Advances in the study of glutathione peroxidase and several human diseases

Glutathione peroxidase was originally discovered and named by Mills for its antioxidant properties[1] . Glutathione peroxidase is a member of the peroxidase family of enzymes, which are found in a wide range of organisms including animals, plants, fungi and bacteria[2] . To date, five glutathione peroxidases have been identified in humans (glutathione peroxidase 1, glutathione peroxidase 2, glutathione peroxidase 3, glutathione peroxidase 4, glutathione peroxidase 6), and five in rodents (glutathione peroxidase 3, glutathione peroxidase 4) [3-4]. Previous studies have shown that glutathione peroxidase is closely related to the development of various diseases such as cancer, cardiovascular diseases, diabetes and inflammation[5-7] .

 

1 Glutathione peroxidase and cancer

Glutathione peroxidase is aberrantly expressed in a variety of tumors, which may play the role of oncogenes[8] , such as lung, liver and breast cancers[9-12] . Among them, the expression products of glutathione peroxidase 1 are mainly found in tissues with high oxygen tension, such as lungs, livers and kidneys, and are up-regulated in tumors such as breast, lung and colon cancers, which may be conducive to the progression and spread of tumors [13-14]; Glutathione peroxidase 2 is selectively expressed in the gastrointestinal tract, livers, and breast tissues, and it has been reported that knockdown of glutathione peroxidase 2 has a negative effect on H2 O2 and H2O2 [14]. It has been reported that knockdown of glutathione peroxidase 2 is more sensitive to H2 O2-induced apoptosis and inhibits tumor cell proliferation[15-16] ; glutathione peroxidase 3 is the only selenocysteine known to contain the extracellular antioxidant isoform, and its aberrant inactivation can lead to the excessive production and accumulation of reactive oxygen species in tissue cells, resulting in DNA damage in epithelial cells, and ultimately leading to the development of tumor[17] ; glutathione peroxidase 4 is a key regulator of iron death. Glutathione peroxidase 4 is a key regulator of iron death, which is a newly discovered mode of programmed death distinct from apoptosis and necrosis[18] .

Wang Shuo[19] analyzed the differences in the expression of glutathione peroxidase 1 between hepatocellular carcinoma tissues and normal tissues as well as among different groups of hepatocellular carcinoma patients with different stages, genders and ages, and searched the database for co-expressed genes of glutathione peroxidase 1, and finally concluded that glutathione peroxidase 1 was highly expressed in hepatocellular carcinoma tissues and was closely related to the occurrence, development and prognosis of hepatocellular carcinoma, so it could be used as one of the markers of hepatocellular carcinoma screening, Liu et al.[20] showed that the target-dependent glutathione peroxidase4 lipid peroxidation repair pathway plays an important role in the treatment of drug-resistant and refractory tumors, and An et al.[21] concluded that glutathione peroxidase3 with its redox properties effectively inhibited the proliferation, migration and invasion of lung cancer cells. Zhang Bo et al[22] found that the expression of glutathione peroxidase 4 promoted Akt phosphorylation and EMT in colorectal cancer cells, and mediated the formation of regrafenib resistance. Wang YX[23] found that glutathione peroxidase 2 could promote the migration and invasion of cervical cancer cells by studying the expression of glutathione peroxidase 2 in cervical cancer tissues and cells.

 

2 Glutathione peroxidase and cardiovascular disease

2.1 Glutathione peroxidase and atherosclerosis

Oxidative stress plays an important role in the development and progression of atherosclerosis and is considered to be central to atherosclerosis[24] . Studies have shown that glutathione peroxidase1 plays an important role in protecting the vascular wall against oxidative stress and atherosclerosis[25] .

