
Citation: | Xiangyu Zhang, Yingchao Hu, Bingwei Wang, Shuo Yang. Ferroptosis: Iron-mediated cell death linked to disease pathogenesis[J]. The Journal of Biomedical Research, 2024, 38(5): 413-435. DOI: 10.7555/JBR.37.20230224 |
Ferroptosis is a pattern of iron-mediated regulatory cell death characterized by oxidative damage. The molecular regulatory mechanisms are related to iron metabolism, lipid peroxidation, and glutathione metabolism. Additionally, some immunological signaling pathways, such as the cyclic GMP-AMP synthase-stimulator of the interferon gene axis, the Janus kinase-signal transducer and activator of transcription 1 axis, and the transforming growth factor beta 1-Smad3 axis, may also participate in the regulation of ferroptosis. Studies have shown that ferroptosis is significantly associated with many diseases such as cancer, neurodegenerative diseases, inflammatory diseases, and autoimmune diseases. Considering the pivotal role of ferroptosis-regulating signaling in the pathogenesis of diverse diseases, the development of ferroptosis inducers or inhibitors may have significant clinical potential for the treatment of aforementioned conditions.
Type 2 diabetes mellitus (T2D) is an important global health problem. Microvascular complication, such as retinopathy or nephropathy, is common in poor glycemic control patients. Furthermore, increased risk of cardiovascular disease is obvious in T2D patients, which is attributable to endothelial dysfunction. In patients with hyperglycemia, oral glucose loading suppressed endothelial-dependent vasodilation through an increase in the production of oxygen-derived free radicals. Epidemiological studies, such as DECODE (Diabetic Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe), have shown that accelerated postprandial blood glucose elevation is strongly associated with occurrence of cardiovascular diseases[1]. Postprandial glucose level is an independent risk factor for cardiovascular disease that has effects greater than glucose level of fasting state[2]. The DECODE study showed a direct relationship between 2-h glucose levels (in oral glucose tolerance test) and risk for cardiovascular death[3].
Generally, management of LDL cholesterol (LDLc) in serum lipids is an important strategy in arterio-sclerotic disease prevention, which has been suggested from the results of a large number of epidemiological studies and large-scale clinical trial. Cohort study in Japan showed a significant correlation between triglyceride (TG) values and coronary artery disease[4-5]. On the other hand, it has been reported[6] that increase of serum triglyceride level, both fasting and postprandial state, is involved in arteriosclerosis. The widely accepted concept of postprandial hyperlipidemia was initially proposed by Zilversmit et al. in 1979[7].
The pathophysiology of postprandial hyperglycemia is characterized by hyperglycemic spikes that induce oxidative stress. Postprandial hyperglycaemia is defined as a plasma glucose level >7.8 μmol/L (140 mg/dL) 1- 2 hours after ingestion of food[8-9]. In contrast, postprandial glucose level in people with normal glucose tolerance is less than 7.8 μmol/L (140 mg/dL) in response to meals and typically returns to premeal levels within two to three hours. However, because of ethnic gap in physique (expressed in body mass index or BMI), the East Asian people in general are relatively small in physique compared to African and Caucasian. Meta-analyses of insulin sensitivity index (SI) and acute insulin response to glucose (AIRg) in three major ethnic groups (i.e. 19 African, 31 Caucasian, and 24 East Asian cohorts) have shown divergent natural courses of diabetes onset among different ethnic groups[10]. Nevertheless, the incidence of progression of atherosclerotic disease appears to coincide with any of the pathological conditions of hyperglycemia and dyslipidemia. In this article, we discuss various aspects of postprandial hyperglycemia and postprandial hyperlipidemia in T2D[11-16].
Postprandial excursion of blood glucose level is dependent upon several rate-limiting factors, including (ⅰ) time course of gastric emptying, (ⅱ) intestinal absorptive rate of glucose, (ⅲ) decreased insulin sensitivity in peripheral tissues, (ⅳ) decreased suppression of hepatic glucose output (glycogenolysis) after meals, (ⅴ) rate of gluconeogenesis of the liver, (ⅵ) insulin secretion rate during postprandial period, and (ⅶ) autonomic nerve imbalance of sympathetic and parasympathetic nerve.
Postprandial excursion of plasma glucose level is a common phenomenon in people with diabetes. For example, in a study in which daily plasma glucose profiles was assessed over a one-week period in 3, 284 subjects with non-insulin-treated T2D, postprandial plasma glucose value >8.9 μmol/L (160 mg/dL) was recorded at least once in 84% of those studied[17]. Deterioration of β-cell function and insulin secretion are prior to clinical diabetes. These metabolic abnormalities are first evident by elevations in postprandial plasma glucose[18].
