Role of hydrogen sulfide in health and disease

Abstract

In the past, hydrogen sulfide (H₂S) was recognized as a toxic and dangerous gas; in recent years, with increased research, we have discovered that H₂S can act as an endogenous regulatory transmitter. In mammals, H₂S-catalyzing enzymes, such as cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, are differentially expressed in a variety of tissues and affect a variety of biological functions, such as transcriptional and posttranslational modification of genes, activation of signaling pathways in the cell, and metabolic processes in tissues, by producing H₂S. Various preclinical studies have shown that H₂S affects physiological and pathological processes in the body. However, a detailed systematic summary of these roles in health and disease is lacking. Therefore, this review provides a thorough overview of the physiological roles of H₂S in different systems and the diseases associated with disorders of H₂S metabolism, such as ischemia-reperfusion injury, hypertension, neurodegenerative diseases, inflammatory bowel disease, and cancer. Meanwhile, this paper also introduces H₂S donors and novel release modes, as well as the latest preclinical experimental results, aiming to provide researchers with new ideas to discover new diagnostic targets and therapeutic options.

Keywords: antioxidant; apoptosis; cancer; hydrogen sulfide; inflammation.

FIGURE 1

Enzyme catalysis of H₂S production. Endogenous H₂S can be produced by two ways: enzyme catalysis and nonenzyme catalysis. Enzyme catalysis is the main way and is catalyzed by four enzymes, such as CBS, CSE, 3‐MST and DAO. By Figdraw. H₂S, hydrogen sulfide; CBS, cystathionine β‐synthase; CSE, cystathionine γ‐lyase; PLP, pyridoxal‐5′‐phosphate; 3‐MST, 3‐mercaptopyruvate sulfurtransferase; 3‐MP, 3‐methylpyridine; CAT, cysteine aminotransferase; DAO, D‐amino acid oxidase.

FIGURE 2

The oxidation pathway of endogenous H₂S. The H₂S oxidation pathway in mitochondria is mainly catalyzed by sulfuroquinone oxidoreductase. Finally, H₂S is discharged from the body in the form of Thiosulfate or sulfate through this pathway. By Figdraw. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Cyt c, cytochrome c; GSH, glutathione; GSSH, glutathione disulfide; H₂S, hydrogen sulfide; NADH, nicotinamide adenine dinucleotide; SQR, sulfur quinone oxidoreductase; SDO, sulfide dioxygenase; TST, rhodanese.

FIGURE 3

The mechanism of ion exchange leading to Ca²⁺ overload during IRI. In IRI, abnormalities in Na⁺–Ca²⁺ exchange are associated with the following three aspects. First, high intracellular Na⁺ directly activates natriuretic proteins during ischemic injury. Second, high intracellular H⁺ decreases pH, which indirectly activates natriuretic proteins. At last, activation of PKC and increased release of catecholamines during reperfusion further promotes Na⁺–Ca²⁺ exchange. By Figdraw. CaBP, calcium binding protein; Ca²⁺, calcium ion; H⁺, hydrogen ion; Na⁺, sodium ion; K⁺, potassium ion.

FIGURE 4

ROS‐induced cell death mechanism. ROS induced oxidative stress may further cause cell damage, even cell death, such as apoptosis, autophagy, and programmed cell death. By Figdraw. APAF‐1, apoptosis protease activating factor 1; Cyt c, cytochrome c; FADD, Fas‐associating protein with a novel death domain; MLKL, mixed lineage kinase like domain; NF‐κB, nuclear factor‐kappa B; RARP, poly(ADP‐ribose) polymerase; ROS, reactive oxygen species; TNF‐α, tumor necrosis factor‐α; TRADD, TNFR‐related death domain.

FIGURE 5

Mechanisms of neuroprotection exerted by H₂S. H₂S can reduce the infarct size of cerebellar tissue and restore neurological function through mechanisms such as antioxidant, anti‐inflammatory, antiapoptotic, regulating autophagy, protecting mitochondrial function, and vasodilation and generation. By Figdraw. COX‐2, cytochrome oxidase subunit 2; γ‐GCS, γ‐glutamyl cysteine synthetase; iNOS, inducible nitric oxide synthase; mPTP, mitochondrial permeability transition pore; NF‐κB, nuclear factor‐kappa B; VEGF, vascular endothelial growth factor.