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PMID	18793162 ( )
Title	NOX family NADPH oxidases in liver and in pancreatic islets: a role in the metabolic syndrome and diabetes?
Abstract	The incidence of obesity and non-esterified ('free') fatty acid-associated metabolic disorders such as the metabolic syndrome and diabetes is increasing dramatically in most countries. Although the pathogenesis of these metabolic disorders is complex, there is emerging evidence that ROS (reactive oxygen species) are critically involved in the aberrant signalling and tissue damage observed in this context. Indeed, it is now widely accepted that ROS not only play an important role in physiology, but also contribute to cell and tissue dysfunction. Inappropriate ROS generation may contribute to tissue dysfunction in two ways: (i) dysregulation of redox-sensitive signalling pathways, and (ii) oxidative damage to biological structures (DNA, proteins, lipids, etc.). An important source of ROS is the NOX family of NADPH oxidases. Several NOX isoforms are expressed in the liver and pancreatic beta-cells. There is now evidence that inappropriate activation of NOX enzymes may damage the liver and pancreatic beta-cells. In the context of the metabolic syndrome, the emerging epidemic of non-alcoholic steatohepatitis is thought to be NOX/ROS-dependent and of particular medical relevance. NOX/ROS-dependent beta-cell damage is thought to be involved in glucolipotoxicity and thereby leads to progression from the metabolic syndrome to Type 2 diabetes. Thus understanding the role of NOX enzymes in liver and beta-cell damage should lead to an increased understanding of pathomechanisms in the metabolic syndrome and diabetes and may identify useful targets for novel therapeutic strategies.

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Targets by SciMiner Summary

HUGO ID	Symbol	Target Name	#Occur	ActualStr
6081	INS	insulin	33	insulin \|
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	23	Nox2 \| NOX2 \|
7889	NOX1	NADPH oxidase 1	16	NOX-derived \| NOX-mediated \| NOX1 \| NOX-dependent \| NOXs \| NOX-knockout \|
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	14	nadph oxidase \| NOX5 \|
7891	NOX4	NADPH oxidase 4	14	NOX4 \|
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	10	Akt \| PKB \| protein kinase b \|
6125	IRS1	insulin receptor substrate 1	7	IRS1 \| insulin receptor substrate 1 \|
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	7	p47 \|
6204	JUN	jun oncogene	6	AP-1 \| c jun \| c-Jun \|
6881	MAPK8	mitogen-activated protein kinase 8	6	c jun n terminal kinase 1 \| JNKs \| JNK \| JNK1 \| JNK1-dependent \|
7661	NCF2	neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)	5	p67 \|
11766	TGFB1	transforming growth factor, beta 1	5	transforming growth factor beta \| TGF-beta \|
2577	CYBA	cytochrome b-245, alpha polypeptide	5	p22 \|
6871	MAPK1	mitogen-activated protein kinase 1	4	p40 \| p38 \| MAPK \|
13633	ADIPOQ	adiponectin, C1Q and collagen domain containing	4	adiponectin \|
3796	FOS	v-fos FBJ murine osteosarcoma viral oncogene homolog	4	ap 1 \| activator protein 1 \|
11892	TNF	tumor necrosis factor (TNF superfamily, member 2)	4	TNFalpha \|
333	AGT	angiotensinogen (serpin peptidase inhibitor, clade A, member 8)	4	angiotensin ii \|
8799	PDGFA	platelet-derived growth factor alpha polypeptide	4	PDGF-induced \| PDGF-stimulated \|
9642	PTPN1	protein tyrosine phosphatase, non-receptor type 1	4	PTP1B \| protein tyrosine phosphatase 1b \|
11916	TNFRSF1A	tumor necrosis factor receptor superfamily, member 1A	3	TNFR1 \|
13273	DUOX2	dual oxidase 2	3	DUOX2 \|
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	3	PI3K \|
7794	NFKB1	nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105)	3	NF-kappaB \|
7890	NOX3	NADPH oxidase 3	3	NOX3 \|
3062	DUOX1	dual oxidase 1	2	DUOX1 \| dual oxidase 1 \|
12744	MLXIPL	MLX interacting protein-like	2	ChREBP \| carbohydrate responsive element binding protein \|
8800	PDGFB	platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog)	2	platelet derived growth factor \|
11920	FAS	Fas (TNF receptor superfamily, member 6)	2	CD95 \|
10668	NOXA1	NADPH oxidase activator 1	2	NOXA1 \|
9393	PRKCA	protein kinase C, alpha	2	protein kinase c \|
1833	CEBPA	CCAAT/enhancer binding protein (C/EBP), alpha	2	ccaat/enhancer binding protein \|
12680	VEGFA	vascular endothelial growth factor A	2	VEGF \| vascular endothelial growth factor \|
2197	COL1A1	collagen, type I, alpha 1	2	collagen \|
5238	HSPA5	heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa)	2	GRP78 \| BiP \|
6206	JUND	jun D proto-oncogene	2	JunD \|
13164	CNBP	CCHC-type zinc finger, nucleic acid binding protein	1	sterol regulatory element binding protein \|
19404	NOXO1	NADPH oxidase organizer 1	1	NOXO1 \|
9802	RAC2	ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2)	1	Rac2 \|
11009	SLC2A4	solute carrier family 2 (facilitated glucose transporter), member 4	1	GLUT4 \|
12805	XDH	xanthine dehydrogenase	1	xanthine oxidase \|
4010	FUS	fusion (involved in t(12;16) in malignant liposarcoma)	1	CHOP \|
6621	LIPE	lipase, hormone-sensitive	1	hormone sensitive lipase \|
9801	RAC1	ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1)	1	Rac1 \|
19986	CYCS	cytochrome c, somatic	1	cytochrome c \|
2726	DDIT3	DNA-damage-inducible transcript 3	1	ccaat/enhancer binding protein homologous protein \|
2615	CYP2B6	cytochrome P450, family 2, subfamily B, polypeptide 6	1	P450 \|
3449	ERN1	endoplasmic reticulum to nucleus signaling 1	1	IRE-1 \|
2631	CYP2E1	cytochrome P450, family 2, subfamily E, polypeptide 1	1	cytochrome p450 2e1 \|
7218	MPO	myeloperoxidase	1	myeloperoxidase \|
6886	MAPK9	mitogen-activated protein kinase 9	1	SAPKs \|
11936	FASLG	Fas ligand (TNF superfamily, member 6)	1	CD95L \|

Targets by SciMiner Full list

HUGO ID	Symbol	Name	ActualStr	Score	FlankingText
11892	TNF	tumor necrosis factor (TNF superfamily, member 2)	TNFalpha	0.3	transforming growth factor beta TNFalpha tumour necrosis factor alpha TNFR1 TNFalpha receptor 1 UPR unfolded protein response VLDL very-low-density lipoprotein
7794	NFKB1	nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105)	NF-kappaB	0.6	disease NASH non-alcoholic steatohepatitis NEFA non-esterified ('free') 'free' fatty acid NF-kappaB nuclear factor kappaB NOX NADPH oxidase PDGF platelet-derived growth factor
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	II type 1 receptor and increases O 2 production and p47 and p22 expression in a rat insulin-producing cell line and