Sneddon et al.[26] showed that lipids, cytokines and antioxidants regulate glutathione peroxidase 4 in a complex manner and that in the presence of sufficient selenium, glutathione peroxidase 4 may be beneficial in preventing the potentially atherogenic process. ebselen[27] demonstrated that glutathione peroxidase 1 can reduce diabetes-related atherosclerosis. Du Xunbo[28] took newly diagnosed coronary heart disease patients as the research object, mainly explored the relationship between Pr0200Leu variant of glutathione peroxidase 1 gene and coronary heart disease, and found that Pr0200Leu polymorphism is one of the risk factors for coronary heart disease, and there is a positive and additive interaction between the Pr0200Leu polymorphism of glutathione peroxidase 1 gene and cigarette smoking in the early onset coronary heart disease, and glutathione peroxidase 1 gene and cigarette smoking. A positive additive interaction between glutathione peroxidase 1 gene Pr0200Leu polymorphism and cigarette smoking in the development of early-onset coronary heart disease.

 

2.2 Glutathione peroxidase and hypertension

Changes in glutathione peroxidase levels are closely related to the occurrence and development of hypertension, and since glutathione peroxidase levels are significantly lower in patients with hypertension, monitoring changes in glutathione peroxidase levels can reflect the severity of the patient's condition, prevent complications, and reduce the incidence of cardiovascular disease and mortality.

Ji Shulan et al.[29] compared the serum of hypertensive patients with that of a normal group and found that SOD and glutathione peroxidase levels were lower and LPO levels were higher in hypertensive patients, and that the levels of SOD and glutathione peroxidase were negatively correlated with the level of blood pressure. Tan HY et al[30] found that serum glutathione peroxidase and catalase activities were lower in patients with hypertension than in healthy subjects. The results of Zhang Xiaoning[31] also showed that OSAHS patients with or without hypertension had lower levels of glutathione peroxidase than controls, and that glutathione peroxidase activity decreased with the aggravation of hypertension. Hao et al[32] found that glutathione peroxidase3 was associated with coronary artery disease in hypertensive patients in the rural Han population of Fuxin, Liaoning province, and that age, smoking, and elevated FPG and LDL-C were all factors that contributed to coronary artery disease in hypertensive patients.

 

2.3 Glutathione peroxidase and other cardiovascular diseases

Changes in glutathione peroxidase levels can cause myocardial and cardiovascular damage and accelerate the progression of coronary heart disease. Min Jin[33] found that the free radical scavenging activity of glutathione peroxidase in patients with cardiovascular diseases at high altitude was significantly lower than that of normal people, and suggested that the antioxidant capacity could be enhanced by supplementation with Se. Doroshow[34] showed that glutathione peroxidase regulated the intracellular level of adriamycin-induced reactive oxygen species (ROS) and played an important role in adriamycin-associated fibroblast apoptosis and cell cycle alteration in the heart of mice. Glutathione peroxidase was shown to regulate amygdalin-induced reactive oxygen species (ROS) intracellular levels and to play an important role in amygdalin-associated fibroblast apoptosis and cell cycle alteration in mouse heart. Ramprasath et al[35] found that variations in genes such as glutathione peroxidase, leading to an imbalance in the oxidative/antioxidant system, accelerated the progression of diabetes and diabetic cardiovascular complications, especially coronary heart disease. It has been shown that reduced glutathione peroxidase 1 function increases the risk of cardiovascular disease in diabetic patients[25] .

 

3 Glutathione peroxidase and diabetes mellitus

The expression and activity of glutathione peroxidase are closely related to diabetes mellitus, and serum glutathione peroxidase activity can be used as a predictive diagnostic indicator for gestational diabetes mellitus (GDM)[36] . In a study by Zhao Yajie et al[37] , plasma activities of reduced glutathione, peroxidase and glutathione reductase were lower than those of the normal population in patients with type II diabetes mellitus, exceeding the scavenging capacity of the antioxidant enzymes, which suggests that the antioxidant capacity of the organism is severely impaired, and this may eventually lead to diabetes mellitus and other syndromes.38 In a study by Schliefsteiner et al, glutathione peroxidase was found to be a key factor in the development and growth of diabetes mellitus in erythrocytes. Schliefsteiner et al.[38] showed that decreased glutathione peroxidase activity in erythrocytes was associated with the development of insulin resistance, suggesting that risk factors for diabetes may induce insulin resistance through oxidative stress. Reactive oxygen species (ROS) are important signals for glucose-stimulated insulin secretion (GSIS), and overproduction of or prolonged exposure to ROS may lead to impairment of GSIS and/or the development of diabetes, with low levels of ROS, particularly hydrogen peroxide, required for glucose sensing and GSIS[39-41] .

