Table 2.

Nox Inhibitors and Antioxidants in Skin Fibrosis.

AGENT	ACTION	TARGETS	COMMENTS
Nox Inhibitors
Statins	Prevents Rac1 migration to the cell membrane	Nox1 and 2, CCL-2, collagen, skin inflammation, dermal thickening	Non-specific Nox inhibitor
p47phox modulators
AEBSF	Small molecule Nox inhibitor - inhibits p47phox subunit	General Nox enzyme inhibitor	Non-specific, general serine protease inhibitor
Apocynin	Small molecule Nox inhibitor - inhibits p47phox subunit	General Nox enzyme inhibitor	Non-specific inhibitor, antioxidative effects
Diphenyl iodonium (DPI)	Small molecule Nox inhibitor - inhibits p47phox subunit	General Nox enzyme inhibitor	Non-specific, general flavoprotein inhibitor, toxic
Gp91ds-tat	Peptide Nox inhibitor - binds p47phox and prevents interaction with other subunits	Nox1 and Nox2	May be limited to parenteral administration given its peptide origin
PR-39	Peptide Nox inhibitor - binds SH3 domain of p47phox limiting Nox activity	Nox1 and Nox2	Non-specific - may interact with any protein with SH3 domain, may be limited to parenteral administration given its peptide origin
S17834	Nox inhibitor - prevents the binding of p47phox to the membrane complex	Nox1 and Nox2	Further investigations needed
Competitive inhibitors of Nox
GKT137831	Small molecule Nox inhibitor - likely competitive substrate inhibitor since it structurally mimics NADPH	Nox1 and Nox4 selective	Currently under clinical investigation in phase I clinical trial
Nox inhibitors with unspecified mechanism
Fulvene-5	Small molecule Nox inhibitor	Nox2 and Nox4	Specificity and activity towards other Nox isoforms is unknown
M090	Small molecule Nox inhibitor	Nox1-selective
ML171	Small molecule Nox inhibitor	Nox1-selective	Potential antipsychotic effects due to phenothiazine structure
VAS2870	Small molecule Nox inhibitor - likely inhibits assembly of Nox once translocation to the membrane has occurred.	General Nox enzyme inhibitor	Investigations needed for off-target effects and toxicity
Antioxidants
Naturallv-ocurring antioxidants
Beta-carotene	Antioxidant	Reactive oxvgen species	Naturally present in many fruits, grains, oils, and vegetables
Caffeine	Antioxidant	Reactive oxvgen species	Caffeine in combination with EGCG reduced ROS in human skin fibroblasts
EGCG	Antioxidant - free radical scavenger, attenuates Nox expression	Signaling pathwavs, PDGF, TGF-beta, type I collagen, alpha- SMA, fibronectin, MMP-1, TIMP-1, CTGF, fibroblast proliferation and differentiation	Natural antioxidant in green tea
Resveratrol	Antioxidant - free radical scavenger	Reactive oxygen species	Natural antioxidant in red wine, skin of grapes, other fruits, and plants
Selenium	Antioxidant - free radical scavenger	Reactive oxygen species	Dietary selenium is derived from meat, mushroom, fish, eggs, cereals, and nuts
Vitamin C	Antioxidant - free radical scavenger	Reactive oxygen species	Clinical study concluded that oral vitamin C ingestion at a dose of 2g resulted in no benefit in endothelial function in 11 scleroderma patients (skin fibrosis not examined)
Vitamins E	Antioxidant - free radical scavenger	Reactive oxygen species	Clinical study concluded that 3-week oral vitamin E treatment at doses 500 to 1000 mg/day has limited benefit in scleroderma patients
Vitamin E and pentoxyphylline	Mechanism of action of pentoxyphylline not fully elucidated	Reactive oxygen species	Small clinical investigation involving 12 scleroderma patients exploring the combined treatment (800 UI of vitamin E and 800 mg of pentoxyphylline daily) revealed improvement in MRSS score (mean reduction from 25.7 to 18.7 at 16th week); patients reported no serious side effects
Synthetic antioxidants
Ebselen	Antioxidant	leukocyte infiltration and activation, collagen contraction, TGF-beta1 activation	Further investigations needed to examine potential as a novel therapeutic in skin fibrosis
Edaravone	Antioxidant - free radical scavenger	inflammatory cell migration to the skin, TGF-beta1 production	Further investigations needed to examine potential as a novel therapeutic in skin fibrosis