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	Furthermore an increased expression of NOX2 occurs in islets and may exacerbate disease aggravation over time
7889	NOX1	NADPH oxidase 1	NOX-dependent	1.4	excessive increase in intracellular Ca via PKC activation may enhance NOX-dependent generation of ROS and thus induce oxidative stress and/or and
7889	NOX1	NADPH oxidase 1	NOX-knockout	1.4	no deficiency in insulin secretion has been reported in various NOX-knockout mice
7661	NCF2	neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)	p67	0.3	and protein for NADPH oxidase subunits NOXA1 p22 p47 and p67 have been detected in human and rat PSCs (pancreatic pancreatic
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	and NOX4 and protein for NADPH oxidase subunits NOXA1 p22 p47 and p67 have been detected in human and rat PSCs
2577	CYBA	cytochrome b-245, alpha polypeptide	p22	0.3	NOX2 and NOX4 and protein for NADPH oxidase subunits NOXA1 p22 p47 and p67 have been detected in human and rat
10668	NOXA1	NADPH oxidase activator 1	NOXA1	1.2	NOX1 NOX2 and NOX4 and protein for NADPH oxidase subunits NOXA1 p22 p47 and p67 have been detected in human and
7661	NCF2	neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)	p67	0.3	gp91 and p22 and its related subunits (p47 p47 and p67 followed by NOX1 NOX4 NOXO1 and NOXA1 have all been
7889	NOX1	NADPH oxidase 1	NOX1	1.4	and its related subunits (p47 p47 and p67 followed by NOX1 NOX4 NOXO1 and NOXA1 have all been shown to be
5238	HSPA5	heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa)	GRP78	0.8	[C/EBP C EBP (CCAAT/enhancer-binding CCAAT enhancer-binding protein -homologous protein and GRP78 (glucose-regulated glucose-regulated protein 78 kDa)/BiP kDa BiP (immunoglobulin immunoglobulin heavy-chain-binding
5238	HSPA5	heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa)	BiP	0.5	-homologous protein and GRP78 (glucose-regulated glucose-regulated protein 78 kDa)/BiP kDa BiP (immunoglobulin immunoglobulin heavy-chain-binding protein chaperone via the activation of IRE-1
3449	ERN1	endoplasmic reticulum to nucleus signaling 1	IRE-1	0.9	BiP (immunoglobulin immunoglobulin heavy-chain-binding protein chaperone via the activation of IRE-1 (insulin-response insulin-response element 1 all hallmarks of the unfolded protein
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	Then the phagocyte-like NADPH oxidase NOX2 (gp91 gp91 and p22 and its related subunits (p47 p47
2577	CYBA	cytochrome b-245, alpha polypeptide	p22	0.3	Then the phagocyte-like NADPH oxidase NOX2 (gp91 gp91 and p22 and its related subunits (p47 p47 and p67 followed by
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	NOX2 (gp91 gp91 and p22 and its related subunits (p47 p47 and p67 followed by NOX1 NOX4 NOXO1 and NOXA1 have
11916	TNFRSF1A	tumor necrosis factor receptor superfamily, member 1A	TNFR1	0.3	TGF-beta transforming growth factor beta TNFalpha tumour necrosis factor alpha TNFR1 TNFalpha receptor 1 UPR unfolded protein response VLDL very-low-density lipoprotein
11892	TNF	tumor necrosis factor (TNF superfamily, member 2)	TNFalpha	0.3	1B ROS reactive oxygen species TGF-beta transforming growth factor beta TNFalpha tumour necrosis factor alpha TNFR1 TNFalpha receptor 1 UPR unfolded
11766	TGFB1	transforming growth factor, beta 1	TGF-beta	1.5	cell PTP1B protein tyrosine phosphatase 1B ROS reactive oxygen species TGF-beta transforming growth factor beta TNFalpha tumour necrosis factor alpha TNFR1
9642	PTPN1	protein tyrosine phosphatase, non-receptor type 1	PTP1B	2.5	kinase B PKC protein kinase C PSC pancreatic stellate cell PTP1B protein tyrosine phosphatase 1B ROS reactive oxygen species TGF-beta transforming
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	0.6	nuclear factor kappaB NOX NADPH oxidase PDGF platelet-derived growth factor PI3K phosphoinositide 3-kinase PKB protein kinase B PKC protein kinase C
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	1.8	NOX NADPH oxidase PDGF platelet-derived growth factor PI3K phosphoinositide 3-kinase PKB protein kinase B PKC protein kinase C PSC pancreatic stellate
8799	PDGFA	platelet-derived growth factor alpha polypeptide	PDGF	1.2	'free' fatty acid NF-kappaB nuclear factor kappaB NOX NADPH oxidase PDGF platelet-derived growth factor PI3K phosphoinositide 3-kinase PKB protein kinase B
6204	JUN	jun oncogene	c-Jun	1.8	HSC hepatic stellate cell IRS1 insulin receptor substrate 1 JNK c-Jun N-terminal kinase NAFLD non-alcoholic fatty liver disease NASH non-alcoholic steatohepatitis
7891	NOX4	NADPH oxidase 4	NOX4	1.4	Recently mRNA for NADPH oxidase components NOX1 NOX2 and NOX4 and protein for NADPH oxidase subunits NOXA1 p22 p47 and
7891	NOX4	NADPH oxidase 4	NOX4	1.4	Recently mRNA for NADPH oxidase components NOX1 NOX2 and NOX4 and protein for NADPH oxidase subunits NOXA1 p22
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	Recently mRNA for NADPH oxidase components NOX1 NOX2 and NOX4 and protein for NADPH oxidase subunits NOXA1 p22
7889	NOX1	NADPH oxidase 1	NOX1	1.4	Recently mRNA for NADPH oxidase components NOX1 NOX2 and NOX4 and protein for NADPH oxidase subunits NOXA1
10668	NOXA1	NADPH oxidase activator 1	NOXA1	1.2	(p47 p47 and p67 followed by NOX1 NOX4 NOXO1 and NOXA1 have all been shown to be expressed in pancreatic islets
19404	NOXO1	NADPH oxidase organizer 1	NOXO1	0.9	related subunits (p47 p47 and p67 followed by NOX1 NOX4 NOXO1 and NOXA1 have all been shown to be expressed in
7891	NOX4	NADPH oxidase 4	NOX4	1.4	its related subunits (p47 p47 and p67 followed by NOX1 NOX4 NOXO1 and NOXA1 have all been shown to be expressed
7889	NOX1	NADPH oxidase 1	NOX1	1.4	the expression of which increases during activation of HSCs and NOX1 which is involved in angiotensin II signalling 50 are the
7889	NOX1	NADPH oxidase 1	NOXs	1.4	in angiotensin II signalling 50 are the most promising fibrogenic NOXs
7889	NOX1	NADPH oxidase 1	NOX-mediated	1.4	a high-fat diet in fa / fa obese rats increases NOX-mediated ROS production
2615	CYP2B6	cytochrome P450, family 2, subfamily B, polypeptide 6	P450	1.2	in the same study hyperlipidaemia decreased xanthine oxidase and cytochrome P450 2E1 activity excluding a role of these other sources of
13633	ADIPOQ	adiponectin, C1Q and collagen domain containing	adiponectin	1.5	Plasma levels of adiponectin an adipocyte-derived antidiabetic anti-atherogenic adipocytokine are inversely correlated with insulin
13633	ADIPOQ	adiponectin, C1Q and collagen domain containing	adiponectin	1.5	High-molecular-mass adiponectin inhibited PDGF-induced proliferation of HSCs via suppression of ROS production
