Table 3.

The effects of H₂ intervention on MS, FL, AS, and obesity.

Disease Type	Model System	Routes of H2 Delivery	H2 Concentration	Duration	Main Effects	Reference
MS	SHR-cp rats	drinking HRW	0.15–0.2 mM	16 weeks	plasma BUN, creatinine:↓, BAP: ↑ plasma TG, TC, FBG, 8-OHdG: NSC, glomerulosclerosis score: ↓ 24 h water intake and urine flow: ↑ urinary albumin to creatinine ratio: ↓	[53]
MS	SHR-cp rats	drinking HRW	0.15–0.2 mM	16 weeks	renal glyoxal, methylglyoxal, and 3-deoxyglucosone levels: ↓ ROS production in kidney: ↓	[55]
ALD	chronic-binge ethanol-fed mice model	drinking HRW (0.25 mM)	0.25–0.3 mM	13 weeks	EtOH-induced anorexia and liver enlargement: ↓ serum TG, TC, ALT, TNF-α, IL-6, oxidative stress: ↓, IL-10, IL-22: ↑ hepatic TG, TC, TNF-α, IL-6: ↓	[56]
NAFLD	STZ (25 mg/kg, single dose) + HFHSD (8 weeks)-induced rats model	intraperitoneal injection of HRS	>0.6 mM	8 weeks	serum ALT, TBIL, TC, TG, FBG, insulin: ↓ insulin sensitivity, glucose tolerance: ↑ hepatocyte apoptosis: ↓ Inflammation, oxidative stress: ↓	[57]
NAFLD	HFD-induced mice model	drinking HRW	0.8 mM	8 weeks	serum ALT, AST, TC, TG: ↓ hepatic expression of MEG3, Nrf2: ↑, miR-136: ↓	[58]
NAFLD	MCDHF diet-induced mice model	HRS (3.5 mM) spread in the liver after clipping hepatic portal vein with a microvascular clamp for ischemia	3.5 mM	1 time	serum ALT, AST: ↓ ischemia–reperfusion injury in fatty liver: ↓ hepatic expression of TNF-α, IL-6, TLR-4, Nlrp3: ↓	[59]
NAFLD	HFFD-induced rats model	hydrogen inhalation	4% or 67%	10 weeks	BW, BMI, abdominal fat index, liver index: ↓ glucose tolerance: ↓ serum TG, ALT, AST, LDH: ↓, TC: NSC hepatic fat: ↓	[60]
NASH and fibrosis	CDAA diet (20 weeks)-induced mice model	drinking HRW	3.5 mM	4, 8, or 20 weeks	serum AST, ALT, TBARS: ↓ hepatic fibrosis, macrophage recruitment, HSC activation, expression of inflammatory cytokines: ↓	[61]
NAFLD	HFD (16 weeks)-induced mice model and db/db mice (6 weeks)	oral intake of hydrogen nanocapsule-mixed HFD	>104 times higher than that of HRW	16 or 6 weeks	BW, WAT mass, liver weight, liver steatosis: ↓ plasma TC, FBG, insulin: ↓, glucose tolerance: ↑ food intake, plasma TG: NSC	[62]
NASH and HCC	MCD diet (8 weeks)-induced mice model and HFD (8 weeks) induced-STAM® mice model	drinking HRW	0.175–0.225 mM	8 weeks	plasma ALT, hepatic TC, plasma and hepatic oxidative stress, hepatocyte apoptosis, NAS: ↓ hepatic expression of free fatty acid uptake-related enzymes, inflammatory cytokines, PPARα: ↓ hepatocarcinogenesis: ↓	[63]
AS	apoE knockout mice model	drinking HRW	>0.6 mM	8 weeks	atherosclerotic lesion: ↓ oxidative stress level of aorta: ↓	[64]
AS	apoE knockout mice model	intraperitoneal injection of HRS	>0.6 mM	8 weeks	LOX-1 expression and NF-κB activation in thoracic aorta: ↓	[65]
AS	apoE knockout mice model	intraperitoneal injection of HRS	>0.6 mM	8 weeks	plasma TC, non-HDL-C, MDA, SAA: ↓, PON-1: ↑ plasma and hepatic apoB: ↓ aortic inflammation: ↓ RCT-related genes expression: ↑ oxidation of non-HDL: ↓, HDL quality: ↑	[66]
AS	Leprdb/db mice fed an atherogenic diet	intraperitoneal injection of HRS	>0.6 mM	28 weeks	atherosclerotic plaque stability: ↑ the formation and apoptosis of macrophage-derived foam cells: ↓ serum ox-LDL, ROS in aorta, peritoneal macrophages: ↓	[67]
AS	mouse macrophage-like cell line	cultured in HRM	0.6 mM	24 h	ox-LDL-induced inflammation: ↓ autophagic flux: ↑	[68]
AS	apoE knockout mice model	intravenously injected with tetrapod needle-like PdH nanozyme loaded by macrophages	NA	8 weeks	plaque area and the necrotic cores in aortic sinus sections: ↓ macrophage infiltration and MMP-9 expression in atherosclerotic plaques: ↓ stability of atherosclerotic plaques: ↑	[69]
obesity	Leprdb/db mice, HFD-induced obesity mice	drinking HRW	0.8 mM	12 weeks	hepatic oxidative stress and lipid accumulation: ↓ BW, serum FBG, TG, insulin: ↓ TC, LDL, HDL: NSC	[17]
obesity	HFD-induced obesity mice	drinking ERW	0.05 mM	12 weeks	BW, epididymal fat, liver fat: ↓ blood neutrophils and lymphocytes: ↑ serum adiponectin: ↑	[70]
obesity	HFD-induced obesity mice	gavage of MgH2 suspension	NA	74 weeks	plasma TG: ↓ the average of lifespan: ↑	[71]
obesity	HFD-induced mice	gavage of HRS	>0.6 mM	2, 4, 6 weeks	BW, blood TC, TG, LDL: ↓, HDL: ↑ intestinal integrity: ↑ abundance of Bacteroides, Bifidobacteria, Lactobacillus in feces: ↑, Enterobacter cloacae: ↓, ICL activity: ↓	[72]
obesity	HFD-induced mice	drinking HRW	~0.45 mM	2 weeks	heart weight: ↓, BAT mass: ↑ cardiac function, vascular bioactivity: ↑ FBG, BW, WAT mass, HR: NSC	[73]
obesity	HFD-induced rats	hydrogen inhalation	4%	10 weeks	hepatic FFA, MDA, 4-HNE, PGPC, PONPC, PAzPC: ↓, TC, TG: ⇓ plasma PONPC: ↓, TC, TG, FFA, MDA, 4-HNE: NSC plasma HDL antioxidant activity: ↑, Lp-PLA2 activity: ↓, PON-1 activity, LCAT expression: ↑	[74]

