantity of complex/PPI Insulin in beta-cells; by modulation of K+ ATP channels and activation of cyclic nucleotidephosphodiesterase 3B and subsequent suppression of cAMP levels.

Comment	Results in Lep deficient ob/ob mouse models show a lack of SIRT1 activation in the hypothalamus in response to caloric restriction, compared to age-matched controls.
Formal Description Interaction-ID: 62262	organism model ob/ob mouse increases_activity of phenotype decreased SIRT1 activation in the hypothalamus

Comment	The complexity of AD pathology is illustrated by the fact that apart from clear links between AD and obesity, weight loss is another prominent early feature of AD that often precedes cognitive decline and clinical diagnosis. In fact, pathologically low Lep levels and disruptions in orexigenic NPY hypothalamic neuron signalling were described in a mouse model overexpressing Abeta, suggesting that Lep regulation may be involved.
Formal Description Interaction-ID: 62263	disease Alzheimer disease increases_activity of phenotype weight loss

Comment	Alzheimer's disease and T2DM share many common features including the deposition of amyloidogenic proteins ‚ÄĒ Abeta and amylin (islet amyloid polypeptide), respectively. Amylin is cosecreted with insulin by the pancreatic beta-cells in response to nutrient stimuli, in the context of the adipoinsular axis.
Formal Description Interaction-ID: 62264	disease Alzheimer disease increases_activity of process islet amyloid polypeptide processing

Comment	Alzheimer's disease and T2DM share many common features including the deposition of amyloidogenic proteins ‚ÄĒ Abeta and amylin (islet amyloid polypeptide), respectively. Amylin is cosecreted with insulin by the pancreatic beta-cells in response to nutrient stimuli, in the context of the adipoinsular axis.
Formal Description Interaction-ID: 62265	disease Diabetes mellitus, type II increases_activity of process islet amyloid polypeptide processing

Comment	Alzheimer's disease and T2DM share many common features including the deposition of amyloidogenic proteins ‚ÄĒ Abeta and amylin (islet amyloid polypeptide), respectively. Amylin is cosecreted with insulin by the pancreatic beta-cells in response to nutrient stimuli, in the context of the adipoinsular axis.
Formal Description Interaction-ID: 62266	tissue/cell line pancreatic beta cell increases_quantity of gene/protein IAPP in response to nutrient stimuli

Comment	One of the roles of amylin is to slow gastric emptying, thereby delaying the delivery of nutrients to the circulation. A second effect is to decrease food intake, and a third effect is to reduce postprandial hyperglucagonemia, thereby inhibiting hepatic glucose release. Despite the beneficial effects of amylin in the CNS, it has also been shown to induce neurotoxicity in embryonic rat hippocampal primary cultures in vitro. This effect may contribute to the prominent neurite degeneration in AD.
Formal Description Interaction-ID: 62282	gene/protein IAPP decreases_activity of process gastric emptying thereby delaying the delivery of nutrients to the circulation

Comment	One of the roles of amylin is to slow gastric emptying, thereby delaying the delivery of nutrients to the circulation. A second effect is to decrease food intake, and a third effect is to reduce postprandial hyperglucagonemia, thereby inhibiting hepatic glucose release. Despite the beneficial effects of amylin in the CNS, it has also been shown to induce neurotoxicity in embryonic rat hippocampal primary cultures in vitro. This effect may contribute to the prominent neurite degeneration in AD.
Formal Description Interaction-ID: 62283	gene/protein IAPP decreases_activity of process eating behavior

Comment	One of the roles of amylin is to slow gastric emptying, thereby delaying the delivery of nutrients to the circulation. A second effect is to decrease food intake, and a third effect is to reduce postprandial hyperglucagonemia, thereby inhibiting hepatic glucose release. Despite the beneficial effects of amylin in the CNS, it has also been shown to induce neurotoxicity in embryonic rat hippocampal primary cultures in vitro. This effect may contribute to the prominent neurite degeneration in AD.
Formal Description Interaction-ID: 62285	gene/protein IAPP decreases_activity of phenotype postprandial hyperglucagonemia thereby inhibiting hepatic glucose release

Comment	One of the roles of amylin is to slow gastric emptying, thereby delaying the delivery of nutrients to the circulation. A second effect is to decrease food intake, and a third effect is to reduce postprandial hyperglucagonemia, thereby inhibiting hepatic glucose release. Despite the beneficial effects of amylin in the CNS, it has also been shown to induce neurotoxicity in embryonic rat hippocampal primary cultures in vitro. This effect may contribute to the prominent neurite degeneration in AD.
Formal Description Interaction-ID: 62286	gene/protein IAPP increases_activity of process neuron death in embryonic rat hippocampal primary cultures in vitro; caused by amylin neurotoxicity.

Comment	Circulating Lep is transported across the BBB into the brain, where it regulates food intake, glucose homeostasis, and energy expenditure mainly via the hypothalamic circuits.
Formal Description Interaction-ID: 62316	gene/protein LEP is localized in tissue/cell line brain

Comment	Circulating Lep is transported across the BBB into the brain, where it regulates food intake, glucose homeostasis, and energy expenditure mainly via the hypothalamic circuits.
Formal Description Interaction-ID: 62318	gene/protein LEP is localized in tissue/cell line blood

Comment	Functional Lep receptors (LepR or ObRb) also have been reported to be expressed in the hippocampus and other cortical regions of the brain. The hippocampus expresses high levels of both insulin and Lep receptors, as well as key components of their associated signalling cascades. Recent studies indicate that both hormones are potential cognitive enhancers.
Formal Description Interaction-ID: 62319	mRNA/protein variant LEPRb is_expressed_in tissue/cell line hippocampus and other cortical regions of the brain

Comment	The hippocampus is an area which is severely affected during the course of AD. The cognitive deficits associated with T2DM have been linked to impaired central insulin modulation in the hippocampus, which is a critical region for memory processing.
Formal Description Interaction-ID: 62322	process memory is localized in tissue/cell line hippocampus

Comment	The hippocampus is an area which is severely affected during the course of AD. The cognitive deficits associated with T2DM have been linked to impaired central insulin modulation in the hippocampus, which is a critical region for memory processing.
Formal Description Interaction-ID: 62323	disease Alzheimer disease decreases_activity of tissue/cell line hippocampus

Comment	The hippocampus is an area which is severely affected during the course of AD. The cognitive deficits associated with T2DM have been linked to impaired central insulin modulation in the hippocampus, which is a critical region for memory processing.
Formal Description Interaction-ID: 62324	disease Diabetes mellitus, type II increases_activity of phenotype cognitive impairment

Comment	The hippocampus is an area which is severely affected during the course of AD. The cognitive deficits associated with T2DM have been linked to impaired central insulin modulation in the hippocampus, which is a critical region for memory processing.
Formal Description Interaction-ID: 62325	complex/PPI Insulin affects_activity of tissue/cell line hippocampus

Comment	The hippocampus is an area which is severely affected during the course of AD. The cognitive deficits associated with T2DM have been linked to impaired central insulin modulation in the hippocampus, which is a critical region for memory processing.
Formal Description Interaction-ID: 62330	phenotype impaired central insulin modulation increases_activity of disease Diabetes mellitus, type II in the hippocampus

Comment	Epidemiological studies have demonstrated that higher circulating Lep levels are associated with lower risk of dementia including AD, whereas lower circulating levels of Lep have been reported in patients with AD. Accumulating data suggest that AD patients may benefit from Lep replacement therapy, and it may constitute a very significant application of Lep. Then, Lep deficiency in AD can be restored by replenishing low Lep levels, and this may also be a legitimate strategy for therapy.
Formal Description Interaction-ID: 62332	phenotype increased circulating leptin level decreases_activity of disease Alzheimer disease

Comment	It has been demonstrated that chronic Lep ad- ministration has led to memory improvements in the CRND8 transgenic mouse model of AD.
Formal Description Interaction-ID: 62334	phenotype increased circulating leptin level increases_activity of process learning or memory in CRND8 transgenic mouse model of AD.

Comment	Epidemiological studies have demonstrated that higher circulating Lep levels are associated with lower risk of dementia including AD, whereas lower circulating levels of Lep have been reported in patients with AD.
Formal Description Interaction-ID: 62341	phenotype increased circulating leptin level decreases_activity of disease Dementia

Comment	Epidemiological studies have demonstrated that higher circulating Lep levels are associated with lower risk of dementia including AD, whereas lower circulating levels of Lep have been reported in patients with AD. Accumulating data suggest that AD patients may benefit from Lep replacement therapy, and it may constitute a very significant application of Lep. Then, Lep deficiency in AD can be restored by replenishing low Lep levels, and this may also be a legitimate strategy for therapy.
Formal Description Interaction-ID: 62343	phenotype decreased circulating leptin level increases_activity of disease Alzheimer disease

Comment	The hippocampus expresses high levels of both insulin and Lep receptors, as well as key components of their associated signalling cascades. Recent studies indicate that both hormones are potential cognitive enhancers.
Formal Description Interaction-ID: 62347	complex/PPI Insulin receptor is_expressed_in tissue/cell line hippocampus

Comment	Lep deficiency in AD contributes to a neuronal imbalance in handling energy requirements, leading to higher Abeta and phosphorylated Tau. Additionally, Lep modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). Lep activates the PI3K/Akt, JAK STAT, and AMPK/SIRT pathways, promoting neuronal survival, reducing Abeta production and increasing its clearance, and reducing Tau hyperphosphorylation.
Formal Description Interaction-ID: 62348	phenotype decreased circulating leptin level increases_quantity of gene/protein Amyloid beta peptide

Comment	Lep deficiency in AD contributes to a neuronal imbalance in handling energy requirements, leading to higher Abeta and phosphorylated Tau. Additionally, Lep modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). Lep activates the PI3K/Akt, JAK STAT, and AMPK/SIRT pathways, promoting neuronal survival, reducing Abeta production and increasing its clearance, and reducing Tau hyperphosphorylation.
Formal Description Interaction-ID: 62349	phenotype decreased circulating leptin level increases_quantity of protein modification MAPT-phos

Comment	Lep deficiency in AD contributes to a neuronal imbalance in handling energy requirements, leading to higher Abeta and phosphorylated Tau. Additionally, Lep modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). Lep activates the PI3K/Akt, JAK STAT, and AMPK/SIRT pathways, promoting neuronal survival, reducing Abeta production and increasing its clearance, and reducing Tau hyperphosphorylation.
Formal Description Interaction-ID: 62351	gene/protein LEP increases_activity of process PI3K/AKT signaling Lep binding to its long-form receptor can activate the signal transduction pathway, finally promoting neuronal survival, reducing Abeta production and increasing its clearance, and reducing Tau hyperphosphorylation.

Comment	Lep deficiency in AD contributes to a neuronal imbalance in handling energy requirements, leading to higher Abeta and phosphorylated Tau. Additionally, Lep modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). Lep activates the PI3K/Akt, JAK STAT, and AMPK/SIRT pathways, promoting neuronal survival, reducing Abeta production and increasing its clearance, and reducing Tau hyperphosphorylation.
Formal Description Interaction-ID: 62352	gene/protein LEP increases_activity of process receptor signaling pathway via JAK-STAT Lep binding to its long-form receptor can activate the signal transduction pathway, finally promoting neuronal survival, reducing Abeta production and increasing its clearance, and reducing Tau hyperphosphorylation.

Comment	Lep deficiency in AD contributes to a neuronal imbalance in handling energy requirements, leading to higher Abeta and phosphorylated Tau. Additionally, Lep modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). Lep activates the PI3K/Akt, JAK STAT, and AMPK/SIRT pathways, promoting neuronal survival, reducing Abeta production and increasing its clearance, and reducing Tau hyperphosphorylation.
Formal Description Interaction-ID: 62353	gene/protein LEP increases_activity of process AMPK/SIRT1 signaling Lep binding to its long-form receptor can activate the signal transduction pathway, finally promoting neuronal survival, reducing Abeta production and increasing its clearance, and reducing Tau hyperphosphorylation.