8799	PDGFA	platelet-derived growth factor alpha polypeptide	PDGF-induced	1.2	High-molecular-mass adiponectin inhibited PDGF-induced proliferation of HSCs via suppression of ROS production and subsequent
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	1.8	suppression of ROS production and subsequent inhibition of the Akt/PKB Akt PKB pathway
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	1.8	of ROS production and subsequent inhibition of the Akt/PKB Akt PKB pathway
8799	PDGFA	platelet-derived growth factor alpha polypeptide	PDGF-stimulated	1.2	ROS production by PDGF-stimulated HSCs was inhibited by DPI implicating NADPH oxidase as the
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	Importantly activity and expression of the phagocyte NADPH oxidase NOX2 are increased in subjects with the metabolic syndrome 53 suggesting
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	with the metabolic syndrome 53 suggesting a possible role for NOX2 in hepatic inflammation
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	Nevertheless the involvement of NOX2 may be more discrete as Nox2 mice fed a steatohepatitis-inducing
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	Nox2	0.3	Nevertheless the involvement of NOX2 may be more discrete as Nox2 mice fed a steatohepatitis-inducing methionine- and choline-deficient diet are not
11916	TNFRSF1A	tumor necrosis factor receptor superfamily, member 1A	TNFR1	0.3	progressive NASH in which disease activity correlates with CD95 and TNFR1 TNFalpha (tumour tumour necrosis factor alpha receptor 1 -dependent hepatocyte
11892	TNF	tumor necrosis factor (TNF superfamily, member 2)	TNFalpha	0.3	NASH in which disease activity correlates with CD95 and TNFR1 TNFalpha (tumour tumour necrosis factor alpha receptor 1 -dependent hepatocyte apoptosis
11920	FAS	Fas (TNF receptor superfamily, member 6)	CD95	0.1	NAFLD develop progressive NASH in which disease activity correlates with CD95 and TNFR1 TNFalpha (tumour tumour necrosis factor alpha receptor 1
11916	TNFRSF1A	tumor necrosis factor receptor superfamily, member 1A	TNFR1	0.3	CD95 and TNFR1 also increase in experimental models of NASH and CD95L and
11892	TNF	tumor necrosis factor (TNF superfamily, member 2)	TNFalpha	0.3	also increase in experimental models of NASH and CD95L and TNFalpha promote hepatocyte apoptosis and inflammation in these fatty liver models
11920	FAS	Fas (TNF receptor superfamily, member 6)	CD95	0.1	CD95 and TNFR1 also increase in experimental models of NASH and
11936	FASLG	Fas ligand (TNF superfamily, member 6)	CD95L	0.1	and TNFR1 also increase in experimental models of NASH and CD95L and TNFalpha promote hepatocyte apoptosis and inflammation in these fatty
7889	NOX1	NADPH oxidase 1	NOX1	1.4	CD95L induces oxidative stress in rat hepatocytes by activation of NOX1 or NOX2 via signalling through sphingomyelinase ceramide and PKC_amp_#x03B6 34
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	oxidative stress in rat hepatocytes by activation of NOX1 or NOX2 via signalling through sphingomyelinase ceramide and PKC_amp_#x03B6 34
12680	VEGFA	vascular endothelial growth factor A	VEGF	2.5	For the vascular part VEGF (vascular vascular endothelial growth factor -resistant apoptosis of sinusoidal endothelial
7889	NOX1	NADPH oxidase 1	NOX1	1.4	-resistant apoptosis of sinusoidal endothelial cells may be driven by NOX1 35
11766	TGFB1	transforming growth factor, beta 1	TGF-beta	1.5	cells and HSCs may cause inflammatory reactions such as macrophage TGF-beta secretion and p47 -dependent O 2 production 57
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	may cause inflammatory reactions such as macrophage TGF-beta secretion and p47 -dependent O 2 production 57
7891	NOX4	NADPH oxidase 4	NOX4	1.4	This specific effect is mediated by a robust up-regulation of NOX4 an activation of ER stress transient intracellular Ca oscillations induction
4010	FUS	fusion (involved in t(12;16) in malignant liposarcoma)	CHOP	0.3	transient intracellular Ca oscillations induction of the cell death effector CHOP [C/EBP C EBP (CCAAT/enhancer-binding CCAAT enhancer-binding protein -homologous protein and
6881	MAPK8	mitogen-activated protein kinase 8	JNK	2.7	reticulum HSC hepatic stellate cell IRS1 insulin receptor substrate 1 JNK c-Jun N-terminal kinase NAFLD non-alcoholic fatty liver disease NASH non-alcoholic
6125	IRS1	insulin receptor substrate 1	IRS1	2.2	DUOX dual oxidase ER endoplasmic reticulum HSC hepatic stellate cell IRS1 insulin receptor substrate 1 JNK c-Jun N-terminal kinase NAFLD non-alcoholic
6204	JUN	jun oncogene	AP-1	1.8	Abbreviations used AGE advanced glycation end-product AP-1 activator protein 1 DPI diphenyleneiodonium DUOX dual oxidase ER endoplasmic
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	mass reduced fibrosis decreased oxidative stress and decreased p22 and NOX2 expression in db / db obese mice 66 ( Figure
2577	CYBA	cytochrome b-245, alpha polypeptide	p22	0.3	increased beta-cell mass reduced fibrosis decreased oxidative stress and decreased p22 and NOX2 expression in db / db obese mice 66
2197	COL1A1	collagen, type I, alpha 1	collagen	0.3	the transdifferentiation of quiescent PSCs to activated PSCs which produce collagen and pro-inflammatory cytokines
6886	MAPK9	mitogen-activated protein kinase 9	SAPKs	1.2	NF-kappaB p38 MAPK (mitogen-activated mitogen-activated protein kinase and JNKs/SAPKs JNKs SAPKs (stress-activated stress-activated protein kinases along with the activation of the
6881	MAPK8	mitogen-activated protein kinase 8	JNKs	3.0	of NF-kappaB p38 MAPK (mitogen-activated mitogen-activated protein kinase and JNKs/SAPKs JNKs SAPKs (stress-activated stress-activated protein kinases along with the activation of
6871	MAPK1	mitogen-activated protein kinase 1	MAPK	2.2	In addition NEFAs induce activation of NF-kappaB p38 MAPK (mitogen-activated mitogen-activated protein kinase and JNKs/SAPKs JNKs SAPKs (stress-activated stress-activated
6871	MAPK1	mitogen-activated protein kinase 1	p38	2.2	In addition NEFAs induce activation of NF-kappaB p38 MAPK (mitogen-activated mitogen-activated protein kinase and JNKs/SAPKs JNKs SAPKs (stress-activated
7794	NFKB1	nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105)	NF-kappaB	0.6	In addition NEFAs induce activation of NF-kappaB p38 MAPK (mitogen-activated mitogen-activated protein kinase and JNKs/SAPKs JNKs SAPKs
7889	NOX1	NADPH oxidase 1	NOX-dependent	1.4	with high glucose stimulate the PKC pathway and subsequently stimulate NOX-dependent O 2 production 82
