Thioredoxin interacting protein, a key molecular switch between oxidative stress and sterile inflammation in cellular response

Table 1 Summary of studies on modulation of thioredoxin interacting protein using natural antioxidants animal models

Ref.	Treatment	Animal model	Main findings
[1]	Taohong Siwu decoction 18, 9 and 4.5mg/kg	Rat with middle cerebral artery occlusion	Improved neubehavioral function and inflammation and inhibited pyroptosis following ischemic stroke
	Intragastric administration for 7 d
[2]	Z-Guggulsterone, 12.5, 25, 50 mg/kg, (ip)	Rat with middle cerebral artery occlusion	Z-Guggulsterone improved neurological deficit and, modulated redox imbalance and inflammation through inhibition of TXNIP/NLRP3 signaling
	Intraperitoneal administration for 6 d
[11]	Curcumin 50 mg/kg,	Rat with cerebral artery occlusion	Attenuated ischemic brain injury. Modulation of TXNIP/NLRP3 inflammasome activation by suppression of ER stress.
	One hour before surgery, (ip)
[70] [69]	Curcumin	HFD/ High sugar diet	Prevented fatty liver via inhibition of TXNIP
[66]	Qurecetin	diabetes	Prevented inflammation, liver TXNIP, lipid accumulation
[6]	Ketogenic diet	Mouse model of middle cerebral artery occlusion	Ketogenic diet improved ischemic tolerance, Attenuated ER stress and TXNIP/NLRP3 activation
	3 wk
[7]	Umbelliferone, 15and 30 mg /kg	Rat with middle cerebral artery occlusion	Protected against cerebral ischemia reperfusion injury by suppressing TXNIP/NLRP3 inflammasome activation
	Pretreatment for 7 d (ip)
[8]	Ruscogenin, 10 mg/kg One hour before surgery, (Intra gastic admin.	Mice with middle cerebral artery occlusion	Decreased brain infarction, edema, improved neurological outcome by suppressing a TXNIP/NLRP3 inflammasome activation and MAPK pathway
[9]	Resveratrol, 5 mg/Kg	WT mice with embolic middle cerebral artery occlusion	Protected from ischemic injury, improved neurological score suppressed TXNIP/NLRP3 inflammasome and apoptosis
	3 h post-embolic occlusion. (iv)
[21]	Salvianolic acid	HFD- Rats	Prevented HFD-induced NAFLD
[65]	Salidroside		Prevented HFD-induced NAFLD
[12]	Compound 10b, 3 mg/kg	Rat with middle cerebral artery occlusion	Attenuated cerebral ischemia by upregulating endogenous antioxidant system and down regulation of oxidative stress.
	At the onset of reperfusion

TXNIP: Thioredoxin interacting protein; NLRP3: NOD-like receptor pyrin domain containing 3; HFD: High fat diet.

Table 2 Summary of studies on modulation of thioredoxin interacting protein expression using drug repurposing in animal models

Ref.	Treatment		Animal model	Main findings
[84]	Verapamil (0.15 mg/kg), intra venous	1 h	Hyperglycemic mouse model middle cerebral artery occlusion	Reduced infarct area, hemorrhagic transformation and blood brain barrier damage. Improved stroke outcome and neuro inflammation in response to hyperglycemic stroke
[7]	Verapamil po	1 h	NMDA- optic neuropathy	Improved retinal neurodegeneration by altering antioxidant status and disrupting the Trx-ASK-1 inhibitory complex
[67]	Verapamil, 25 mg/kg/d, IP	1 wk	high-fat diet-induced obesity- 10 wk	Improved hepatic inflammation, metabolic homeostasis in NAFLD via TXNIP-NLRP3 inflammasome activation
[104]	Verapamil		High-fat diet-prediabetic neuropathy	improved prediabetic neuropathy, inflammation via inhibition of TXNIP and NLRP3-inflammasome activation
[10], [105]	Verapamil, 100 mg/kg	Po daily	STZ- and HFD-obesity model	Inhibit TXNIP expression and restore beta-cell function, improve glucose level in STZ- and HFD-obesity model
[100]	Metformin		STZ-diabetes mouse	Suppressed TXNIP/NLRP3 inflammasome activation, reduced cell apoptosis in adipose tissue
[99]	Metformin		ApoE-/- + STZ mice	Inhibited TXNIP/NLRP3 inflammasome activation, and suppressed diabetes-accelerated atherosclerosis in apoE-/- mice
[101]	Ezetimibe (250 µg, 500 µg, 1 mg)	1 hIntra-nasal	Rat model middle cerebral artery occlusion	Improved infarct volume, neurological outcome Increased activation of AMPK, modulated oxidative stress, microglial activation and TXNIP/NLRP3 activation
[103]	SRI-37330	Po daily	STZ-mouse model and obesity-induced (db/db) diabetes	Inhibited glucagon secretion and function, reduced hepatic glucose production, and reversed hepatic steatosis
[105]	W2476, 200 mg/kg	Po daily	STZ- and HFD-obesity model	Inhibit TXNIP expression and restore beta-cell function, improve glucose level in STZ- and HFD-obesity model
[34]	GW0742 (25 μg/kg; intranasal)	1 h/ 24 h	Rat pups with hypoxic ischemia	GW0742 significantly reduced the activation of TXNIP/NLRP3 inflammasome, pro-inflammatory microglia

TXNIP: Thioredoxin interacting protein; NLRP3: NOD-like receptor pyrin domain containing 3; HFD: High fat diet; NMDA: N-methyl D-aspartate.