Comment	Lep deficiency in AD contributes to a neuronal imbalance in handling energy requirements, leading to higher Abeta and phosphorylated Tau. Additionally, Lep modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). Lep activates the PI3K/Akt, JAK STAT, and AMPK/SIRT pathways, promoting neuronal survival, reducing Abeta production and increasing its clearance, and reducing Tau hyperphosphorylation.
Formal Description Interaction-ID: 62354	gene/protein LEP increases_activity of process negative regulation of neuron apoptotic process

Comment	Lep modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). Lep activates the PI3K/Akt, JAK STAT, and AMPK/SIRT pathways, promoting neuronal survival, reducing Abeta production and increasing its clearance. Leptin has been shown to reduce Abeta production by decreasing BACE1 activity and expression levels.
Formal Description Interaction-ID: 62355	gene/protein LEP decreases_quantity of gene/protein Amyloid beta peptide via increasing its clearance, by decreasing BACE1 activity and expression levels.

Comment	Lep deficiency in AD contributes to a neuronal imbalance in handling energy requirements, leading to higher Abeta and phosphorylated Tau. Additionally, Lep modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). Lep activates the PI3K/Akt, JAK STAT, and AMPK/SIRT pathways, promoting neuronal survival, reducing Abeta production and increasing its clearance, and reducing Tau hyperphosphorylation.
Formal Description Interaction-ID: 62356	gene/protein LEP decreases_phosphorylation of gene/protein MAPT

Comment	Lep deficiency in AD contributes to a neuronal imbalance in handling energy requirements, leading to higher Abeta and phosphorylated Tau. Additionally, Lep modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). Lep activates the PI3K/Akt, JAK STAT, and AMPK/SIRT pathways, promoting neuronal survival, reducing Abeta production and increasing its clearance, and reducing Tau hyperphosphorylation.
Formal Description Interaction-ID: 62357	gene/protein LEP decreases_quantity of protein modification MAPT-hyperphos

Comment	Lep promotes neurogenesis and synaptogenesis, thus facilitating learning and memory processes in the hippocampus. Nevertheless, the ability of Lep to regulate hippocampal synaptic function markedly declines with age, and these changes have been linked to neurodegenerative disorders such as AD.
Formal Description Interaction-ID: 62358	gene/protein LEP increases_activity of process neurogenesis

Comment	Lep promotes neurogenesis and synaptogenesis, thus facilitating learning and memory processes in the hippocampus. Nevertheless, the ability of Lep to regulate hippocampal synaptic function markedly declines with age, and these changes have been linked to neurodegenerative disorders such as AD.
Formal Description Interaction-ID: 62359	gene/protein LEP increases_activity of process synapse assembly

Comment	Lep promotes neurogenesis and synaptogenesis, thus facilitating learning and memory processes in the hippocampus. Nevertheless, the ability of Lep to regulate hippocampal synaptic function markedly declines with age, and these changes have been linked to neurodegenerative disorders such as AD.
Formal Description Interaction-ID: 62360	gene/protein LEP increases_activity of process learning or memory

Comment	Lep promotes neurogenesis and synaptogenesis, thus facilitating learning and memory processes in the hippocampus. Nevertheless, the ability of Lep to regulate hippocampal synaptic function markedly declines with age, and these changes have been linked to neurodegenerative disorders such as AD.
Formal Description Interaction-ID: 62361	process aging decreases_activity of gene/protein LEP

Comment	Leptin and insulin receptors are widely expressed in the central nervous system.
Formal Description Interaction-ID: 62362	complex/PPI Insulin receptor is_expressed_in tissue/cell line central nervous system

Comment	Leptin and insulin receptors are widely expressed in the central nervous system. The human Leptin receptor ObRb is a member of the superfamily of cytokine receptor class I (gp130). The best-described signalling pathway activated in response to receptor activation involves the coordinated functions of JAK2/STAT3.
Formal Description Interaction-ID: 62363	mRNA/protein variant LEPRb is_expressed_in tissue/cell line central nervous system

Comment	Leptin is involved in the activity of kinases like mTOR, which could perhaps explain the significance of Lep resistance to both AD and T2DM, since mTOR hyperactivity is common to both diabetes and AD. mTOR signalling could be considered a molecular link between these two age-related diseases.
Formal Description Interaction-ID: 62364	gene/protein LEP affects_activity of gene/protein MTOR
Drugbank entries	Show/Hide entries for MTOR
Drugbank DB00337	Pimecrolimus potentiator MTOR
Drugbank DB00877	Sirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR

Comment	The Leptin receptor ObRb is negatively regulated by the suppressor of cytokine signalling 3 (SOCS3) and protein tyrosine phosphatase 1beta (PTP1beta).
Formal Description Interaction-ID: 62365	gene/protein SOCS3 decreases_activity of mRNA/protein variant LEPRb

Comment	The Leptin receptor ObRb is negatively regulated by the suppressor of cytokine signalling 3 (SOCS3) and protein tyrosine phosphatase 1beta (PTP1beta).
Formal Description Interaction-ID: 62366	gene/protein PTPN1 decreases_activity of mRNA/protein variant LEPRb
Drugbank entries	Show/Hide entries for PTPN1
Drugbank DB01133	Tiludronate inhibitor PTPN1
Drugbank DB01734	3-(Oxalyl-Amino)-Naphthalene-2-Carboxyli ... not specified PTPN1
Drugbank DB01769	Double Oxidized Cysteine not specified PTPN1
Drugbank DB01820	Compound 12, N-Acetyl-4-[(Carboxycarbony ... not specified PTPN1
Drugbank DB02014	Compound 9 not specified PTPN1
Drugbank DB02072	2-(Oxalyl-Amino)-4,7-Dihydro-5h-Thieno[2 ... not specified PTPN1
Drugbank DB02259	3-(3,5-Dibromo-4-Hydroxy-Benzoyl)-2-Ethy ... not specified PTPN1
Drugbank DB02420	[[4-(Aminomethyl)Phenyl]Amino]Oxo-Acetic ... not specified PTPN1
Drugbank DB02436	2-{4-[(2s)-2-[({[(1s)-1-Carboxy-2-Phenyl ... not specified PTPN1
Drugbank DB02615	Compound 19 not specified PTPN1
Drugbank DB02620	Sp7343-Sp7964 not specified PTPN1
Drugbank DB02622	2-(Oxalyl-Amino)-Benzoic Acid not specified PTPN1
Drugbank DB02651	{[2-(1h-1,2,3-Benzotriazol-1-Yl)-2-(3,4- ... not specified PTPN1
Drugbank DB02662	Novo Nordisk a/S Compound not specified PTPN1
Drugbank DB02784	N-[4-(2-{2-[3-(2-Bromo-Acetylamino)-Prop ... not specified PTPN1
Drugbank DB02827	7-(1,1-Dioxo-1h-Benzo[D]Isothiazol-3-Ylo ... not specified PTPN1
Drugbank DB02977	PNU177836 not specified PTPN1
Drugbank DB03102	2-(Oxalyl-Amino)-4,7-Dihydro-5h-Thieno[2 ... not specified PTPN1
Drugbank DB03154	{[7-(Difluoro-Phosphono-Methyl)-Naphthal ... not specified PTPN1
Drugbank DB03311	3-(3,5-Dibromo-4-Hydroxy-Benzoyl)-2-Ethy ... not specified PTPN1
Drugbank DB03483	4-Benzoylamino-4-{1-{1-Carbamoyl-2-[4-(D ... not specified PTPN1
Drugbank DB03557	N-{1-[5-(1-Carbamoyl-2-Mercapto-Ethylcar ... not specified PTPN1
Drugbank DB03661	Cysteinesulfonic Acid not specified PTPN1
Drugbank DB03670	2-(Oxalyl-Amino)-4,5,6,7-Tetrahydro-Thie ... not specified PTPN1
Drugbank DB03714	4-Carbamoyl-4-{[6-(Difluoro-Phosphono-Me ... not specified PTPN1
Drugbank DB03982	Compound 5, 2-(Naphthalen-1-Yl-Oxalyl-Am ... not specified PTPN1
Drugbank DB04001	6-(Oxalyl-Amino)-1h-Indole-5-Carboxylic ... not specified PTPN1
Drugbank DB04088	N-(Allyloxycarbonyl)-4-[N-(Carboxy-Formy ... not specified PTPN1
Drugbank DB04142	3-(3,5-Dibromo-4-Hydroxy-Benzoyl)-2-Ethy ... not specified PTPN1
Drugbank DB04204	[(4-{4-[4-(Difluoro-Phosphono-Methyl)-Ph ... not specified PTPN1
Drugbank DB04285	{4-[(2s,4e)-2-(1,3-Benzothiazol-2-Yl)-2- ... not specified PTPN1
Drugbank DB04525	2-(Carboxymethoxy)-5-[(2s)-2-({(2s)-2-[( ... not specified PTPN1
Drugbank DB04800	1-METHYL-3-PHENYL-1H-PYRAZOL-5-YLSULFAMI ... not specified PTPN1
Drugbank DB06829	4-BROMO-3-(CARBOXYMETHOXY)-5-[3-(CYCLOHE ... not specified PTPN1
Drugbank DB06887	3(S)-METHYLCARBAMOYL-7-SULFOAMINO-3,4-DI ... not specified PTPN1
Drugbank DB07130	4-BROMO-3-(CARBOXYMETHOXY)-5-PHENYLTHIOP ... not specified PTPN1
Drugbank DB07134	5-(4-CHLORO-5-PHENYL-3-THIENYL)-1,2,5-TH ... not specified PTPN1
Drugbank DB07197	4-BROMO-3-(CARBOXYMETHOXY)-5-(4-HYDROXYP ... not specified PTPN1
Drugbank DB07263	[{2-bromo-4-[(2R)-3-oxo-2,3-diphenylprop ... not specified PTPN1
Drugbank DB07289	5-[3-(BENZYLAMINO)PHENYL]-4-BROMO-3-(CAR ... not specified PTPN1
Drugbank DB07295	2-[(7-HYDROXY-NAPHTHALEN-1-YL)-OXALYL-AM ... not specified PTPN1
Drugbank DB07298	3-(CARBOXYMETHOXY)THIENO[2,3-B]PYRIDINE- ... not specified PTPN1
Drugbank DB07480	4-PHOSPHONOOXY-PHENYL-METHYL-[4-PHOSPHON ... not specified PTPN1
Drugbank DB07651	N-ACETYL-L-PHENYLALANYL-4-[DIFLUORO(PHOS ... not specified PTPN1
Drugbank DB07719	3(R)-METHYLCARBAMOYL-7-SULFOAMINO-3,4-DI ... not specified PTPN1
Drugbank DB07730	5-(3-HYDROXYPHENYL)ISOTHIAZOL-3(2H)-ONE ... not specified PTPN1
Drugbank DB08001	5-(3-{3-[3-HYDROXY-2-(METHOXYCARBONYL)PH ... not specified PTPN1
Drugbank DB08003	ISOTHIAZOLIDINONE ANALOG not specified PTPN1
Drugbank DB08147	4-[3-(dibenzylamino)phenyl]-2,4-dioxobut ... not specified PTPN1
Drugbank DB08371	PARA-(BENZOYL)-PHENYLALANINE not specified PTPN1
Drugbank DB08397	6-(DIFLUORO-PHOSPHONO-METHYL)-NAPHTHALEN ... not specified PTPN1
Drugbank DB08549	(3R)-METHYLCARBAMOYL-7-SULFOAMINO-3,4-DI ... not specified PTPN1
Drugbank DB08591	5-(4-METHOXYBIPHENYL-3-YL)-1,2,5-THIADIA ... not specified PTPN1
Drugbank DB08593	1,2,5-THIADIAZOLIDIN-3-ONE-1,1-DIOXIDE not specified PTPN1
Drugbank DB08783	(4-{(2S)-2-[(tert-butoxycarbonyl)amino]- ... not specified PTPN1
Drugbank DB01734	3-(Oxalyl-Amino)-Naphthalene-2-Carboxyli ... not specified PTPN1
Drugbank DB01769	Double Oxidized Cysteine not specified PTPN1
Drugbank DB01820	Compound 12, N-Acetyl-4-[(Carboxycarbony ... not specified PTPN1
Drugbank DB02014	Compound 9 not specified PTPN1
Drugbank DB02072	2-(Oxalyl-Amino)-4,7-Dihydro-5h-Thieno[2 ... not specified PTPN1
Drugbank DB02259	3-(3,5-Dibromo-4-Hydroxy-Benzoyl)-2-Ethy ... not specified PTPN1
Drugbank DB02420	[[4-(Aminomethyl)Phenyl]Amino]Oxo-Acetic ... not specified PTPN1
Drugbank DB02436	2-{4-[(2s)-2-[({[(1s)-1-Carboxy-2-Phenyl ... not specified PTPN1
Drugbank DB02615	Compound 19 not specified PTPN1
Drugbank DB02620	Sp7343-Sp7964 not specified PTPN1
Drugbank DB02622	2-(Oxalyl-Amino)-Benzoic Acid not specified PTPN1
Drugbank DB02651	{[2-(1h-1,2,3-Benzotriazol-1-Yl)-2-(3,4- ... not specified PTPN1
Drugbank DB02662	Novo Nordisk a/S Compound not specified PTPN1
Drugbank DB02784	N-[4-(2-{2-[3-(2-Bromo-Acetylamino)-Prop ... not specified PTPN1
Drugbank DB02827	7-(1,1-Dioxo-1h-Benzo[D]Isothiazol-3-Ylo ... not specified PTPN1
Drugbank DB02977	PNU177836 not specified PTPN1
Drugbank DB03102	2-(Oxalyl-Amino)-4,7-Dihydro-5h-Thieno[2 ... not specified PTPN1
Drugbank DB03154	{[7-(Difluoro-Phosphono-Methyl)-Naphthal ... not specified PTPN1
Drugbank DB03311	3-(3,5-Dibromo-4-Hydroxy-Benzoyl)-2-Ethy ... not specified PTPN1
Drugbank DB03483	4-Benzoylamino-4-{1-{1-Carbamoyl-2-[4-(D ... not specified PTPN1
Drugbank DB03557	N-{1-[5-(1-Carbamoyl-2-Mercapto-Ethylcar ... not specified PTPN1
Drugbank DB03661	Cysteinesulfonic Acid not specified PTPN1
Drugbank DB03670	2-(Oxalyl-Amino)-4,5,6,7-Tetrahydro-Thie ... not specified PTPN1
Drugbank DB03714	4-Carbamoyl-4-{[6-(Difluoro-Phosphono-Me ... not specified PTPN1
Drugbank DB03982	Compound 5, 2-(Naphthalen-1-Yl-Oxalyl-Am ... not specified PTPN1
Drugbank DB04001	6-(Oxalyl-Amino)-1h-Indole-5-Carboxylic ... not specified PTPN1
Drugbank DB04088	N-(Allyloxycarbonyl)-4-[N-(Carboxy-Formy ... not specified PTPN1
Drugbank DB04142	3-(3,5-Dibromo-4-Hydroxy-Benzoyl)-2-Ethy ... not specified PTPN1
Drugbank DB04204	[(4-{4-[4-(Difluoro-Phosphono-Methyl)-Ph ... not specified PTPN1
Drugbank DB04285	{4-[(2s,4e)-2-(1,3-Benzothiazol-2-Yl)-2- ... not specified PTPN1
Drugbank DB04525	2-(Carboxymethoxy)-5-[(2s)-2-({(2s)-2-[( ... not specified PTPN1
Drugbank DB04800	1-METHYL-3-PHENYL-1H-PYRAZOL-5-YLSULFAMI ... not specified PTPN1