2577	CYBA	cytochrome b-245, alpha polypeptide	p22	0.3	1 receptor and increases O 2 production and p47 and p22 expression in a rat insulin-producing cell line and in isolated
7891	NOX4	NADPH oxidase 4	NOX4	1.4	NOX4 the expression of which increases during activation of HSCs and
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	which have a defect in activation of both NOX1 and NOX2 show attenuated liver injury and fibrosis after bile duct ligation
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	for p47 which have a defect in activation of both NOX1 and NOX2 show attenuated liver injury and fibrosis after bile
7889	NOX1	NADPH oxidase 1	NOX1	1.4	for p47 which have a defect in activation of both NOX1 and NOX2 show attenuated liver injury and fibrosis after bile
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	Moreover knockout mice for p47 which have a defect in activation of both NOX1 and
7891	NOX4	NADPH oxidase 4	NOX4	1.4	Furthermore TGF-beta (transforming transforming growth factor beta induces NOX4 expression upon the transdifferentiation of activated HSCs to myofibroblastoid cells
11766	TGFB1	transforming growth factor, beta 1	TGF-beta	1.5	Furthermore TGF-beta (transforming transforming growth factor beta induces NOX4 expression upon the
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	1.8	IRS1 and PI3K (phosphoinositide phosphoinositide 3-kinase activity causing reduced Akt/PKB Akt PKB (protein protein kinase B phosphorylation 2
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	1.8	and PI3K (phosphoinositide phosphoinositide 3-kinase activity causing reduced Akt/PKB Akt PKB (protein protein kinase B phosphorylation 2
6206	JUND	jun D proto-oncogene	JunD	1.8	Enhanced JunD/JNK1-dependent JunD JNK1-dependent liver injury correlated with the acute induction of NOX-dependent
6881	MAPK8	mitogen-activated protein kinase 8	JNK1-dependent	2.7	Enhanced JunD/JNK1-dependent JunD JNK1-dependent liver injury correlated with the acute induction of NOX-dependent O
7889	NOX1	NADPH oxidase 1	NOX-dependent	1.4	JunD JNK1-dependent liver injury correlated with the acute induction of NOX-dependent O 2 production following hepatic ischaemia/reperfusion ischaemia reperfusion
6206	JUND	jun D proto-oncogene	JunD	1.8	JunD and JNK1 may act in concert to control NOX2 and
6881	MAPK8	mitogen-activated protein kinase 8	JNK1	2.7	JunD and JNK1 may act in concert to control NOX2 and NOX4 gene
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	JunD and JNK1 may act in concert to control NOX2 and NOX4 gene expression in the liver which influences ROS-dependent
7891	NOX4	NADPH oxidase 4	NOX4	1.4	JunD and JNK1 may act in concert to control NOX2 and NOX4 gene expression in the liver which influences ROS-dependent
7891	NOX4	NADPH oxidase 4	NOX4	1.4	and JNK1 may act in concert to control NOX2 and NOX4 gene expression in the liver which influences ROS-dependent AP-1 (activator
6204	JUN	jun oncogene	AP-1	1.8	and NOX4 gene expression in the liver which influences ROS-dependent AP-1 (activator activator protein 1 response 42
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	1.8	Furthermore Akt activity and cell growth are stimulated significantly by treating hepatoma
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	0.6	Finally the PI3K inhibitor wortmannin inhibited Akt/PKB Akt PKB phosphorylation induced by ROS
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	Akt	1.8	Finally the PI3K inhibitor wortmannin inhibited Akt/PKB Akt PKB phosphorylation induced by ROS in these cells 43
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	PKB	1.8	Finally the PI3K inhibitor wortmannin inhibited Akt/PKB Akt PKB phosphorylation induced by ROS in these cells 43
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	Thus NADPH oxidases especially NOX2 and NOX4 seem to be involved in pathways leading to
7891	NOX4	NADPH oxidase 4	NOX4	1.4	Thus NADPH oxidases especially NOX2 and NOX4 seem to be involved in pathways leading to
7891	NOX4	NADPH oxidase 4	NOX4	1.4	Thus NADPH oxidases especially NOX2 and NOX4 seem to be involved in pathways leading to insulin resistance
2197	COL1A1	collagen, type I, alpha 1	collagen	0.3	High glucose stimulates HSCs to proliferate and to produce collagen through free radical production 45 46
8799	PDGFA	platelet-derived growth factor alpha polypeptide	PDGF	1.2	Interestingly DPI and apocynin specific NOX inhibitors inhibit the PDGF (platelet-derived platelet-derived growth factor -induced-proliferation of the human HSC line
11009	SLC2A4	solute carrier family 2 (facilitated glucose transporter), member 4	GLUT4	0.3	Insufficient translocation of GLUT4 glucose transporters to the plasma membrane of adipocytes and myocytes
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	of NADPH oxidases which includes the prototypical phagocyte NADPH oxidase NOX2
7889	NOX1	NADPH oxidase 1	NOX-derived	1.4	NOX-derived ROS play a physiological role in response to stimulation of
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	The prototypical NADPH oxidase NOX2 initially discovered in phagocytes is an electron transporter 15 that
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	which is composed of two subunits gp91 (also also called NOX2 and p22 is located in the plasma membrane and in
2577	CYBA	cytochrome b-245, alpha polypeptide	p22	0.3	composed of two subunits gp91 (also also called NOX2 and p22 is located in the plasma membrane and in specific granules
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	The other components of the NADPH complex (p47 p47 p67 p40 and small G-protein Rac1/2) Rac1 2 are cytosolic
7661	NCF2	neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)	p67	0.3	The other components of the NADPH complex (p47 p47 p67 p40 and small G-protein Rac1/2) Rac1 2 are cytosolic proteins
6871	MAPK1	mitogen-activated protein kinase 1	p40	2.2	The other components of the NADPH complex (p47 p47 p67 p40 and small G-protein Rac1/2) Rac1 2 are cytosolic proteins
9801	RAC1	ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1)	Rac1	0.8	NADPH complex (p47 p47 p67 p40 and small G-protein Rac1/2) Rac1 2 are cytosolic proteins
7660	NCF1	neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)	p47	0.6	various stimuli such as PMA triggers the phosphorylation of the p47 p67 and p40 cytosolic components and their translocation to the
7661	NCF2	neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)	p67	0.3	stimuli such as PMA triggers the phosphorylation of the p47 p67 and p40 cytosolic components and their translocation to the plasma