Glutathione peroxidase 1 is one of the major enzymes involved in scavenging intracellular H2 O2 and lipid peroxides [42]. When glutathione peroxidase 1 is deficient, excessive ROS accumulation inhibits gene expression or protein production of key transcription factors such as PDX1, resulting in reduced islet B cell mass, insulin synthesis, and insulin secretion. However, when glutathione peroxidase 1 is overexpressed, the excessive reduction of intracellular ROS decreases the sensitivity of insulin signaling [43]. Yun et al. [44] found that overexpression of glutathione peroxidase 1 in mice (OE) led to an increase in glucose-stimulated insulin secretion and an excess of blood insulin. This phenotype was found to be strongly correlated with reduced expression of regenerative islet-derived protein 2 (REG2) in OE, and it was also found that the down-regulation of Reg2 expression in glutathione peroxidase 1 over-secreted pancreatic islets was mediated by the transcriptional repression of this gene by two ROS-responsive transcription factors, AP-1 and DBP. This reveals that glutathione peroxidase 1 is a novel regulator of Reg2 expression.

 

4 Glutathione peroxidase and inflammation

Glutathione peroxidase acts as an anti-inflammatory factor and regulates the inflammatory process. Hypercytokinemia and oxidative stress are important factors contributing to the inadequate immune response in the early course of acute pancreatitis (AP).Urszula et al.45 found that serum glutathione peroxidase concentrations were significantly lower in patients with severe AP when comparing them to normal subjects.46 Xu Weiwei[46] found that gingival sulcus fluid and serum glutathione peroxidase concentrations in patients with periapical inflammation were significantly higher than those in normal subjects. Xu Weiwei[46] found that gingival sulcus fluid and serum glutathione peroxidase levels were significantly lower in patients with periodontal inflammation than in healthy subjects, and after treatment, gingival sulcus fluid and serum glutathione peroxidase levels were higher than those before treatment, which led to the conclusion that the gingival sulcus fluid and serum glutathione peroxidase levels were an important reference for the state of periodontal tissues. Glutathione peroxidase 4 is a GSH-dependent enzyme that counteracts iron-dependent and lipid peroxidation, and the addition of the formula Yi-Qi, Detoxification, and Resolving Blood Stasis (YQDRBS) to conventional Western medicine treatment of ulcerative colitis (UC) resulted in an increase in the glutathione peroxidase 4 protein content and up-regulation of its expression, which attenuates iron death and facilitates mucosal repair.47 Koeberle et al.48 investigated the anti-inflammatory mechanism of glutathione peroxidase in the presence of a glutathione peroxidase enzyme in the gingival fluid and serum as an indicator of periodontal tissue status. Koeberle et al. [48] investigated the anti-inflammatory mechanism of glutathione peroxidase and demonstrated that glutathione peroxidase 2 and glutathione peroxidase 1 have overlapping functions in controlling the synthesis of lipid mediators of inflammation, and that they likely exert their anti-inflammatory effects by preventing excessive production of prostaglandin E2 (PGE2).

 

5 Outlook

The moderate expression of glutathione peroxidase plays an important role in maintaining the normal metabolism of the body, and people have gradually explored the evidence that it is closely related to certain diseases, but from the current study, the mechanism of action of glutathione peroxidase is still unclear due to the different roles of glutathione peroxidase in various tumors, which needs to be further investigated; the specific mechanism of glutathione peroxidase's role in inflammation is still understudied, and whether it participates in the pathway of inflammation factors needs to be further studied; there is no systematic study on the clinical value of glutathione peroxidase in diseases. The specific mechanism of glutathione peroxidase in inflammation is not well studied, and whether it is involved in the inflammatory pathway needs to be further researched; there is no systematic study on the clinical value of glutathione peroxidase in diseases.

 

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