Comment	Leptin signalling also induces the activation of the ubiquitous and broad spectrum PI3K/Akt/mTOR pathway.
Formal Description Interaction-ID: 62367	gene/protein LEP increases_activity of process PI3K/AKT/TOR signaling Lep binding to its long-form receptor can activate the signal transduction pathway

Comment	It has been shown that Lep binding to its long-form receptor can activate four major signal transduction pathways: JAK/STAT pathway; ERK pathway; PI3K/Akt/mTOR pathway as well as the AMPK/SIRT1 signal transduction pathways.
Formal Description Interaction-ID: 62368	gene/protein LEP interacts (colocalizes) with mRNA/protein variant LEPRb

Comment	The mammalian mTOR plays a key role in maintaining energy homeostasis in the brain and other tissue types. As an energy sensor, mTOR regulates numerous cellular pathways including protein translation, cell growth and proliferation. In fact, mTOR mediates the synthesis and aggregation of Tau, resulting in compromised microtubule stability. mTOR has been shown to modulate insulin signalling in a context of high nutrient exposure. mTOR directly phosphorylates the insulin receptor leading to its internalization; this, in turn, results in a decrease of mTOR signalling. However, through the same mechanisms, chronic mTOR hyperactivity leads to insulin resistance, a key feature of T2DM.
Formal Description Interaction-ID: 62371	gene/protein MTOR affects_activity of process energy homeostasis in the brain and other tissue types of mammalia
Drugbank entries	Show/Hide entries for MTOR
Drugbank DB00337	Pimecrolimus potentiator MTOR
Drugbank DB00877	Sirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR

Comment	The mammalian mTOR plays a key role in maintaining energy homeostasis in the brain and other tissue types. As an energy sensor, mTOR regulates numerous cellular pathways including protein translation, cell growth and proliferation.
Formal Description Interaction-ID: 62387	gene/protein MTOR affects_activity of process cell population proliferation
Drugbank entries	Show/Hide entries for MTOR
Drugbank DB00337	Pimecrolimus potentiator MTOR
Drugbank DB00877	Sirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR

Comment	mTOR mediates the synthesis and aggregation of Tau, resulting in compromised microtubule stability.
Formal Description Interaction-ID: 62392	gene/protein MTOR increases_activity of process MAPT biosynthesis
Drugbank entries	Show/Hide entries for MTOR
Drugbank DB00337	Pimecrolimus potentiator MTOR
Drugbank DB00877	Sirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR

Comment	mTOR mediates the synthesis and aggregation of Tau, resulting in compromised microtubule stability.
Formal Description Interaction-ID: 62394	gene/protein MTOR increases_quantity of complex/PPI MAPT aggregation
Drugbank entries	Show/Hide entries for MTOR
Drugbank DB00337	Pimecrolimus potentiator MTOR
Drugbank DB00877	Sirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR

Comment	mTOR mediates the synthesis and aggregation of Tau, resulting in compromised microtubule stability.
Formal Description Interaction-ID: 62401	gene/protein MTOR affects_activity of process microtubule
Drugbank entries	Show/Hide entries for MTOR
Drugbank DB00337	Pimecrolimus potentiator MTOR
Drugbank DB00877	Sirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR

Comment	mTOR has been shown to modulate insulin signalling in a context of high nutrient exposure. mTOR directly phosphorylates the insulin receptor leading to its internalization; this, in turn, results in a decrease of mTOR signalling. However, through the same mechanisms, chronic mTOR hyperactivity leads to insulin resistance, a key feature of T2DM.
Formal Description Interaction-ID: 62403	gene/protein MTOR affects_activity of process insulin receptor signaling pathway
Drugbank entries	Show/Hide entries for MTOR
Drugbank DB00337	Pimecrolimus potentiator MTOR
Drugbank DB00877	Sirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR

Comment	mTOR has been shown to modulate insulin signalling in a context of high nutrient exposure. mTOR directly phosphorylates the insulin receptor leading to its internalization; this, in turn, results in a decrease of mTOR signalling. However, through the same mechanisms, chronic mTOR hyperactivity leads to insulin resistance, a key feature of T2DM.
Formal Description Interaction-ID: 62407	gene/protein MTOR increases_phosphorylation of complex/PPI Insulin receptor leading to its internalization.
Drugbank entries	Show/Hide entries for MTOR
Drugbank DB00337	Pimecrolimus potentiator MTOR
Drugbank DB00877	Sirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR

Comment	mTOR has been shown to modulate insulin signalling in a context of high nutrient exposure. mTOR directly phosphorylates the insulin receptor leading to its internalization; this, in turn, results in a decrease of mTOR signalling. However, through the same mechanisms, chronic mTOR hyperactivity leads to insulin resistance, a key feature of T2DM.
Formal Description Interaction-ID: 62409	gene/protein MTOR increases_activity of process receptor internalization
Drugbank entries	Show/Hide entries for MTOR
Drugbank DB00337	Pimecrolimus potentiator MTOR
Drugbank DB00877	Sirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR

Comment	mTOR has been shown to modulate insulin signalling in a context of high nutrient exposure. mTOR directly phosphorylates the insulin receptor leading to its internalization; this, in turn, results in a decrease of mTOR signalling. However, through the same mechanisms, chronic mTOR hyperactivity leads to insulin resistance, a key feature of T2DM.
Formal Description Interaction-ID: 62410	process receptor internalization decreases_activity of process TOR signaling

Comment	mTOR has been shown to modulate insulin signalling in a context of high nutrient exposure. mTOR directly phosphorylates the insulin receptor leading to its internalization; this, in turn, results in a decrease of mTOR signalling. However, through the same mechanisms, chronic mTOR hyperactivity leads to insulin resistance, a key feature of T2DM.
Formal Description Interaction-ID: 62412	gene/protein MTOR increases_activity of phenotype insulin resistance in case of chronic mTOR hyperactivity
Drugbank entries	Show/Hide entries for MTOR
Drugbank DB00337	Pimecrolimus potentiator MTOR
Drugbank DB00877	Sirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR
Drugbank DB01590	Everolimus inhibitor MTOR
Drugbank DB06287	Temsirolimus inhibitor MTOR

Comment	Previous data suggest that AMPK can also phosphorylate substrates like Tau proteins, thereby favouring their aggregation. Phosphorylated Tau becomes soluble and causes microtubule disassembly. In extreme cases, including in AD, hyperphosphorylation of Tau leads to the formation of neurofibrillary tangles.
Formal Description Interaction-ID: 62415	gene/protein MAPT increases_activity of process microtubule depolymerization if TAU / MAPT is phosphorylated