6871	MAPK1	mitogen-activated protein kinase 1	p40	2.2	as PMA triggers the phosphorylation of the p47 p67 and p40 cytosolic components and their translocation to the plasma membrane where
9802	RAC2	ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2)	Rac2	1.0	Concomitantly Rac2 dissociates from a RhoGDP dissociation inhibitor and interacts with flavocytochrome
7661	NCF2	neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)	p67	0.3	with flavocytochrome b 558 to form a binding partner for p67
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	on the basis of their homology with the gp91 /NOX2 NOX2 catalytic subunit of phagocyte NADPH oxidase
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	In mammals six NOX2 homologues NOX1 NOX3 NOX4 NOX5 DUOX (dual-oxidase) dual-oxidase 1 and
7889	NOX1	NADPH oxidase 1	NOX1	1.4	In mammals six NOX2 homologues NOX1 NOX3 NOX4 NOX5 DUOX (dual-oxidase) dual-oxidase 1 and DUOX2 have
7890	NOX3	NADPH oxidase 3	NOX3	0.9	In mammals six NOX2 homologues NOX1 NOX3 NOX4 NOX5 DUOX (dual-oxidase) dual-oxidase 1 and DUOX2 have been
7891	NOX4	NADPH oxidase 4	NOX4	1.4	In mammals six NOX2 homologues NOX1 NOX3 NOX4 NOX5 DUOX (dual-oxidase) dual-oxidase 1 and DUOX2 have been identified
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	NOX5	0.9	In mammals six NOX2 homologues NOX1 NOX3 NOX4 NOX5 DUOX (dual-oxidase) dual-oxidase 1 and DUOX2 have been identified 14
13273	DUOX2	dual oxidase 2	DUOX2	0.9	homologues NOX1 NOX3 NOX4 NOX5 DUOX (dual-oxidase) dual-oxidase 1 and DUOX2 have been identified 14 17 21 22
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	These homologues share many structural features with NOX2 and similarly are electron transporters that reduce O 2 to
7889	NOX1	NADPH oxidase 1	NOX1	1.4	However although the activation mechanisms of NOX1 and NOX3 includes the cytosolic subunit similar to that seen
7890	NOX3	NADPH oxidase 3	NOX3	0.9	However although the activation mechanisms of NOX1 and NOX3 includes the cytosolic subunit similar to that seen
7890	NOX3	NADPH oxidase 3	NOX3	0.9	However although the activation mechanisms of NOX1 and NOX3 includes the cytosolic subunit similar to that seen for NOX2
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	NOX3 includes the cytosolic subunit similar to that seen for NOX2 the situation is different for other NOX isoforms
7891	NOX4	NADPH oxidase 4	NOX4	1.4	NOX4 might be constitutively active with its activity depending on the
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	NOX5	0.9	NOX5 contains EF-hands and is activated by Ca 24 but probably
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	The presence of the phagocyte NADPH oxidase NOX2 has been suggested for a long time in the liver
7889	NOX1	NADPH oxidase 1	NOX1	1.4	NOX1 is expressed in hepatic sinusoidal endothelial cells 35 36 in
7891	NOX4	NADPH oxidase 4	NOX4	1.4	NOX4 is expressed in hepatocytes Kupffer cells and culture-activated (but but
3062	DUOX1	dual oxidase 1	DUOX1	1.9	Finally DUOX1 and DUOX2 are expressed in rat hepatocytes Kupffer cells and
13273	DUOX2	dual oxidase 2	DUOX2	0.9	Finally DUOX1 and DUOX2 are expressed in rat hepatocytes Kupffer cells and
13273	DUOX2	dual oxidase 2	DUOX2	0.9	Finally DUOX1 and DUOX2 are expressed in rat hepatocytes Kupffer cells and either activated
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	The role of NOX2 in Kupffer cells should be similar to the role of
2578	CYBB	cytochrome b-245, beta polypeptide (chronic granulomatous disease)	NOX2	0.3	in Kupffer cells should be similar to the role of NOX2 in other macrophages namely killing of micro-organisms participation in the
7794	NFKB1	nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105)	NF-kappaB	0.6	NF-kappaB (nuclear nuclear factor kappaB activation
12744	MLXIPL	MLX interacting protein-like	ChREBP	1.0	of SREBP-1c (sterol-regulatory-element-binding sterol-regulatory-element-binding protein 1c and the activation of ChREBP (carbohydrate-responsive-element-binding carbohydrate-responsive-element-binding protein thereby contributing to the development of hepatic
7891	NOX4	NADPH oxidase 4	NOX4	1.4	NOX4 has been shown to oxidize and inhibit the reduced cysteine
9642	PTPN1	protein tyrosine phosphatase, non-receptor type 1	PTP1B	2.5	shown to oxidize and inhibit the reduced cysteine residues containing PTP1B (protein protein tyrosine phosphatase 1B facilitating the tyrosine phosphorylation of
6125	IRS1	insulin receptor substrate 1	IRS1	2.2	(protein protein tyrosine phosphatase 1B facilitating the tyrosine phosphorylation of IRS1 (insulin insulin receptor substrate 1 and thus glucose uptake (reviewed
6881	MAPK8	mitogen-activated protein kinase 8	JNK	2.7	This involves increased JNK (c-Jun c-Jun N-terminal kinase 1-mediated-serine/threonine 1-mediated-serine threonine phosphorylation of IRS1
6204	JUN	jun oncogene	c-Jun	1.8	This involves increased JNK (c-Jun c-Jun N-terminal kinase 1-mediated-serine/threonine 1-mediated-serine threonine phosphorylation of IRS1 increased proteasomal
6125	IRS1	insulin receptor substrate 1	IRS1	2.2	JNK (c-Jun c-Jun N-terminal kinase 1-mediated-serine/threonine 1-mediated-serine threonine phosphorylation of IRS1 increased proteasomal degradation of IRS1 impaired insulin-stimulated redistribution of IRS1
6125	IRS1	insulin receptor substrate 1	IRS1	2.2	1-mediated-serine/threonine 1-mediated-serine threonine phosphorylation of IRS1 increased proteasomal degradation of IRS1 impaired insulin-stimulated redistribution of IRS1 and PI3K (phosphoinositide phosphoinositide 3-kinase
6125	IRS1	insulin receptor substrate 1	IRS1	2.2	IRS1 increased proteasomal degradation of IRS1 impaired insulin-stimulated redistribution of IRS1 and PI3K (phosphoinositide phosphoinositide 3-kinase activity causing reduced Akt/PKB Akt
8975	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	PI3K	0.6	proteasomal degradation of IRS1 impaired insulin-stimulated redistribution of IRS1 and PI3K (phosphoinositide phosphoinositide 3-kinase activity causing reduced Akt/PKB Akt PKB (protein
6204	JUN	jun oncogene	c jun	1.0	: age advanced glycation end product; ap 1 activator protein 1; dpi diphenyleneiodonium; duox dual oxidase; er endoplasmic reticulum; hsc hepatic stellate cell; irs1 insulin receptor substrate 1; jnk c jun n terminal kinase; nafld non alcoholic fatty liver disease; nash non alcoholic steatohepatitis; nefa non esterified 'free' fatty acid; nf kappab nuclear factor kappab; nox nadph oxidase; pdgf platele