Blood glucose levels mainly regulate the balance of input and output the liver (i.e. gluconeogenesis and glycogenolysis). The liver is chiefly responsible for this glucose homeostasis. The kidneys are also contributing an average 20% of glucose release, and the gut supplying up to 15 to 20%. During fasting state, pancreatic α-cells secrete glucagon to increase hepatic gluconeogenesis and glycogenolysis, resulting in an increase in circulating glucose levels. After meal, pancreatic β-cells release insulin to inhibit hepatic gluconeogenesis and glycogenolysis, thus decreasing glucose output to the blood stream. Insulin also acts at peripheral tissues to increase glucose uptake, contributing to decreased blood glucose levels. In patients with T2D, insulin action is decreased at the liver and/or peripheral tissue, whereas the glucagon action is increased. As a result, T2D is invariably associated with increased hepatic gluconeogenesis and glycogenolysis, increased glucose output to the circulation, repressed glucose uptake into the peripheral tissues, and eventually increased blood glucose levels.
Prior to clinical diabetes, the above metabolic abnormalities are first evident by elevated concentration of postprandial plasma glucose. Emerging evidence shows that postprandial plasma glucose levels are elevated due to deficiencies in amylin, a glucoregulatory peptide that is normally co-secreted with insulin from the β-cells, as well as glucagon-like peptide-1 (GLP-1) and glucose-dependent gastric inhibitory peptide (GIP), which are incretin hormones secreted by the gut[19-22]. Released during absorption of meals, the intestinederived incretin hormones GLP-1 and GIP can stimulate pancreatic β-cells to secrete insulin. It is estimated that GLP-1 and GIP are responsible for 50%-70% of postprandial insulin release[23]. In addition, GLP-1 suppresses inappropriate glucagon secretion from pancreatic α-cells, and at pharmacologic doses, GLP-1 delays gastric emptying by inhibiting gastroduodenal motility[24], which is associated with an increase in satiety and reduced food intake. Both GLP-1 and GIP are rapidly broken down by DPP-4 after secretion[25].
Postprandial hyperglycemic state includes production of AGEs and lipid peroxidation products as activators of upstream kinase such as protein kinase C (PKC) and p38α mitogen activated protein kinase (MAPK), resulting in endothelial dysfunction and inflammatory genes response[26-27]. Oxidative stress plays an important role for vascular endothelial dysfunction. Endothelial dysfunction of vessels is characterized by decreased endothelium-derived relaxing factor such as nitric oxide (NO) and endothelial NO synthase (eNOS)[28]. Oxidative stress also contributes to progression of atherogenesis, including proliferation of smooth muscle cells and formation of vascular plaque[29-30].
The superoxide anion is produced in mitochondria through univalent reduction of molecular oxygen. Xanthine oxidase, NADH/NADPH oxidase, lipoxygenase and NOS are key enzymes in the process of generation of superoxide anions. Superoxide anions are reduced to hydrogen peroxide by enzymatically catalyzed dismutation. Among reactive oxygen species (ROS), hydroxyl radical is generated by hydrogen peroxide and a transition metal catalyzed reaction (Haber-Weiss reaction). Hydroxyl radical has extremely high reactivity and is involved in a number of tissue damage, including DNA damage, lipid peroxidation, and protein degeneration that are associated with progression of atherosclerosis[31]. Nitrotyrosine and 8- iso-prostaglandin F2α (8-iso-PGF2α), two strong oxidative stress markers, are increased in postprandial hyperglycemia. A strong positive correlation between urinary 8-iso-PGF2α and glycemic variability assessed by MAGE (mean amplitude of glycemic excursions) has been described[32-33].
It is well known that inflammation is closely related to the pathogenesis of atherosclerosis and vascular failure[12, 34-36]. Inflammatory cells and mediators play an essential role in the initiation and progression of atherosclerosis. Various circulating adhesion molecules, such as intracellular adhesion molecule 1 (ICAM-1) and vascular adhesion molecule 1 (VCAM-1), are increased in diabetes with or without vascular disease[34]. These molecules are strongly related to the recruitment of monocytes and T-lymphocytes to the endothelium of the artery wall, resulting in activation of early inflammatory process. Other adhesion molecule, for instance β2- integrin Mac1 (CD11b/CD18), binds to endothelial surface ICAM-1 and platelets through interacting with either fibrinogen or several platelets receptors, such as glycoprotein Ib-α (GP Ib-α) and ICAM2[36].
Firth et al.[37] have measured, using multiple tracer approach, the rate of appearances of glucose, either derived from the ingested glucose or from the endogenous glucose production. It was found that people with T2D showed no increase in the appearance of the ingested glucose as compared with normal subjects. However, the rate of appearance of endogenous glucose production was increased in T2D patients as compared to normal subjects. These data suggest that delayed postprandial excursion of glucose in T2D patients is not attributable to over-absorption of ingested glucose. Rather, increase in the rate of glucose appearance is mainly attributable to hepatic insulin resistance.
T2D has been considered as a bi-hormonal disease characterized by relative hypoinsulinemia and hyperglucagonemia[38]. Patients with T2D display postprandial hyperglycemia due to decreased insulin secretion and a concomitant increase in glucagon secretion. The uncontrolled glucagon release under postprandial stage under T2D conditions may not be attributable to lack of an insulin action, because experiments with an α-cellspecific insulin receptor knockout mouse (αIRKO) model showed that insulin exerts no direct effect on glucagon secretion from α-cells[39].