Comment	Leptin has been shown to reduce Abeta production by decreasing BACE1 activity and expression levels.
Formal Description Interaction-ID: 62417	gene/protein LEP decreases_expression of gene/protein BACE1 hereby reducing Abeta production
Drugbank entries	Show/Hide entries for BACE1
Drugbank DB02378	MMI-175 not specified BACE1
Drugbank DB06930	N-[amino(imino)methyl]-2-(2,5-diphenyl-1 ... not specified BACE1
Drugbank DB07019	N-[(5R,14R)-5-AMINO-5,14-DIMETHYL-4-OXO- ... not specified BACE1
Drugbank DB07089	N-[amino(imino)methyl]-2-[2-(2-chlorophe ... not specified BACE1
Drugbank DB07110	4-(4-FLUOROBENZYL)PIPERIDINE not specified BACE1
Drugbank DB07175	N-{2-methyl-5-[(6-phenylpyrimidin-4-yl)a ... not specified BACE1
Drugbank DB07206	6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMIN ... not specified BACE1
Drugbank DB07245	6-[2-(3'-METHOXYBIPHENYL-3-YL)ETHYL]PYRI ... not specified BACE1
Drugbank DB07281	N~3~-BENZYLPYRIDINE-2,3-DIAMINE not specified BACE1
Drugbank DB07284	N~3~-(3-PYRIDIN-3-YLBENZYL)PYRIDINE-2,3- ... not specified BACE1
Drugbank DB07303	N~3~-[3-(5-METHOXYPYRIDIN-3-YL)BENZYL]PY ... not specified BACE1
Drugbank DB07345	4-(2-aminoethyl)-2-cyclohexylphenol not specified BACE1
Drugbank DB07346	4-(2-aminoethyl)-2-ethylphenol not specified BACE1
Drugbank DB07415	4-[(1S)-1-(3-fluoro-4-methoxyphenyl)-2-( ... not specified BACE1
Drugbank DB07519	(6R)-2-amino-6-[2-(3'-methoxybiphenyl-3- ... not specified BACE1
Drugbank DB07535	2-amino-6-[2-(1H-indol-6-yl)ethyl]pyrimi ... not specified BACE1
Drugbank DB07573	(2S)-1-(2,5-dimethylphenoxy)-3-morpholin ... not specified BACE1
Drugbank DB07734	N-(1-benzylpiperidin-4-yl)-4-sulfanylbut ... not specified BACE1
Drugbank DB07735	N-[1-(2,6-dimethoxybenzyl)piperidin-4-yl ... not specified BACE1
Drugbank DB07736	(2S)-4-(4-fluorobenzyl)-N-(2-sulfanyleth ... not specified BACE1
Drugbank DB07737	(2S)-4-(4-fluorobenzyl)-N-(3-sulfanylpro ... not specified BACE1
Drugbank DB07738	N-[1-(5-bromo-2,3-dimethoxybenzyl)piperi ... not specified BACE1
Drugbank DB07874	(6S)-2-amino-6-(3'-methoxybiphenyl-3-yl) ... not specified BACE1
Drugbank DB07993	N~3~-[3-(1H-INDOL-6-YL)BENZYL]PYRIDINE-2 ... not specified BACE1
Drugbank DB07994	N~3~-[5-(1H-INDOL-6-YL)-2-(PYRIDIN-2-YLM ... not specified BACE1
Drugbank DB08749	3-(2-AMINO-6-BENZOYLQUINAZOLIN-3(4H)-YL) ... not specified BACE1
Drugbank DB02378	MMI-175 not specified BACE1

Comment	Leptin increases the expression and activity of SIRT1, which results in decreased NF-kappB-mediated transcription of BACE1.
Formal Description Interaction-ID: 62418	gene/protein LEP increases_expression of gene/protein SIRT1 resulting in decreased NF-kappB-mediated transcription of BACE1.

Comment	Leptin has been shown to reduce Abeta production by decreasing BACE1 activity and expression levels.
Formal Description Interaction-ID: 62421	gene/protein LEP decreases_activity of gene/protein BACE1 hereby reducing Abeta production
Drugbank entries	Show/Hide entries for BACE1
Drugbank DB02378	MMI-175 not specified BACE1
Drugbank DB06930	N-[amino(imino)methyl]-2-(2,5-diphenyl-1 ... not specified BACE1
Drugbank DB07019	N-[(5R,14R)-5-AMINO-5,14-DIMETHYL-4-OXO- ... not specified BACE1
Drugbank DB07089	N-[amino(imino)methyl]-2-[2-(2-chlorophe ... not specified BACE1
Drugbank DB07110	4-(4-FLUOROBENZYL)PIPERIDINE not specified BACE1
Drugbank DB07175	N-{2-methyl-5-[(6-phenylpyrimidin-4-yl)a ... not specified BACE1
Drugbank DB07206	6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMIN ... not specified BACE1
Drugbank DB07245	6-[2-(3'-METHOXYBIPHENYL-3-YL)ETHYL]PYRI ... not specified BACE1
Drugbank DB07281	N~3~-BENZYLPYRIDINE-2,3-DIAMINE not specified BACE1
Drugbank DB07284	N~3~-(3-PYRIDIN-3-YLBENZYL)PYRIDINE-2,3- ... not specified BACE1
Drugbank DB07303	N~3~-[3-(5-METHOXYPYRIDIN-3-YL)BENZYL]PY ... not specified BACE1
Drugbank DB07345	4-(2-aminoethyl)-2-cyclohexylphenol not specified BACE1
Drugbank DB07346	4-(2-aminoethyl)-2-ethylphenol not specified BACE1
Drugbank DB07415	4-[(1S)-1-(3-fluoro-4-methoxyphenyl)-2-( ... not specified BACE1
Drugbank DB07519	(6R)-2-amino-6-[2-(3'-methoxybiphenyl-3- ... not specified BACE1
Drugbank DB07535	2-amino-6-[2-(1H-indol-6-yl)ethyl]pyrimi ... not specified BACE1
Drugbank DB07573	(2S)-1-(2,5-dimethylphenoxy)-3-morpholin ... not specified BACE1
Drugbank DB07734	N-(1-benzylpiperidin-4-yl)-4-sulfanylbut ... not specified BACE1
Drugbank DB07735	N-[1-(2,6-dimethoxybenzyl)piperidin-4-yl ... not specified BACE1
Drugbank DB07736	(2S)-4-(4-fluorobenzyl)-N-(2-sulfanyleth ... not specified BACE1
Drugbank DB07737	(2S)-4-(4-fluorobenzyl)-N-(3-sulfanylpro ... not specified BACE1
Drugbank DB07738	N-[1-(5-bromo-2,3-dimethoxybenzyl)piperi ... not specified BACE1
Drugbank DB07874	(6S)-2-amino-6-(3'-methoxybiphenyl-3-yl) ... not specified BACE1
Drugbank DB07993	N~3~-[3-(1H-INDOL-6-YL)BENZYL]PYRIDINE-2 ... not specified BACE1
Drugbank DB07994	N~3~-[5-(1H-INDOL-6-YL)-2-(PYRIDIN-2-YLM ... not specified BACE1
Drugbank DB08749	3-(2-AMINO-6-BENZOYLQUINAZOLIN-3(4H)-YL) ... not specified BACE1
Drugbank DB02378	MMI-175 not specified BACE1

Comment	Leptin increases the expression and activity of SIRT1, which results in decreased NF-kappB-mediated transcription of BACE1.
Formal Description Interaction-ID: 62422	gene/protein LEP increases_activity of gene/protein SIRT1 resulting in decreased NF-kappB-mediated transcription of BACE1.

Comment	Leptin increases the expression and activity of SIRT1, which results in decreased NF-kappB-mediated transcription of BACE1.
Formal Description Interaction-ID: 62460	gene/protein SIRT1 decreases_expression of gene/protein BACE1 resulting in decreased NF-kappB-mediated transcription of BACE1.
Drugbank entries	Show/Hide entries for BACE1
Drugbank DB02378	MMI-175 not specified BACE1
Drugbank DB06930	N-[amino(imino)methyl]-2-(2,5-diphenyl-1 ... not specified BACE1
Drugbank DB07019	N-[(5R,14R)-5-AMINO-5,14-DIMETHYL-4-OXO- ... not specified BACE1
Drugbank DB07089	N-[amino(imino)methyl]-2-[2-(2-chlorophe ... not specified BACE1
Drugbank DB07110	4-(4-FLUOROBENZYL)PIPERIDINE not specified BACE1
Drugbank DB07175	N-{2-methyl-5-[(6-phenylpyrimidin-4-yl)a ... not specified BACE1
Drugbank DB07206	6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMIN ... not specified BACE1
Drugbank DB07245	6-[2-(3'-METHOXYBIPHENYL-3-YL)ETHYL]PYRI ... not specified BACE1
Drugbank DB07281	N~3~-BENZYLPYRIDINE-2,3-DIAMINE not specified BACE1
Drugbank DB07284	N~3~-(3-PYRIDIN-3-YLBENZYL)PYRIDINE-2,3- ... not specified BACE1
Drugbank DB07303	N~3~-[3-(5-METHOXYPYRIDIN-3-YL)BENZYL]PY ... not specified BACE1
Drugbank DB07345	4-(2-aminoethyl)-2-cyclohexylphenol not specified BACE1
Drugbank DB07346	4-(2-aminoethyl)-2-ethylphenol not specified BACE1
Drugbank DB07415	4-[(1S)-1-(3-fluoro-4-methoxyphenyl)-2-( ... not specified BACE1
Drugbank DB07519	(6R)-2-amino-6-[2-(3'-methoxybiphenyl-3- ... not specified BACE1
Drugbank DB07535	2-amino-6-[2-(1H-indol-6-yl)ethyl]pyrimi ... not specified BACE1
Drugbank DB07573	(2S)-1-(2,5-dimethylphenoxy)-3-morpholin ... not specified BACE1
Drugbank DB07734	N-(1-benzylpiperidin-4-yl)-4-sulfanylbut ... not specified BACE1
Drugbank DB07735	N-[1-(2,6-dimethoxybenzyl)piperidin-4-yl ... not specified BACE1
Drugbank DB07736	(2S)-4-(4-fluorobenzyl)-N-(2-sulfanyleth ... not specified BACE1
Drugbank DB07737	(2S)-4-(4-fluorobenzyl)-N-(3-sulfanylpro ... not specified BACE1
Drugbank DB07738	N-[1-(5-bromo-2,3-dimethoxybenzyl)piperi ... not specified BACE1
Drugbank DB07874	(6S)-2-amino-6-(3'-methoxybiphenyl-3-yl) ... not specified BACE1
Drugbank DB07993	N~3~-[3-(1H-INDOL-6-YL)BENZYL]PYRIDINE-2 ... not specified BACE1
Drugbank DB07994	N~3~-[5-(1H-INDOL-6-YL)-2-(PYRIDIN-2-YLM ... not specified BACE1
Drugbank DB08749	3-(2-AMINO-6-BENZOYLQUINAZOLIN-3(4H)-YL) ... not specified BACE1
Drugbank DB02378	MMI-175 not specified BACE1

Comment	Key downstream effectors of the leptin receptor ObRb include AMP-activated protein kinase (AMPK), PGC-1alpha (involved in mitochondrial biogenesis), as PPAR, as well as aspartyl protease beta-site AbetaPP-cleaving enzyme (BACE1). PGC-1alpha appears to decrease Abeta generation, therapeutic modulation of PGC-1alpha could have real potential as a treatment for Alzheimer disease. Thus, Lep emerges as a general activity modulator of AMPK, PGC-1alpha and the molecules downstream of them: PPARgamma and BACE1.
Formal Description Interaction-ID: 62461	complex/PPI AMPK affects_activity of mRNA/protein variant LEPRb

Comment	Key downstream effectors of the leptin receptor ObRb include AMP-activated protein kinase (AMPK), PGC-1alpha (involved in mitochondrial biogenesis), as PPAR, as well as aspartyl protease beta-site AbetaPP-cleaving enzyme (BACE1). PGC-1alpha appears to decrease Abeta generation, therapeutic modulation of PGC-1alpha could have real potential as a treatment for Alzheimer disease. Thus, Lep emerges as a general activity modulator of AMPK, PGC-1alpha and the molecules downstream of them: PPARgamma and BACE1.
Formal Description Interaction-ID: 62463	gene/protein PPARGC1A affects_activity of mRNA/protein variant LEPRb