3796	FOS	v-fos FBJ murine osteosarcoma viral oncogene homolog	activator protein 1	1.0	abbreviations used: age advanced glycation end product; ap 1 activator protein 1; dpi diphenyleneiodonium; duox dual oxidase; er endoplasmic reticulum; hsc hepatic stellate cell; irs1 insulin receptor substrate 1; jnk c jun n terminal kinase; nafld non alcoholic fatty liver disea
11766	TGFB1	transforming growth factor, beta 1	transforming growth factor beta	1.0	d growth factor; pi3k phosphoinositide 3 kinase; pkb protein kinase b; pkc protein kinase c; psc pancreatic stellate cell; ptp1b protein tyrosine phosphatase 1b; ros reactive oxygen species; tgf beta transforming growth factor beta; tnfalpha tumour necrosis factor alpha; tnfr1 tnfalpha receptor 1; upr unfolded protein response; vldl very low density lipoprotein.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	ptor substrate 1; jnk c jun n terminal kinase; nafld non alcoholic fatty liver disease; nash non alcoholic steatohepatitis; nefa non esterified 'free' fatty acid; nf kappab nuclear factor kappab; nox nadph oxidase; pdgf platelet derived growth factor; pi3k phosphoinositide 3 kinase; pkb protein kinase b; pkc protein kinase c; psc pancreatic stellate cell; ptp1b protein tyrosine phosphatase 1b; ros reactive oxy
9642	PTPN1	protein tyrosine phosphatase, non-receptor type 1	protein tyrosine phosphatase 1b	1.0	f kappab nuclear factor kappab; nox nadph oxidase; pdgf platelet derived growth factor; pi3k phosphoinositide 3 kinase; pkb protein kinase b; pkc protein kinase c; psc pancreatic stellate cell; ptp1b protein tyrosine phosphatase 1b; ros reactive oxygen species; tgf beta transforming growth factor beta; tnfalpha tumour necrosis factor alpha; tnfr1 tnfalpha receptor 1; upr unfolded protein response; vldl very low density lipoprot
9393	PRKCA	protein kinase C, alpha	protein kinase c	1.0	atohepatitis; nefa non esterified 'free' fatty acid; nf kappab nuclear factor kappab; nox nadph oxidase; pdgf platelet derived growth factor; pi3k phosphoinositide 3 kinase; pkb protein kinase b; pkc protein kinase c; psc pancreatic stellate cell; ptp1b protein tyrosine phosphatase 1b; ros reactive oxygen species; tgf beta transforming growth factor beta; tnfalpha tumour necrosis factor alpha; tnfr1 tnfalpha rece
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	protein kinase b	1.0	nash non alcoholic steatohepatitis; nefa non esterified 'free' fatty acid; nf kappab nuclear factor kappab; nox nadph oxidase; pdgf platelet derived growth factor; pi3k phosphoinositide 3 kinase; pkb protein kinase b; pkc protein kinase c; psc pancreatic stellate cell; ptp1b protein tyrosine phosphatase 1b; ros reactive oxygen species; tgf beta transforming growth factor beta; tnfalpha tumour necrosis factor alph
6125	IRS1	insulin receptor substrate 1	insulin receptor substrate 1	1.0	abbreviations used: age advanced glycation end product; ap 1 activator protein 1; dpi diphenyleneiodonium; duox dual oxidase; er endoplasmic reticulum; hsc hepatic stellate cell; irs1 insulin receptor substrate 1; jnk c jun n terminal kinase; nafld non alcoholic fatty liver disease; nash non alcoholic steatohepatitis; nefa non esterified 'free' fatty acid; nf kappab nuclear factor kappab; nox nadph oxidase; p
3796	FOS	v-fos FBJ murine osteosarcoma viral oncogene homolog	ap 1	1.0	abbreviations used: age advanced glycation end product; ap 1 activator protein 1; dpi diphenyleneiodonium; duox dual oxidase; er endoplasmic reticulum; hsc hepatic stellate cell; irs1 insulin receptor substrate 1; jnk c jun n terminal kinase; nafld non alcohol
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	key words: diabetes liver metabolic syndrome nadph oxidase nox family pancreatic islet.
8800	PDGFB	platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog)	platelet derived growth factor	1.0	k c jun n terminal kinase; nafld non alcoholic fatty liver disease; nash non alcoholic steatohepatitis; nefa non esterified 'free' fatty acid; nf kappab nuclear factor kappab; nox nadph oxidase; pdgf platelet derived growth factor; pi3k phosphoinositide 3 kinase; pkb protein kinase b; pkc protein kinase c; psc pancreatic stellate cell; ptp1b protein tyrosine phosphatase 1b; ros reactive oxygen species; tgf beta transforming gr
6081	INS	insulin	insulin	1.0	chronic or overwhelming er stress stimuli associated with the metabolic syndrome can disrupt protein folding in the er reduce insulin secretion invoke oxidative stress and activate cell death pathways [ 85 ].
333	AGT	angiotensinogen (serpin peptidase inhibitor, clade A, member 8)	angiotensin ii	1.0	inversely angiotensin ii type 1 receptor blockers such as candesartan and losartan improved glucose tolerance increased beta cell mass reduced fibrosis decreased oxidative stress and decreased p22 and nox2 expression in db /
333	AGT	angiotensinogen (serpin peptidase inhibitor, clade A, member 8)	angiotensin ii	1.0	chronic hyperglycaemia inhibits insulin secretion activates angiotensin ii type 1 receptor and increases o 2 production and p47 and p22 expression in a rat insulin producing cell line and in isolated human pancreatic islets [ 65 80 81 ] figure 3 .
6081	INS	insulin	insulin	1.0	chronic hyperglycaemia inhibits insulin secretion activates angiotensin ii type 1 receptor and increases o 2 production and p47 and p22 expression in a rat insulin producing cell line and in isolated human pancreatic islets [ 65 80 81 ] figure 3 .
6081	INS	insulin	insulin	1.0	indeed the severity of insulin resistance a key feature of the metabolic syndrome varies widely among obese people [ 1 ].
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	recently mrna for nadph oxidase components nox1 nox2 and nox4 and protein for nadph oxidase subunits noxa1 p22 p47 and p67 have been detected in human and rat pscs pancreatic stellate cells [ 68 69 ].
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	then the phagocyte like nadph oxidase nox2 gp91 and p22 and its related subunits p47 and p67 followed by nox1 nox4 noxo1 and noxa1 have all been shown to be expressed in pancreatic islets [ 63 67 ].
19986	CYCS	cytochrome c, somatic	cytochrome c	1.0	o 2 generation was first demonstrated by the cytochrome c reduction method in insulin producing cell lines [ 62 ].
6081	INS	insulin	insulin	1.0	o 2 generation was first demonstrated by the cytochrome c reduction method in insulin producing cell lines [ 62 ].
6081	INS	insulin	insulin	1.0	altogether these data place nox enzymes in the middle of nash pathogenesis thereby representing an important therapeutic target in insulin resistance and hepatic complications such as fibrosis inflammation and apoptosis.