Table 3 Summary of the in vivo studies

Ref.	Duration of Studies	Insult	TXNIP	NLRP3	CASP-1	IL-1β	TNF-a	NFKB	Casp-3	NY	Other markers
Mohamed et al[2], 2015	Rat retina, 10 wk	HFD	+	+	+	+	+	+	+	+	Acellular capillaries
Coucha et al[11], 2017	Mouse retina, 8 wk	HFD	+ mRNA								ER-stress, miR17-5p
Mohamed et al[41], 2020	Mouse retina, 8 wk	HFD	+	-	-	+					Leukostasis, acellular capillaries
Mohamed et al[58], 2018	Mouse liver, 8 wk	HFD	+	+	+	+	Trend	+			TLR2 signal +, fibrosis
Elshaer et al[40], 2017	Mouse sk. Muscle, 8 wk	HFD	+	-	+	+				+	Systemic IL-1b, vascular recovery
Coucha et al[33], 2019	Mouse-retina, 1-3 d, 14 d	I/R	+ protein + mRNA	+	+	+	+				Acellular capillary, visual acuity
El-Azab et al[19], 2014	Mouse-retina, 1-d	NMDA	+			+	+		+	+	Acellular capillary, neurodegeneration, ERG
Al-Gayyar et al[7], 2011	Rat-retina, 1-d	NMDA	+			+	+	+	+	+	Neurodegeneration
Ishrat et al[80],2015	Mouse; Brain	Embolicstroke	+	+	+	+	+		+	+	Neurological function, cerebral blood flow
Ismael et al[94], 2021	Mouse brain, 24 h	Stroke+ HG	+	=	+	+	+	+ trend			Hemorrhagic transformation
Wang et al[24], 2020	Rat brain, 7-d	Stroke	+	+	+	+		+			Pyroptosis, inflammation
Liu et al[97], 2020	Rat brain, 7 d	Stroke	+ mRNA + protein	+	-	+	+				Neurological deficit, inflamm
Gamdzyk et al[34], 2020	Rat pups brain, 24 h	Hyp-oxia	+	+	+	+					Microglial activation, TXNIP
Ding et al[21], 2016	Rat brain, 14 d	Thrombosis	+	+	+	+				+	ER- stress neural pyroptosis
Yin et al[29], 2021	Rat brain, 72 h	Stroke	+	+	+	+					Microglial activation, ROS
Tian et al[81], 2012	Rat brain, 24 h	Stroke	+								MAPK activation and Nrf2
Guo et al[3], 2018	Mice, 72 h	Stroke	+	+	+ active	+					Elevated ER stress, neurodegeneration
Hou et al[102], 2018	Rat brain, 24 h	Stroke	+	+		+					Nrf2 and NLRP3 through TXNIP
Cao et al[43], 2016	Mice brain, 24 h	Stroke	+	+		+					Neuro. deficit, BBB damage
Guo et al[3], 2016	Rat brain, 24 h	HG + stroke	+	+	+	+					Hemorrhagic transformation
Hua et al[83], 2015	Rat brain, 24 h	Stroke	+					+	+		Neurological deficit
Wang et al[98], 2015	Rat brain	Stroke	+	+	+	+					PPARγ, negative regulator of TXNIP
Li et al[20], 2015	Rat brain, 24 h	Stroke	+	+	+	+					ER stress mediates TXNIP activation

HFD: High fat diet; TXNIP: Thioredoxin interacting protein; NLRP3: NOD-like receptor pyrin domain containing 3; ROS: Reactive oxygen species; ER: Endoplasmic reticulum; BBB: Blood brain barrier.

Table 4 Summary of the in vitro Studies

Ref.	Cell type	Insult	TXNIP	NLRP3	CASP-1	IL-1β	TNF-a	NFKB	Casp-3	Other markers
Mohamed et al[2], 2015	EC	Palmitate	+	+	+	+			+	IL1-b in cell lysate and CM Adhesion Molecules
Mohamed et al[41], 2020	EC	TXNIP++		+	trend	+	+			Adhesion Molecules
Coucha et al[11], 2017	Muller	Palmitate	+ protein + mRNA	trend	trend	+				IL1-b in cell lysate
Coucha et al[33], 2019	Muller	Hypoxia	+ mRNA	trend	+	+				IL-1b in cell lysate
El-Azab et al[19], 2014		NMDA	+	+	+	+	+			IL1-b in CM
Gamdzyk et al[34], 2020	P12 cells	OGD	+			+	+			Cell death, miR-17-5p
Tian et al[81], 2012	Primary rat cortical neuron	OGD	+							Oxidative stress and activation of MAPK
Liu et al[97], 2020	Primary rat neurons	OGD	+	+	+	+				TXNIP NLRP3
Guo et al[3], 2018	SH-SY-5Y cells	OGD		+	+ activity	+				Activation of ER stress
Cao et al[43], 2016	bEnd.3	OGD	+	+	+					MAPK activation, EC-damage

TXNIP: Thioredoxin interacting protein; NLRP3: NOD-like receptor pyrin domain containing 3; ER: Endoplasmic reticulum; TNF-α: Tumor necrosis factor alpha; NMDA: N-methyl D-aspartate.