Comment	Key downstream effectors of the leptin receptor ObRb include AMP-activated protein kinase (AMPK), PGC-1alpha (involved in mitochondrial biogenesis), as PPAR, as well as aspartyl protease beta-site AbetaPP-cleaving enzyme (BACE1). PGC-1alpha appears to decrease Abeta generation, therapeutic modulation of PGC-1alpha could have real potential as a treatment for Alzheimer disease. Thus, Lep emerges as a general activity modulator of AMPK, PGC-1alpha and the molecules downstream of them: PPARgamma and BACE1.
Formal Description Interaction-ID: 62464	gene/protein BACE1 affects_activity of mRNA/protein variant LEPRb
Drugbank entries	Show/Hide entries for BACE1
Drugbank DB02378	MMI-175 not specified BACE1
Drugbank DB06930	N-[amino(imino)methyl]-2-(2,5-diphenyl-1 ... not specified BACE1
Drugbank DB07019	N-[(5R,14R)-5-AMINO-5,14-DIMETHYL-4-OXO- ... not specified BACE1
Drugbank DB07089	N-[amino(imino)methyl]-2-[2-(2-chlorophe ... not specified BACE1
Drugbank DB07110	4-(4-FLUOROBENZYL)PIPERIDINE not specified BACE1
Drugbank DB07175	N-{2-methyl-5-[(6-phenylpyrimidin-4-yl)a ... not specified BACE1
Drugbank DB07206	6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMIN ... not specified BACE1
Drugbank DB07245	6-[2-(3'-METHOXYBIPHENYL-3-YL)ETHYL]PYRI ... not specified BACE1
Drugbank DB07281	N~3~-BENZYLPYRIDINE-2,3-DIAMINE not specified BACE1
Drugbank DB07284	N~3~-(3-PYRIDIN-3-YLBENZYL)PYRIDINE-2,3- ... not specified BACE1
Drugbank DB07303	N~3~-[3-(5-METHOXYPYRIDIN-3-YL)BENZYL]PY ... not specified BACE1
Drugbank DB07345	4-(2-aminoethyl)-2-cyclohexylphenol not specified BACE1
Drugbank DB07346	4-(2-aminoethyl)-2-ethylphenol not specified BACE1
Drugbank DB07415	4-[(1S)-1-(3-fluoro-4-methoxyphenyl)-2-( ... not specified BACE1
Drugbank DB07519	(6R)-2-amino-6-[2-(3'-methoxybiphenyl-3- ... not specified BACE1
Drugbank DB07535	2-amino-6-[2-(1H-indol-6-yl)ethyl]pyrimi ... not specified BACE1
Drugbank DB07573	(2S)-1-(2,5-dimethylphenoxy)-3-morpholin ... not specified BACE1
Drugbank DB07734	N-(1-benzylpiperidin-4-yl)-4-sulfanylbut ... not specified BACE1
Drugbank DB07735	N-[1-(2,6-dimethoxybenzyl)piperidin-4-yl ... not specified BACE1
Drugbank DB07736	(2S)-4-(4-fluorobenzyl)-N-(2-sulfanyleth ... not specified BACE1
Drugbank DB07737	(2S)-4-(4-fluorobenzyl)-N-(3-sulfanylpro ... not specified BACE1
Drugbank DB07738	N-[1-(5-bromo-2,3-dimethoxybenzyl)piperi ... not specified BACE1
Drugbank DB07874	(6S)-2-amino-6-(3'-methoxybiphenyl-3-yl) ... not specified BACE1
Drugbank DB07993	N~3~-[3-(1H-INDOL-6-YL)BENZYL]PYRIDINE-2 ... not specified BACE1
Drugbank DB07994	N~3~-[5-(1H-INDOL-6-YL)-2-(PYRIDIN-2-YLM ... not specified BACE1
Drugbank DB08749	3-(2-AMINO-6-BENZOYLQUINAZOLIN-3(4H)-YL) ... not specified BACE1
Drugbank DB02378	MMI-175 not specified BACE1

Comment	Key downstream effectors of the leptin receptor ObRb include AMP-activated protein kinase (AMPK), PGC-1alpha (involved in mitochondrial biogenesis), as PPAR, as well as aspartyl protease beta-site AbetaPP-cleaving enzyme (BACE1). PGC-1alpha appears to decrease Abeta generation, therapeutic modulation of PGC-1alpha could have real potential as a treatment for Alzheimer disease. Thus, Lep emerges as a general activity modulator of AMPK, PGC-1alpha and the molecules downstream of them: PPARgamma and BACE1.
Formal Description Interaction-ID: 62465	gene/protein PPARGC1A affects_quantity of gene/protein Amyloid beta peptide

Comment	Lep emerges as a general activity modulator of AMPK, PGC-1alpha and the molecules downstream of them: PPARgamma and BACE1.
Formal Description Interaction-ID: 62467	gene/protein LEP affects_activity of complex/PPI AMPK

Comment	Lep emerges as a general activity modulator of AMPK, PGC-1alpha and the molecules downstream of them: PPARgamma and BACE1.
Formal Description Interaction-ID: 62468	gene/protein LEP affects_activity of gene/protein PPARGC1A

Comment	Lep emerges as a general activity modulator of AMPK, PGC-1alpha and the molecules downstream of them: PPARgamma and BACE1.
Formal Description Interaction-ID: 62469	gene/protein LEP affects_activity of gene/protein PPARG
Drugbank entries	Show/Hide entries for PPARG
Drugbank DB00159	Icosapent agonist PPARG
Drugbank DB00197	Troglitazone agonist PPARG
Drugbank DB00244	Mesalazine agonist PPARG
Drugbank DB00328	Indomethacin activator PPARG
Drugbank DB00412	Rosiglitazone agonist PPARG
Drugbank DB00731	Nateglinide inhibitor PPARG
Drugbank DB00795	Sulfasalazine agonist PPARG
Drugbank DB00912	Repaglinide agonist PPARG
Drugbank DB00966	Telmisartan partial agonist PPARG
Drugbank DB01014	Balsalazide agonist PPARG
Drugbank DB01067	Glipizide agonist PPARG
Drugbank DB01132	Pioglitazone agonist PPARG
Drugbank DB01252	Mitiglinide agonist PPARG
Drugbank DB01393	Bezafibrate agonist PPARG
Drugbank DB04270	(S)-3-(4-(2-Carbazol-9-Yl-Ethoxy)-Phenyl ... not specified PPARG
Drugbank DB04689	2-{5-[3-(6-BENZOYL-1-PROPYLNAPHTHALEN-2- ... not specified PPARG
Drugbank DB06908	(2S)-3-(1-{[2-(2-CHLOROPHENYL)-5-METHYL- ... not specified PPARG
Drugbank DB06926	(9Z,11E,13S)-13-hydroxyoctadeca-9,11-die ... not specified PPARG
Drugbank DB07053	2-{5-[3-(7-PROPYL-3-TRIFLUOROMETHYLBENZO ... not specified PPARG
Drugbank DB07111	(4S,5E,7Z,10Z,13Z,16Z,19Z)-4-hydroxydoco ... not specified PPARG
Drugbank DB07172	(5R,6E,8Z,11Z,14Z,17Z)-5-hydroxyicosa-6, ... not specified PPARG
Drugbank DB07208	(8E,10S,12Z)-10-hydroxy-6-oxooctadeca-8, ... not specified PPARG
Drugbank DB07209	(8R,9Z,12Z)-8-hydroxy-6-oxooctadeca-9,12 ... not specified PPARG
Drugbank DB07302	(9S,10E,12Z)-9-hydroxyoctadeca-10,12-die ... not specified PPARG
Drugbank DB07509	difluoro(5-{2-[(5-octyl-1H-pyrrol-2-yl-k ... not specified PPARG
Drugbank DB07675	(2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10 ... not specified PPARG
Drugbank DB07723	3-(5-methoxy-1H-indol-3-yl)propanoic aci ... not specified PPARG
Drugbank DB07724	3-{5-methoxy-1-[(4-methoxyphenyl)sulfony ... not specified PPARG
Drugbank DB07842	(2S)-2-(4-ethylphenoxy)-3-phenylpropanoi ... not specified PPARG
Drugbank DB07863	2-chloro-5-nitro-N-phenylbenzamide not specified PPARG
Drugbank DB08121	(2S)-2-(biphenyl-4-yloxy)-3-phenylpropan ... not specified PPARG
Drugbank DB08302	3-[5-(2-nitropent-1-en-1-yl)furan-2-yl]b ... not specified PPARG
Drugbank DB08402	2-[(2,4-DICHLOROBENZOYL)AMINO]-5-(PYRIMI ... not specified PPARG
Drugbank DB08435	(5E,14E)-11-oxoprosta-5,9,12,14-tetraen- ... not specified PPARG
Drugbank DB08483	(2S)-2-methoxy-3-{4-[2-(5-methyl-2-pheny ... not specified PPARG
Drugbank DB08560	3-FLUORO-N-[1-(4-FLUOROPHENYL)-3-(2-THIE ... not specified PPARG
Drugbank DB08760	(2S)-2-(4-chlorophenoxy)-3-phenylpropano ... not specified PPARG
Drugbank DB00197	Troglitazone agonist PPARG
Drugbank DB00412	Rosiglitazone agonist PPARG
Drugbank DB01132	Pioglitazone agonist PPARG
Drugbank DB04689	2-{5-[3-(6-BENZOYL-1-PROPYLNAPHTHALEN-2- ... not specified PPARG

Comment	Chronic inflammation is known to cause Lep resistance that, as previously discussed, is a status related to T2DM and AD.
Formal Description Interaction-ID: 62470	phenotype chronic inflammation increases_activity of phenotype leptin resistance

Comment	Chronic inflammation is known to cause Lep resistance that, as previously discussed, is a status related to T2DM and AD.
Formal Description Interaction-ID: 62472	disease Alzheimer disease increases_activity of phenotype leptin resistance

Comment	It has been shown that both the accumulation of Abeta and apoE4 genotype result in a transient enhancement of Lep signalling that might lead to Lep resistance over time. The mechanisms by which Abeta and apoE4 affect LepR expression are unknown.
Formal Description Interaction-ID: 62473	gene/protein Amyloid beta peptide increases_activity of process leptin-mediated signaling pathway Accumulation of Abeta results in a transient enhancement of Lep signalling that might lead to Lep resistance over time.

Comment	It has been shown that both the accumulation of Abeta and apoE4 genotype result in a transient enhancement of Lep signalling that might lead to Lep resistance over time. The mechanisms by which Abeta and apoE4 affect LepR expression are unknown.
Formal Description Interaction-ID: 62475	gene/protein mutant APOE (isoform E4) increases_activity of process leptin-mediated signaling pathway Accumulation of ApoE4 results in a transient enhancement of Lep signalling that might lead to Lep resistance over time.