1833	CEBPA	CCAAT/enhancer binding protein (C/EBP), alpha	ccaat/enhancer binding protein	1.0	this specific effect is mediated by a robust up regulation of nox4 an activation of er stress transient intracellular ca oscillations induction of the cell death effector chop [c/ebp ccaat/enhancer binding protein homologous protein] and grp78 glucose regulated protein 78 kda /bip immunoglobulin heavy chain binding protein chaperone via the activation of ire 1 insulin response element 1 all hallmarks of the un
2726	DDIT3	DNA-damage-inducible transcript 3	ccaat/enhancer binding protein homologous protein	1.0	this specific effect is mediated by a robust up regulation of nox4 an activation of er stress transient intracellular ca oscillations induction of the cell death effector chop [c/ebp ccaat/enhancer binding protein homologous protein] and grp78 glucose regulated protein 78 kda /bip immunoglobulin heavy chain binding protein chaperone via the activation of ire 1 insulin response element 1 all hallmarks of the unfolded protein resp
6204	JUN	jun oncogene	c jun	1.0	this involves increased jnk c jun n terminal kinase 1 mediated serine/threonine phosphorylation of irs1 increased proteasomal degradation of irs1 impaired insulin stimulated redistribution of irs1 and pi3k phosphoinositide 3 kinase a
391	AKT1	v-akt murine thymoma viral oncogene homolog 1	protein kinase b	1.0	rine/threonine phosphorylation of irs1 increased proteasomal degradation of irs1 impaired insulin stimulated redistribution of irs1 and pi3k phosphoinositide 3 kinase activity causing reduced akt/pkb protein kinase b phosphorylation [ 2 ].
6081	INS	insulin	insulin	1.0	this involves increased jnk c jun n terminal kinase 1 mediated serine/threonine phosphorylation of irs1 increased proteasomal degradation of irs1 impaired insulin stimulated redistribution of irs1 and pi3k phosphoinositide 3 kinase activity causing reduced akt/pkb protein kinase b phosphorylation [ 2 ].
6081	INS	insulin	insulin	1.0	chronic elevation of ros leads to impaired insulin signalling by way of a complex mechanism.
9642	PTPN1	protein tyrosine phosphatase, non-receptor type 1	protein tyrosine phosphatase 1b	1.0	nox4 has been shown to oxidize and inhibit the reduced cysteine residues containing ptp1b protein tyrosine phosphatase 1b facilitating the tyrosine phosphorylation of irs1 insulin receptor substrate 1 and thus glucose uptake reviewed in [ 13 ] .
6125	IRS1	insulin receptor substrate 1	insulin receptor substrate 1	1.0	nox4 has been shown to oxidize and inhibit the reduced cysteine residues containing ptp1b protein tyrosine phosphatase 1b facilitating the tyrosine phosphorylation of irs1 insulin receptor substrate 1 and thus glucose uptake reviewed in [ 13 ] .
6081	INS	insulin	insulin	1.0	insulin resistance
6081	INS	insulin	insulin	1.0	under physiological conditions the involvement of transient small bursts of ros in insulin action has been suggested for decades figure 2 .
6081	INS	insulin	insulin	1.0	although the hepatic accumulation of lipids is widely believed to result in insulin resistance it remains uncertain whether a causal relationship exists [ 6 40 ].
6081	INS	insulin	insulin	1.0	insufficient translocation of glut4 glucose transporters to the plasma membrane of adipocytes and myocytes limits glucose uptake and hence the cells require enhanced insulin secretion.
6081	INS	insulin	insulin	1.0	the presence of saturated fat in the liver in turn causes insulin resistance in this organ as well [ 3 4 ].
6081	INS	insulin	insulin	1.0	chronic elevation of both blood glucose and nefas [non esterified 'free' fatty acids] are thought to exert islet toxicity and hence reduce glucose stimulated insulin secretion trigger the reduction of pancreatic beta cell mass and finally lead to diabetes [ 7 ].
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	a major source of ros generation is the nox family of nadph oxidases which includes the prototypical phagocyte nadph oxidase nox2.
6081	INS	insulin	insulin	1.0	nox derived ros play a physiological role in response to stimulation of various growth factors cytokines and hormones including insulin [ 13 ] and have pathophysiological roles in endothelial dysfunction inflammation apoptosis fibrosis angiogenesis and important processes underlying diabetes and liver injury [ 14 ].
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	the prototypical nadph oxidase nox2 initially discovered in phagocytes is an electron transporter [ 15 ] that catalyses the nadph dependent reduction of oxygen to o 2 which is the precursor of the other ros figure 1 .
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	the complete assembly of nadph oxidase components is crucial for o 2 production [ 16 19 ].
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	a new family of oxidases the nox family has been defined on the basis of their homology with the gp91 /nox2 catalytic subunit of phagocyte nadph oxidase.
3062	DUOX1	dual oxidase 1	dual oxidase 1	1.0	in mammals six nox2 homologues [nox1 nox3 nox4 nox5 duox dual oxidase 1 and duox2] have been identified [ 14 17 21 22 ].
9393	PRKCA	protein kinase C, alpha	protein kinase c	1.0	nox5 contains ef hands and is activated by ca [ 24 ] but probably also by pkc protein kinase c [ 25 ].
7218	MPO	myeloperoxidase	myeloperoxidase	1.0	apocynin is an antioxidant [ 27 ] which in inflammatory cells is possibly converted through a myeloperoxidase dependent reaction into a lowaffinity nox inhibitor.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	we first describe the expression pattern of nadph oxidase and then recall the mechanisms that associate oxidative stress with high levels of circulating glucose and fatty acids in metabolic diseases in each of the considered organs.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	the presence of the phagocyte nadph oxidase nox2 has been suggested for a long time in the liver [ 28 ] especially in murine kupffer cells which are hepatic resident macrophages [ 29 ] in rat hepatocytes [ 30 31 ] in endothelial cells [ 32 ] a
6081	INS	insulin	insulin	1.0	insulin resistance steatosis and steatohepatitis
6081	INS	insulin	insulin	1.0	under conditions of insulin resistance insulin does not adequately inhibit hormone sensitive lipase and lipolysis in white adipose tissue is not suppressed.
6621	LIPE	lipase, hormone-sensitive	hormone sensitive lipase	1.0	under conditions of insulin resistance insulin does not adequately inhibit hormone sensitive lipase and lipolysis in white adipose tissue is not suppressed.
6081	INS	insulin	insulin	1.0	in addition the combination of elevated plasma glucose and insulin concentrations promotes de novo fatty acid synthesis lipogenesis through the up regulation of srebp 1c sterol regulatory element binding protein 1c and the activation of chrebp carbohydrate responsiv
13164	CNBP	CCHC-type zinc finger, nucleic acid binding protein	sterol regulatory element binding protein	1.0	in addition the combination of elevated plasma glucose and insulin concentrations promotes de novo fatty acid synthesis lipogenesis through the up regulation of srebp 1c sterol regulatory element binding protein 1c and the activation of chrebp carbohydrate responsive element binding protein thereby contributing to the development of hepatic steatosis.
12744	MLXIPL	MLX interacting protein-like	carbohydrate responsive element binding protein	1.0	ma glucose and insulin concentrations promotes de novo fatty acid synthesis lipogenesis through the up regulation of srebp 1c sterol regulatory element binding protein 1c and the activation of chrebp carbohydrate responsive element binding protein thereby contributing to the development of hepatic steatosis.
6081	INS	insulin	insulin	1.0	nevertheless both glucose and fatty acids may cause adaptive or toxic actions on the beta cell and non islet tissues and contribute to the development of insulin resistance in peripheral tissues depending on their concentrations and the time during which they are elevated.