Abbreviations: SHR-cp, SHR.Cg-Leprcp/NDmcr; BUN, blood urea nitrogen; BAP, biological antioxidant potential; EtOH, ethyl alcohol; IL-10, interleukin-10; IL-22, interleukin-22; HFHSD, high fat and high sugar diet; TBIL, total bilirubin; MEG3, maternally expressed gene 3; Nrf2, nuclear factor erythroid 2-related factor 2; miR-136, microRNA-136; MCDHF, methionine and choline-deficient plus high fat; TLR-4, toll-like receptor-4; Nlrp3, nucleotide-binding oligomerization domain (NOD)-like receptor 3; HFFD, high fat and fructose diet; NASH, nonalcoholic steatohepatitis; CDAA, choline-deficient, L-amino acid-defined; HSC, hepatic stellate cell; WAT, white adipose tissue; MCD, methionine and choline-deficient; NAS, NAFLD activity score; PPARα, peroxisome proliferator-activated receptor alpha; LOX-1, lectin-like oxidized LDL receptor-1; SAA, serum amyloid A; PON-1, paraoxonase-1; RCT, reverse cholesterol transport; HRM, hydrogen-rich medium; ICL, isocitrate lyase; BAT, brown adipose tissue; HR, heart rate; FFA, free fatty acids; 4-HNE, 4-hydoxy-2-nonenal; PGPC, 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphatidylcholine; PONPC, 1-palmitoyl-2-(9-oxo-nonanoyl)-sn-glycero-3-phosphatidylcholine; PAzPC, 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphatidylcholine; Lp-PLA2, lipoprotein-associated phospholipase A2; LCAT, lecithin:cholesterol acyltransferase; ⇓, decrease without significance; NSC, no significant change.