Comment	Abeta and apoE4 genotype have been shown to cause inflammation, and LepR upregulation has been demonstrated in response to proinflammatory stimuli, such as treatments with LPS and TNFalpha. Transgenic animal models overexpressing human forms of Abeta or human apoE4, showed enhanced inflammatory reactions in the brain, including TNFalpha generation and gliosis. Thus, it may be speculated that the initial up-regulation of LepR could result from the pro-inflammatory effects of Abeta or apoE4.
Formal Description Interaction-ID: 62478	gene/protein Amyloid beta peptide increases_activity of process inflammatory response

Comment	Abeta and apoE4 genotype have been shown to cause inflammation, and LepR upregulation has been demonstrated in response to proinflammatory stimuli, such as treatments with LPS and TNFalpha. Transgenic animal models overexpressing human forms of Abeta or human apoE4, showed enhanced inflammatory reactions in the brain, including TNFalpha generation and gliosis. Thus, it may be speculated that the initial up-regulation of LepR could result from the pro-inflammatory effects of Abeta or apoE4.
Formal Description Interaction-ID: 62483	gene/protein mutant APOE (isoform E4) increases_activity of process inflammatory response

Comment	Abeta and apoE4 genotype have been shown to cause inflammation, and LepR upregulation has been demonstrated in response to proinflammatory stimuli, such as treatments with LPS and TNFalpha. Transgenic animal models overexpressing human forms of Abeta or human apoE4, showed enhanced inflammatory reactions in the brain, including TNFalpha generation and gliosis. Thus, it may be speculated that the initial up-regulation of LepR could result from the pro-inflammatory effects of Abeta or apoE4.
Formal Description Interaction-ID: 62487	drug/chemical compound Lipopolysaccharide increases_activity of gene/protein LEPR

Comment	Abeta and apoE4 genotype have been shown to cause inflammation, and LepR upregulation has been demonstrated in response to proinflammatory stimuli, such as treatments with LPS and TNFalpha. Transgenic animal models overexpressing human forms of Abeta or human apoE4, showed enhanced inflammatory reactions in the brain, including TNFalpha generation and gliosis. Thus, it may be speculated that the initial up-regulation of LepR could result from the pro-inflammatory effects of Abeta or apoE4.
Formal Description Interaction-ID: 62488	drug/chemical compound Lipopolysaccharide increases_expression of gene/protein LEPR

Comment	Abeta and apoE4 genotype have been shown to cause inflammation, and LepR upregulation has been demonstrated in response to proinflammatory stimuli, such as treatments with LPS and TNFalpha. Transgenic animal models overexpressing human forms of Abeta or human apoE4, showed enhanced inflammatory reactions in the brain, including TNFalpha generation and gliosis. Thus, it may be speculated that the initial up-regulation of LepR could result from the pro-inflammatory effects of Abeta or apoE4.
Formal Description Interaction-ID: 62489	gene/protein TNF increases_activity of gene/protein LEPR
Drugbank entries	Show/Hide entries for TNF
Drugbank DB00005	Etanercept antibody TNF
Drugbank DB00051	Adalimumab antibody TNF
Drugbank DB00065	Infliximab inhibitor TNF
Drugbank DB00608	Chloroquine not specified TNF
Drugbank DB01041	Thalidomide inhibitor TNF
Drugbank DB01296	Glucosamine not specified TNF
Drugbank DB01407	Clenbuterol other/unknown TNF
Drugbank DB01411	Pranlukast other/unknown TNF
Drugbank DB01427	Amrinone inhibitor TNF
Drugbank DB00051	Adalimumab antibody TNF
Drugbank DB00065	Infliximab inhibitor TNF
Drugbank DB01427	Amrinone inhibitor TNF

Comment	Abeta and apoE4 genotype have been shown to cause inflammation, and LepR upregulation has been demonstrated in response to proinflammatory stimuli, such as treatments with LPS and TNFalpha. Transgenic animal models overexpressing human forms of Abeta or human apoE4, showed enhanced inflammatory reactions in the brain, including TNFalpha generation and gliosis. Thus, it may be speculated that the initial up-regulation of LepR could result from the pro-inflammatory effects of Abeta or apoE4.
Formal Description Interaction-ID: 62490	gene/protein TNF increases_expression of gene/protein LEPR
Drugbank entries	Show/Hide entries for TNF
Drugbank DB00005	Etanercept antibody TNF
Drugbank DB00051	Adalimumab antibody TNF
Drugbank DB00065	Infliximab inhibitor TNF
Drugbank DB00608	Chloroquine not specified TNF
Drugbank DB01041	Thalidomide inhibitor TNF
Drugbank DB01296	Glucosamine not specified TNF
Drugbank DB01407	Clenbuterol other/unknown TNF
Drugbank DB01411	Pranlukast other/unknown TNF
Drugbank DB01427	Amrinone inhibitor TNF
Drugbank DB00051	Adalimumab antibody TNF
Drugbank DB00065	Infliximab inhibitor TNF
Drugbank DB01427	Amrinone inhibitor TNF

Comment	Abeta and apoE4 genotype have been shown to cause inflammation, and LepR upregulation has been demonstrated in response to proinflammatory stimuli, such as treatments with LPS and TNFalpha. Transgenic animal models overexpressing human forms of Abeta or human apoE4, showed enhanced inflammatory reactions in the brain, including TNFalpha generation and gliosis. Thus, it may be speculated that the initial up-regulation of LepR could result from the pro-inflammatory effects of Abeta or apoE4.
Formal Description Interaction-ID: 62515	gene/protein Amyloid beta peptide increases_activity of phenotype gliosis in the brain; in transgenic animal models overexpressing human form of Abeta.

Comment	Abeta and apoE4 genotype have been shown to cause inflammation, and LepR upregulation has been demonstrated in response to proinflammatory stimuli, such as treatments with LPS and TNFalpha. Transgenic animal models overexpressing human forms of Abeta or human apoE4, showed enhanced inflammatory reactions in the brain, including TNFalpha generation and gliosis. Thus, it may be speculated that the initial up-regulation of LepR could result from the pro-inflammatory effects of Abeta or apoE4.
Formal Description Interaction-ID: 62516	gene/protein mutant APOE (isoform E4) increases_activity of phenotype gliosis in the brain; in transgenic animal models overexpressing human form of apoE4 .

Comment	Diet-induced obesity (DIO), or HFD-induced obesity, accelerates AD progression.
Formal Description Interaction-ID: 62522	phenotype obesity, diet-induced increases_activity of disease Alzheimer disease

Comment	Diet-induced obesity (DIO), or HFD-induced obesity, accelerates AD progression.
Formal Description Interaction-ID: 62523	phenotype obesity, high-fat diet-induced increases_activity of disease Alzheimer disease

Comment	It has been shown that DIO (obesity, diet-induced) increases amyloid deposition in amyloidogenic transgenic mice.
Formal Description Interaction-ID: 62524	phenotype obesity, diet-induced increases_quantity of phenotype amyloid beta deposits in amyloidogenic transgenic mice

Comment	In WT rats, DIO causes Tau phosphorylation, increases glial fibrillary acidic protein (GFAP) expression and astroglial activation in the hippocampus and impairs cognitive function. Interestingly, these changes were associated with enhanced astrocytic LepR expression and mild microgliosis, but not Abeta accumulation.
Formal Description Interaction-ID: 62584	phenotype obesity, diet-induced increases_phosphorylation of gene/protein MAPT in WT rats

Comment	In WT rats, DIO causes Tau phosphorylation, increases glial fibrillary acidic protein (GFAP) expression and astroglial activation in the hippocampus and impairs cognitive function. Interestingly, these changes were associated with enhanced astrocytic LepR expression and mild microgliosis, but not Abeta accumulation.
Formal Description Interaction-ID: 62585	phenotype obesity, diet-induced increases_expression of gene/protein GFAP in WT rats

Comment	In WT rats, DIO causes Tau phosphorylation, increases glial fibrillary acidic protein (GFAP) expression and astroglial activation in the hippocampus and impairs cognitive function. Interestingly, these changes were associated with enhanced astrocytic LepR expression and mild microgliosis, but not Abeta accumulation.
Formal Description Interaction-ID: 62586	phenotype obesity, diet-induced increases_activity of process astrocyte activation in the hippocampus of WT rats

Comment	In WT rats, DIO causes Tau phosphorylation, increases glial fibrillary acidic protein (GFAP) expression and astroglial activation in the hippocampus and impairs cognitive function. Interestingly, these changes were associated with enhanced astrocytic LepR expression and mild microgliosis, but not Abeta accumulation.
Formal Description Interaction-ID: 62587	phenotype obesity, diet-induced increases_activity of phenotype cognitive impairment in WT rats

Comment	In WT rats, DIO causes Tau phosphorylation, increases glial fibrillary acidic protein (GFAP) expression and astroglial activation in the hippocampus and impairs cognitive function. Interestingly, these changes were associated with enhanced astrocytic LepR expression and mild microgliosis, but not Abeta accumulation.
Formal Description Interaction-ID: 62588	phenotype obesity, diet-induced increases_expression of gene/protein LEPR in astrocytes of WT rats

Comment	In WT rats, DIO causes Tau phosphorylation, increases glial fibrillary acidic protein (GFAP) expression and astroglial activation in the hippocampus and impairs cognitive function. Interestingly, these changes were associated with enhanced astrocytic LepR expression and mild microgliosis, but not Abeta accumulation.
Formal Description Interaction-ID: 62589	phenotype obesity, diet-induced increases_activity of phenotype microgliosis in WT rats

Comment	Saturated fatty acids can stimulate microglia, leading to upregulation of NF-kappaB and pro-inflammatory cytokine expression.
Formal Description Interaction-ID: 62590	drug/chemical compound Saturated fatty acid increases_activity of tissue/cell line microglia leading to upregulation of NF-kappaB and pro-inflammatory cytokine expression

Comment	Saturated fatty acids can stimulate microglia, leading to upregulation of NF-kappaB and proinflammatory cytokine expression.
Formal Description Interaction-ID: 62591	drug/chemical compound Saturated fatty acid increases_expression of gene/protein NFKB1 via stimulated microglia
Drugbank entries	Show/Hide entries for NFKB1
Drugbank DB01041	Thalidomide antagonist NFKB1
Drugbank DB01411	Pranlukast other/unknown NFKB1
Drugbank DB08814	Triflusal antagonist NFKB1

Comment	Saturated fatty acids can stimulate microglia, leading to upregulation of NF-kappaB and proinflammatory cytokine expression.
Formal Description Interaction-ID: 62592	drug/chemical compound Saturated fatty acid increases_expression of gene/protein Proinflammatory cytokine via stimulated microglia

Comment	It has been demonstrated that Lep was able to protect hippocampal neurons against kainate excitotoxicity in an experimental model of epilepsia in Lep deficient ob/ob mice.
Formal Description Interaction-ID: 62597	gene/protein LEP increases_activity of phenotype decreased susceptibility to neuronal excitotoxicity in Lep deficient ob/ob mice; via protecting hippocampal neurons against kainate excitotoxicity.

Comment	Ghrelin prevented kainate-induced activation of microglia and astrocytes, and inhibited the expression of proinflammatory mediator TNFalpha, IL-1beta, and cyclooxygenase-2. The inhibitory effect of ghrelin appears to be associated with the reduction in matrix metalloproteinase-3 expression in damaged hippocampal neurons.
Formal Description Interaction-ID: 62599	gene/protein Ghrelin decreases_activity of process microglial cell activation if microglia activation is kainate-induced.