6081	INS	insulin	insulin	1.0	after a meal in lean persons a mild increase in glucose causes a mild increase in the release of insulin by pancreatic beta cells.
6081	INS	insulin	insulin	1.0	increased glycolytic flux in beta cells results in a rapid increase in the production of atp in mitochondria facilitating exocytosis of insulin [ 2 ].
6081	INS	insulin	insulin	1.0	on adipocytes and peripheral tissues such as skeletal muscles and liver insulin activates specific signalling pathways that in turn cause efficient glucose uptake which limits the increase in glucose and insulin.
6081	INS	insulin	insulin	1.0	activates specific signalling pathways that in turn cause efficient glucose uptake which limits the increase in glucose and insulin.
6081	INS	insulin	insulin	1.0	in obese people however both fat engorged adipocytes and fat laden myocytes are resistant to the signalling effects of insulin a condition referred to as insulin resistance.
6081	INS	insulin	insulin	1.0	on the basis of studies using the non selective flavoprotein inhibitor dpi and the antioxidant/nox inhibitor apocynin [ 27 ] a role for nox enzymes in insulin secretion [ 67 70 72 ] has been suggested.
6081	INS	insulin	insulin	1.0	however so far no deficiency in insulin secretion has been reported in various nox knockout mice.
6081	INS	insulin	insulin	1.0	in early type 1 diabetes systemic markers of oxidative stress correlate with insulin requirements.
6081	INS	insulin	insulin	1.0	it has been suggested that this reflects oxidative stress in the pancreatic islets damaging insulin secreting beta cells [ 78 ].
6081	INS	insulin	insulin	1.0	furthermore an increased expression of nox2 occurs in islets and may exacerbate disease aggravation over time by damaging insulin producing cells [ 64 ].
6881	MAPK8	mitogen-activated protein kinase 8	c jun n terminal kinase 1	1.0	this involves increased jnk c jun n terminal kinase 1 mediated serine/threonine phosphorylation of irs1 increased proteasomal degradation of irs1 impaired insulin stimulated redistribution of irs1 and pi3k phosphoinositide 3 kinase activity causing redu
3796	FOS	v-fos FBJ murine osteosarcoma viral oncogene homolog	ap 1	1.0	jund and jnk1 may act in concert to control nox2 and nox4 gene expression in the liver which influences ros dependent ap 1 activator protein 1 response [ 42 ].
3796	FOS	v-fos FBJ murine osteosarcoma viral oncogene homolog	activator protein 1	1.0	jund and jnk1 may act in concert to control nox2 and nox4 gene expression in the liver which influences ros dependent ap 1 activator protein 1 response [ 42 ].
6081	INS	insulin	insulin	1.0	thus nadph oxidases especially nox2 and nox4 seem to be involved in pathways leading to insulin resistance and steatosis in the liver constituting the first line of the 'two risk factors' theory for nash pathogenesis: steatosis insulin resistance and inflammation/fibrosis.
6081	INS	insulin	insulin	1.0	resistance and steatosis in the liver constituting the first line of the 'two risk factors' theory for nash pathogenesis: steatosis insulin resistance and inflammation/fibrosis.
8800	PDGFB	platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog)	platelet derived growth factor	1.0	interestingly dpi and apocynin specific nox inhibitors inhibit the pdgf platelet derived growth factor induced proliferation of the human hsc line li 90 and murine primary cultured hscs [ 47 ].
11766	TGFB1	transforming growth factor, beta 1	transforming growth factor beta	1.0	furthermore tgf beta transforming growth factor beta induces nox4 expression upon the transdifferentiation of activated hscs to myofibroblastoid cells demonstrating the important role of nox in hsc activation and the onset of fibrosis [ 48 ].
333	AGT	angiotensinogen (serpin peptidase inhibitor, clade A, member 8)	angiotensin ii	1.0	a deficiency of angiotensin ii signalling may be responsible for this protection [ 49 ].
333	AGT	angiotensinogen (serpin peptidase inhibitor, clade A, member 8)	angiotensin ii	1.0	nox4 the expression of which increases during activation of hscs and nox1 which is involved in angiotensin ii signalling [ 50 ] are the most promising fibrogenic noxs.
6081	INS	insulin	insulin	1.0	increased plasma concentration of nefas and fibrosis are also associated with liver insulin resistant states.
2631	CYP2E1	cytochrome P450, family 2, subfamily E, polypeptide 1	cytochrome p450 2e1	1.0	interestingly in the same study hyperlipidaemia decreased xanthine oxidase and cytochrome p450 2e1 activity excluding a role of these other sources of ros [ 51 ].
12805	XDH	xanthine dehydrogenase	xanthine oxidase	1.0	interestingly in the same study hyperlipidaemia decreased xanthine oxidase and cytochrome p450 2e1 activity excluding a role of these other sources of ros [ 51 ].
6081	INS	insulin	insulin	1.0	plasma levels of adiponectin an adipocyte derived antidiabetic anti atherogenic adipocytokine are inversely correlated with insulin resistance fibrosis and diabetes in obese individuals.
13633	ADIPOQ	adiponectin, C1Q and collagen domain containing	adiponectin	1.0	plasma levels of adiponectin an adipocyte derived antidiabetic anti atherogenic adipocytokine are inversely correlated with insulin resistance fibrosis and diabetes in obese individuals.
13633	ADIPOQ	adiponectin, C1Q and collagen domain containing	adiponectin	1.0	high molecular mass adiponectin inhibited pdgf induced proliferation of hscs via suppression of ros production and subsequent inhibition of the akt/pkb pathway.
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	ros production by pdgf stimulated hscs was inhibited by dpi implicating nadph oxidase as the source [ 52 ].
14874	NOX5	NADPH oxidase, EF-hand calcium binding domain 5	nadph oxidase	1.0	importantly activity and expression of the phagocyte nadph oxidase nox2 are increased in subjects with the metabolic syndrome [ 53 ] suggesting a possible role for nox2 in hepatic inflammation.
12680	VEGFA	vascular endothelial growth factor A	vascular endothelial growth factor	1.0	for the vascular part vegf vascular endothelial growth factor resistant apoptosis of sinusoidal endothelial cells may be driven by nox1 [ 35 ].
6081	INS	insulin	insulin	1.0	ffector chop [c/ebp ccaat/enhancer binding protein homologous protein] and grp78 glucose regulated protein 78 kda /bip immunoglobulin heavy chain binding protein chaperone via the activation of ire 1 insulin response element 1 all hallmarks of the unfolded protein response linking upr mediated apoptosis to nox enzymes [ 60 61 ] figure 2 .
1833	CEBPA	CCAAT/enhancer binding protein (C/EBP), alpha	ccaat/enhancer binding protein	1.0	this specific effect is mediated by a robust up regulation of nox4 an activation of er stress transient intracellular ca oscillations induction of the cell death effector chop [c/ebp ccaat/enhancer binding protein homologous protein] and grp78 glucose regulated protein 78 kda /bip immunoglobulin heavy chain binding protein chaperone via the activation of ire 1 insulin response element 1 all hallmarks of the un