Comment	It is becoming apparent that neuroendocrine hormones including oxytocin, progesterone and prolactin (PRL), apart from their roles in lactation, may also have neuroprotective effects on hippocampal neurons. Among the pituitary hormones, PRL is the most versatile in the spectrum and number of functions it regulates. PRL modulates virtually every aspect of vertebrate physiology, including osmoregulation, growth, metabolism, development, reproduction, parental behaviour, and immune function. In mammals, this hormone may act in cooperation with Lep to transfer information to the brain about the caloric state of the animal. It has been shown that PRL prevents the damaging effects of excitotoxicity in the dorsal hippocampus.
Formal Description Interaction-ID: 62605	gene/protein PRL affects_activity of process water homeostasis

Comment	Trophic actions of PRL in the CNS include mediating development and maturation of dopaminergic tuberoinfundibular neurons. It also regulates neurogenesis and brain cell proliferation. Prolactin also shows mitogenic actions on astroglia and protects hippocampal neurogenesis in the dentate gyrus of chronically stressed mice. Prolactin is also involved in immune regulation.
Formal Description Interaction-ID: 62606	gene/protein PRL affects_activity of tissue/cell line dopaminergic tuberoinfundibular neuron in CNS; via mediating development and maturation

Comment	In the brain, prolactin receptors (Prl-Rs), which belong to the class I cytokine receptor superfamily, have been detected in the cortex, hypothalamus and hippocampus, in both astrocytes and glial cells.
Formal Description Interaction-ID: 62609	gene/protein PRLR is localized in tissue/cell line cerebral cortex
Drugbank entries	Show/Hide entries for PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR
Drugbank DB01185	Fluoxymesterone antagonist PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR

Comment	PRL gene is down-regulated at early stages of amyloidogenesis, in an APPswe/PS1dE9 double transgenic murine model of AD. We observed a significant down-regulation of the Prl-Rs and PRL genes in the hippocampus of 3 month-old APPswe/PS1dE9 mice, when compared to a wild-type control group. The results indicate early perturbations in this particular biological route, at early stages of the neurodegenerative process, when both cognitive impairments and Abeta deposits have yet to develop.
Formal Description Interaction-ID: 62610	phenotype amyloidosis decreases_activity of gene/protein PRL in an APPswe/PS1dE9 double transgenic murine model of AD; at early stages of amyloidogenesis

Comment	It has been shown that amylin augmented Lep signalling/receptor binding.
Formal Description Interaction-ID: 62618	gene/protein IAPP increases_activity of process leptin-mediated signaling pathway

Comment	AMPK activity decreases in AD brain, indicating decreased mitochondrial biogenesis and function. The roles of AMPK in the pathogenesis of AD include Abeta generation and Tau phosphorylation at Thr-231 and Ser-396/404, and an inhibition of mTOR signalling pathway, thus facilitating autophagy and promoting lysosomal degradation of Abeta.
Formal Description Interaction-ID: 62621	disease Alzheimer disease decreases_activity of complex/PPI AMPK indicating decreased mitochondrial biogenesis and function.

Comment	It has been demonstrated that Lep was able to protect hippocampal neurons against kainate excitotoxicity in an experimental model of epilepsia in Lep deficient ob/ob mice.
Formal Description Interaction-ID: 62629	gene/protein LEP decreases_activity of phenotype hippocampal neuron degeneration in Lep deficient ob/ob mice; via protecting hippocampal neurons against kainate excitotoxicity.

Comment	Ghrelin prevented kainate-induced activation of microglia and astrocytes, and inhibited the expression of proinflammatory mediator TNFalpha, IL-1beta, and cyclooxygenase-2. The inhibitory effect of ghrelin appears to be associated with the reduction in matrix metalloproteinase-3 expression in damaged hippocampal neurons.
Formal Description Interaction-ID: 62631	gene/protein Ghrelin decreases_activity of process astrocyte activation if astrocyte activation is kainate-induced.

Comment	Ghrelin prevented kainate-induced activation of microglia and astrocytes, and inhibited the expression of proinflammatory mediator TNFalpha, IL-1beta, and cyclooxygenase-2. The inhibitory effect of ghrelin appears to be associated with the reduction in matrix metalloproteinase-3 expression in damaged hippocampal neurons.
Formal Description Interaction-ID: 62634	gene/protein Ghrelin decreases_expression of gene/protein TNF
Drugbank entries	Show/Hide entries for TNF
Drugbank DB00005	Etanercept antibody TNF
Drugbank DB00051	Adalimumab antibody TNF
Drugbank DB00065	Infliximab inhibitor TNF
Drugbank DB00608	Chloroquine not specified TNF
Drugbank DB01041	Thalidomide inhibitor TNF
Drugbank DB01296	Glucosamine not specified TNF
Drugbank DB01407	Clenbuterol other/unknown TNF
Drugbank DB01411	Pranlukast other/unknown TNF
Drugbank DB01427	Amrinone inhibitor TNF
Drugbank DB00051	Adalimumab antibody TNF
Drugbank DB00065	Infliximab inhibitor TNF
Drugbank DB01427	Amrinone inhibitor TNF

Comment	Ghrelin prevented kainate-induced activation of microglia and astrocytes, and inhibited the expression of proinflammatory mediator TNFalpha, IL-1beta, and cyclooxygenase-2. The inhibitory effect of ghrelin appears to be associated with the reduction in matrix metalloproteinase-3 expression in damaged hippocampal neurons.
Formal Description Interaction-ID: 62635	gene/protein Ghrelin decreases_expression of gene/protein IL1B
Drugbank entries	Show/Hide entries for IL1B
Drugbank DB01017	Minocycline modulator IL1B
Drugbank DB05260	Gallium nitrate antagonist IL1B
Drugbank DB06168	Canakinumab not specified IL1B
Drugbank DB06168	Canakinumab not specified IL1B

Comment	Ghrelin prevented kainate-induced activation of microglia and astrocytes, and inhibited the expression of proinflammatory mediator TNFalpha, IL-1beta, and cyclooxygenase-2. The inhibitory effect of ghrelin appears to be associated with the reduction in matrix metalloproteinase-3 expression in damaged hippocampal neurons.
Formal Description Interaction-ID: 62638	gene/protein Ghrelin decreases_expression of gene/protein PTGS2
Drugbank entries	Show/Hide entries for PTGS2
Drugbank DB00154	gamma-Homolinolenic acid not specified PTGS2
Drugbank DB00159	Icosapent inhibitor PTGS2
Drugbank DB00233	Aminosalicylic Acid inhibitor PTGS2
Drugbank DB00244	Mesalazine inhibitor PTGS2
Drugbank DB00316	Acetaminophen inhibitor PTGS2
Drugbank DB00328	Indomethacin inhibitor PTGS2
Drugbank DB00461	Nabumetone inhibitor PTGS2
Drugbank DB00465	Ketorolac inhibitor PTGS2
Drugbank DB00469	Tenoxicam inhibitor PTGS2
Drugbank DB00480	Lenalidomide negative modulator PTGS2
Drugbank DB00482	Celecoxib inhibitor PTGS2
Drugbank DB00500	Tolmetin inhibitor PTGS2
Drugbank DB00533	Rofecoxib inhibitor PTGS2
Drugbank DB00554	Piroxicam inhibitor PTGS2
Drugbank DB00573	Fenoprofen inhibitor PTGS2
Drugbank DB00580	Valdecoxib inhibitor PTGS2
Drugbank DB00586	Diclofenac inhibitor PTGS2
Drugbank DB00605	Sulindac inhibitor PTGS2
Drugbank DB00712	Flurbiprofen inhibitor PTGS2
Drugbank DB00749	Etodolac inhibitor PTGS2
Drugbank DB00784	Mefenamic acid inhibitor PTGS2
Drugbank DB00788	Naproxen inhibitor PTGS2
Drugbank DB00795	Sulfasalazine inhibitor PTGS2
Drugbank DB00812	Phenylbutazone inhibitor PTGS2
Drugbank DB00814	Meloxicam inhibitor PTGS2
Drugbank DB00821	Carprofen inhibitor PTGS2
Drugbank DB00861	Diflunisal inhibitor PTGS2
Drugbank DB00870	Suprofen inhibitor PTGS2
Drugbank DB00936	Salicyclic acid inhibitor PTGS2
Drugbank DB00939	Meclofenamic acid inhibitor PTGS2
Drugbank DB00945	Acetylsalicylic acid inhibitor PTGS2
Drugbank DB00963	Bromfenac inhibitor PTGS2
Drugbank DB00991	Oxaprozin inhibitor PTGS2
Drugbank DB01009	Ketoprofen inhibitor PTGS2
Drugbank DB01014	Balsalazide inhibitor PTGS2
Drugbank DB01041	Thalidomide antagonist PTGS2
Drugbank DB01050	Ibuprofen inhibitor PTGS2
Drugbank DB01283	Lumiracoxib inhibitor PTGS2
Drugbank DB01294	Bismuth Subsalicylate inhibitor PTGS2
Drugbank DB01397	Magnesium salicylate inhibitor PTGS2
Drugbank DB01398	Salicylate-sodium inhibitor PTGS2
Drugbank DB01399	Salsalate inhibitor PTGS2
Drugbank DB01401	Trisalicylate-choline inhibitor PTGS2
Drugbank DB01404	Ginseng inhibitor PTGS2
Drugbank DB01419	Antrafenine inhibitor PTGS2
Drugbank DB01435	Antipyrine inhibitor PTGS2
Drugbank DB01600	Tiaprofenic acid inhibitor PTGS2
Drugbank DB01628	Etoricoxib inhibitor PTGS2
Drugbank DB02266	Flufenamic Acid not specified PTGS2
Drugbank DB02709	Resveratrol inhibitor PTGS2
Drugbank DB03014	Heme not specified PTGS2
Drugbank DB03477	1-Phenylsulfonamide-3-Trifluoromethyl-5- ... not specified PTGS2
Drugbank DB03866	Prostaglandin G2 not specified PTGS2
Drugbank DB04552	Niflumic Acid inhibitor PTGS2
Drugbank DB04743	Nimesulide inhibitor PTGS2
Drugbank DB06725	Lornoxicam inhibitor PTGS2
Drugbank DB06802	Nepafenac inhibitor PTGS2
Drugbank DB00154	gamma-Homolinolenic acid not specified PTGS2
Drugbank DB00482	Celecoxib inhibitor PTGS2
Drugbank DB00533	Rofecoxib inhibitor PTGS2
Drugbank DB00573	Fenoprofen inhibitor PTGS2
Drugbank DB00580	Valdecoxib inhibitor PTGS2
Drugbank DB00784	Mefenamic acid inhibitor PTGS2
Drugbank DB00812	Phenylbutazone inhibitor PTGS2
Drugbank DB00814	Meloxicam inhibitor PTGS2
Drugbank DB00821	Carprofen inhibitor PTGS2
Drugbank DB00939	Meclofenamic acid inhibitor PTGS2
Drugbank DB01283	Lumiracoxib inhibitor PTGS2
Drugbank DB01404	Ginseng inhibitor PTGS2
Drugbank DB01600	Tiaprofenic acid inhibitor PTGS2
Drugbank DB01628	Etoricoxib inhibitor PTGS2
Drugbank DB03014	Heme not specified PTGS2
Drugbank DB04743	Nimesulide inhibitor PTGS2

Comment	It is becoming apparent that neuroendocrine hormones including oxytocin, progesterone and prolactin (PRL), apart from their roles in lactation, may also have neuroprotective effects on hippocampal neurons. Among the pituitary hormones, PRL is the most versatile in the spectrum and number of functions it regulates. PRL modulates virtually every aspect of vertebrate physiology, including osmoregulation, growth, metabolism, development, reproduction, parental behaviour, and immune function. In mammals, this hormone may act in cooperation with Lep to transfer information to the brain about the caloric state of the animal. It has been shown that PRL prevents the damaging effects of excitotoxicity in the dorsal hippocampus.
Formal Description Interaction-ID: 62648	gene/protein PRL affects_activity of process growth

Comment	It is becoming apparent that neuroendocrine hormones including oxytocin, progesterone and prolactin (PRL), apart from their roles in lactation, may also have neuroprotective effects on hippocampal neurons. Among the pituitary hormones, PRL is the most versatile in the spectrum and number of functions it regulates. PRL modulates virtually every aspect of vertebrate physiology, including osmoregulation, growth, metabolism, development, reproduction, parental behaviour, and immune function. In mammals, this hormone may act in cooperation with Lep to transfer information to the brain about the caloric state of the animal. It has been shown that PRL prevents the damaging effects of excitotoxicity in the dorsal hippocampus.
Formal Description Interaction-ID: 62649	gene/protein PRL affects_activity of process metabolic process

Comment	It is becoming apparent that neuroendocrine hormones including oxytocin, progesterone and prolactin (PRL), apart from their roles in lactation, may also have neuroprotective effects on hippocampal neurons. Among the pituitary hormones, PRL is the most versatile in the spectrum and number of functions it regulates. PRL modulates virtually every aspect of vertebrate physiology, including osmoregulation, growth, metabolism, development, reproduction, parental behaviour, and immune function. In mammals, this hormone may act in cooperation with Lep to transfer information to the brain about the caloric state of the animal. It has been shown that PRL prevents the damaging effects of excitotoxicity in the dorsal hippocampus.
Formal Description Interaction-ID: 62651	gene/protein PRL affects_activity of process reproduction

Comment	It is becoming apparent that neuroendocrine hormones including oxytocin, progesterone and prolactin (PRL), apart from their roles in lactation, may also have neuroprotective effects on hippocampal neurons. Among the pituitary hormones, PRL is the most versatile in the spectrum and number of functions it regulates. PRL modulates virtually every aspect of vertebrate physiology, including osmoregulation, growth, metabolism, development, reproduction, parental behaviour, and immune function. In mammals, this hormone may act in cooperation with Lep to transfer information to the brain about the caloric state of the animal. It has been shown that PRL prevents the damaging effects of excitotoxicity in the dorsal hippocampus.
Formal Description Interaction-ID: 62652	gene/protein PRL affects_activity of process parental behaviour

Comment	It is becoming apparent that neuroendocrine hormones including oxytocin, progesterone and prolactin (PRL), apart from their roles in lactation, may also have neuroprotective effects on hippocampal neurons. Among the pituitary hormones, PRL is the most versatile in the spectrum and number of functions it regulates. PRL modulates virtually every aspect of vertebrate physiology, including osmoregulation, growth, metabolism, development, reproduction, parental behaviour, and immune function. In mammals, this hormone may act in cooperation with Lep to transfer information to the brain about the caloric state of the animal. It has been shown that PRL prevents the damaging effects of excitotoxicity in the dorsal hippocampus.
Formal Description Interaction-ID: 62653	gene/protein PRL affects_activity of process immune response

Comment	It is becoming apparent that neuroendocrine hormones including oxytocin, progesterone and prolactin (PRL), apart from their roles in lactation, may also have neuroprotective effects on hippocampal neurons. Among the pituitary hormones, PRL is the most versatile in the spectrum and number of functions it regulates. PRL modulates virtually every aspect of vertebrate physiology, including osmoregulation, growth, metabolism, development, reproduction, parental behaviour, and immune function. In mammals, this hormone may act in cooperation with Lep to transfer information to the brain about the caloric state of the animal. It has been shown that PRL prevents the damaging effects of excitotoxicity in the dorsal hippocampus.
Formal Description Interaction-ID: 62654	gene/protein PRL decreases_activity of phenotype increased susceptibility to neuronal excitotoxicity in the dorsal hippocampus

Comment	Trophic actions of PRL in the CNS include mediating development and maturation of dopaminergic tuberoinfundibular neurons. It also regulates neurogenesis and brain cell proliferation. Prolactin also shows mitogenic actions on astroglia and protects hippocampal neurogenesis in the dentate gyrus of chronically stressed mice. Prolactin is also involved in immune regulation.
Formal Description Interaction-ID: 62656	gene/protein PRL affects_activity of process neurogenesis in the dentate gyrus of chronically stressed mice

Comment	Trophic actions of PRL in the CNS include mediating development and maturation of dopaminergic tuberoinfundibular neurons. It also regulates neurogenesis and brain cell proliferation. Prolactin also shows mitogenic actions on astroglia and protects hippocampal neurogenesis in the dentate gyrus of chronically stressed mice. Prolactin is also involved in immune regulation.
Formal Description Interaction-ID: 62658	gene/protein PRL affects_activity of process cell population proliferation in brain

Comment	Trophic actions of PRL in the CNS include mediating development and maturation of dopaminergic tuberoinfundibular neurons. It also regulates neurogenesis and brain cell proliferation. Prolactin also shows mitogenic actions on astroglia and protects hippocampal neurogenesis in the dentate gyrus of chronically stressed mice. Prolactin is also involved in immune regulation.
Formal Description Interaction-ID: 62659	gene/protein PRL affects_activity of process mitogenic actions on astroglia

Comment	In the brain, prolactin receptors (Prl-Rs), which belong to the class I cytokine receptor superfamily, have been detected in the cortex, hypothalamus and hippocampus, in both astrocytes and glial cells.
Formal Description Interaction-ID: 62660	gene/protein PRLR is localized in tissue/cell line hypothalamus
Drugbank entries	Show/Hide entries for PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR
Drugbank DB01185	Fluoxymesterone antagonist PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR

Comment	In the brain, prolactin receptors (Prl-Rs), which belong to the class I cytokine receptor superfamily, have been detected in the cortex, hypothalamus and hippocampus, in both astrocytes and glial cells.
Formal Description Interaction-ID: 62661	gene/protein PRLR is localized in tissue/cell line hippocampus
Drugbank entries	Show/Hide entries for PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR
Drugbank DB01185	Fluoxymesterone antagonist PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR

Comment	In the brain, prolactin receptors (Prl-Rs), which belong to the class I cytokine receptor superfamily, have been detected in the cortex, hypothalamus and hippocampus, in both astrocytes and glial cells.
Formal Description Interaction-ID: 62662	gene/protein PRLR is localized in tissue/cell line astrocyte
Drugbank entries	Show/Hide entries for PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR
Drugbank DB01185	Fluoxymesterone antagonist PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR

Comment	In the brain, prolactin receptors (Prl-Rs), which belong to the class I cytokine receptor superfamily, have been detected in the cortex, hypothalamus and hippocampus, in both astrocytes and glial cells.
Formal Description Interaction-ID: 62663	gene/protein PRLR is localized in tissue/cell line glial cell
Drugbank entries	Show/Hide entries for PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR
Drugbank DB01185	Fluoxymesterone antagonist PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR

Comment	PRL gene is down-regulated at early stages of amyloidogenesis, in an APPswe/PS1dE9 double transgenic murine model of AD. We observed a significant down-regulation of the Prl-Rs and PRL genes in the hippocampus of 3 month-old APPswe/PS1dE9 mice, when compared to a wild-type control group. The results indicate early perturbations in this particular biological route, at early stages of the neurodegenerative process, when both cognitive impairments and Abeta deposits have yet to develop.
Formal Description Interaction-ID: 62667	phenotype amyloidosis decreases_expression of gene/protein PRL in an APPswe/PS1dE9 double transgenic murine model of AD; at early stages of amyloidogenesis

Comment	A significant down-regulation of the Prl-Rs and PRL genes in the hippocampus of 3 month-old APPswe/PS1dE9 mice was observed, when compared to a wild-type control group. The results indicate early perturbations in this particular biological route, at early stages of the neurodegenerative process, when both cognitive impairments and Abeta deposits have yet to develop.
Formal Description Interaction-ID: 62677	organism model APPswe/PS1dE9 mouse decreases_expression of gene/protein PRLR compared to a wild-type control group
Drugbank entries	Show/Hide entries for PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR
Drugbank DB01185	Fluoxymesterone antagonist PRLR
Drugbank DB00052	Somatropin recombinant not specified PRLR

Comment	A significant down-regulation of the Prl-Rs (prolactin receptors) and PRL genes in the hippocampus of 3 month-old APPswe/PS1dE9 mice was observed, when compared to a wild-type control group. The results indicate early perturbations in this particular biological route, at early stages of the neurodegenerative process, when both cognitive impairments and Abeta deposits have yet to develop.
Formal Description Interaction-ID: 62678	organism model APPswe/PS1dE9 mouse decreases_expression of gene/protein PRL compared to a wild-type control group

Comment	The roles of AMPK in the pathogenesis of AD include Abeta generation and Tau phosphorylation at Thr-231 and Ser-396/404, and an inhibition of mTOR signalling pathway, thus facilitating autophagy and promoting lysosomal degradation of Abeta.
Formal Description Interaction-ID: 62679	complex/PPI AMPK decreases_quantity of gene/protein Amyloid beta peptide

Comment	The roles of AMPK in the pathogenesis of AD include Abeta generation and Tau phosphorylation at Thr-231 and Ser-396/404, and an inhibition of mTOR signalling pathway, thus facilitating autophagy and promoting lysosomal degradation of Abeta.
Formal Description Interaction-ID: 62680	complex/PPI AMPK increases_phosphorylation of gene/protein MAPT at Thr-231 and Ser-396/404.

Comment	The roles of AMPK in the pathogenesis of AD include Abeta generation and Tau phosphorylation at Thr-231 and Ser-396/404, and an inhibition of mTOR signalling pathway, thus facilitating autophagy and promoting lysosomal degradation of Abeta.
Formal Description Interaction-ID: 62681	complex/PPI AMPK decreases_activity of process TOR signaling at Thr-231 and Ser-396/404, thus facilitating autophagy and promoting lysosomal degradation of Abeta.

Comment	Chronic inflammation is known to cause Lep resistance that, as previously discussed, is a status related to T2DM and AD.
Formal Description Interaction-ID: 62925	process inflammatory response increases_activity of phenotype leptin resistance in hypothalamus

Comment	It has been shown that hypercaloric diets (HCD) used in a majority of diet-induced obesity studies, typically induce glucose metabolism abnormalities and insulin resistance (including diabetes mellitus) and persistent hyperleptinaemia. In addition, the consumption of Western diets, rich in sugar and saturated fat, stimulates an inflammatory response in the hypothalamus, a contributing factor to the development of central Lep resistance and obesity .
Formal Description Interaction-ID: 62929	environment hypercaloric diet increases_activity of phenotype insulin resistance

Comment	It has been shown that hypercaloric diets (HCD) used in a majority of diet-induced obesity studies, typically induce glucose metabolism abnormalities and insulin resistance (including diabetes mellitus) and persistent hyperleptinaemia. In addition, the consumption of Western diets, rich in sugar and saturated fat, stimulates an inflammatory response in the hypothalamus, a contributing factor to the development of central Lep resistance and obesity .
Formal Description Interaction-ID: 62931	environment hypercaloric diet increases_activity of phenotype increased circulating leptin level

Comment	It has been shown that hypercaloric diets (HCD) used in a majority of diet-induced obesity studies, typically induce glucose metabolism abnormalities and insulin resistance (including diabetes mellitus) and persistent hyperleptinaemia. In addition, the consumption of Western diets, rich in sugar and saturated fat, stimulates an inflammatory response in the hypothalamus, a contributing factor to the development of central Lep resistance and obesity .
Formal Description Interaction-ID: 62933	environment hypercaloric diet increases_activity of phenotype abnormal glucose metabolic process

Comment	It has been shown that hypercaloric diets (HCD) used in a majority of diet-induced obesity studies, typically induce glucose metabolism abnormalities and insulin resistance (including diabetes mellitus) and persistent hyperleptinaemia. In addition, the consumption of Western diets, rich in sugar and saturated fat, stimulates an inflammatory response in the hypothalamus, a contributing factor to the development of central Lep resistance and obesity .
Formal Description Interaction-ID: 62936	environment hypercaloric diet increases_activity of process inflammatory response in hypothalamus; hypercaloric diet = e.g. the consumption of Western diets, rich in sugar and saturated fat.

Comment	It has been shown that hypercaloric diets (HCD) used in a majority of diet-induced obesity studies, typically induce glucose metabolism abnormalities and insulin resistance (including diabetes mellitus) and persistent hyperleptinaemia. In addition, the consumption of Western diets, rich in sugar and saturated fat, stimulates an inflammatory response in the hypothalamus, a contributing factor to the development of central Lep resistance and obesity .
Formal Description Interaction-ID: 62941	process inflammatory response increases_activity of disease Obesity hypercaloric diet = e.g. the consumption of Western diets, rich in sugar and saturated fat.