Longitudinal monitoring of insulin and glucagon secretion in Caucasian women with impaired glucose tolerance (IGT) versus normal glucose tolerance (NGT), over a 12-year period, showed that β- and α-cell dysfunction are evident several years before diagnosis of IGT, and islet dysfunction is manifested by impaired glucose sensitivity of the β- and α-cells and reduced maximal insulin secretion[40].
Besides impaired β-cell functions, a lowered number of β-cell mass may also contribute to insufficient secretion of insulin in these patients. Analysis of autopsy samples of pancreas from 50 T2D subjects showed that β-cell mass in pancreas was 36% lower than that of 52 non-diabetic subjects[41]. While the topography of α and β-cells was similar in both groups, the ratio of α/β cell areas increased (from 0.42 to 0.72) in T2D subjects whereas the α-cell mass was virtually identical[41]. Thus, the high proportion of α- to β-cells in the islets of some T2D subjects is due to decrease in β- cell number rather than increase in α-cell number. This imbalance may lead to the relative hyperglucagonemia observed in T2D.
Recently, it has been suggested that hepatic insulin resistance is associated with several molecules that are related to insulin signal modulation. Of which, regulation of IRS-1 and IRS-2 were observed in diabetic models[42, 43]. IRS-1 acts mainly in fasting stage whereas IRS-2 acts mainly under postprandial conditions. Further, it was suggested that a sufficiently high level of IRS-2 expression in the liver during fasting state (i.e. between meals) is important in suppressing postprandial hyperglycemia. Thus, suboptimal level of IRS-2 expression, often observed under hyperinsulinsecretion conditions (e.g. obesity or taking snacks besides meals), was thought to be a contributing factor to postprandial hyperglycemia.
Diabetic vascular disorders encompass microvascular and macrovascular disorders. The microangiopathy is mainly diabetic retinopathy and diabetic nephropathy, while the macrovascular disorder includes myocardial infarction, cerebral infarction and lower extremity arteriosclerosis. The effects of chronically sustained hyperglycemia are related to the progression of microvascular complications. In the Diabetic Control and Complications Trial (DCCT), it was proved that strict blood glucose level control is important for the onset and progression of retinopathy and diabetic nephropathy[44]. The DCCT study was a comparative analysis between subjects with type 1 diabetes mellitus who received intensive insulin treatment and those receiving conventional treatment. Evidence for the onset and suppression of progression of microvascular complications by glycemic control is also shown in UKPDS 33[45] and Kumamoto study[46]. It is thought that factors, such as consistent hyperglycemia by polyol pathway, activation of protein kinase C, increased accumulation of glycated protein, and enhancement of oxidative stress, contribute to in vascular endothelial dysfunction.
On the other hand, macroangiopathy is not specific to diabetes mellitus, and diabetes mellitus is one of the risk factors for vascular disorders. For example, it has been reported that contributing risk factors to the onset of coronary artery disease in type 2 diabetes are LDLc, HDLc, HbA1c, systolic blood pressure, and current smoking status[47]. A study of Japanese type 2 diabetic patients also confirmed that the risk factors for coronary artery disease are triglyceride, LDL cholesterol, HbA1c, and systolic blood pressure[4]. In comparison with diabetic microvascular complications, it is suggested that the involvement of dyslipidemia is greater than the blood glucose risk expressed by HbA1c in macrovascular complications.
From the viewpoint of blood glucose control in diabetes, postprandial blood glucose level is more relevant than fasting blood glucose level to the development and progression of macroangiopathy. The DECODE study has shown that accelerated postprandial excursion is strongly associated with occurrence of cardiovascular diseases[3]. In Funagata Diabetes Study, it was demonstrated that even a mild rise in postprandial blood glucose is associated with cardiovascular death[48]. Similarly, the results of the DECODA Study targeting Asian races reported that blood glucose levels are important for prediction of total death and cardiovascular death after 2 h of glucose tolerance[49]. In the result of meta-analysis that integrated results of seven studies that tracked over 52 weeks in acarbose and placebo group for T2D, it was reported that the relative risk of onset of myocardial infarction was significantly reduced to 64% and the relative risk of onset of systemic vascular events was reduced by 35%[50]. On the other hand, basic research also showed that glucose spike (rapid increase in blood glucose) provokes endothelial cell apoptosis and induces endothelial cell damage[51]. Therefore, as a goal of blood glucose control of diabetic patients, it is necessary to control postprandial hyperglycemia to suppress the development of diabetic macrovascular diseases.
Therefore, the phenomenon of postprandial blood glucose excursion in T2D is similar to the effect of sustained increase in blood glucose with fasting blood glucose level in microvascular complications. While in diabetic macrovascular complications, postprandial blood glucose excursion is considered to be more specifically involved than sustained hyperglycemia.
Postprandial hypertriglyceridemia refers to a state in which serum TG shows abnormally high value after meals and its peak is delayed/prolonged. Diagnosis of dyslipidemia is generally carried out in "early morning fasting" for more than 12 hours. T2D is one of the most common diseases associated with elevation in serum triglyceride levels[52-56]. Hypertriglyceridemia contributes to progression of arteriosclerosis indirectly through increased small dense low density lipoproteins (sdLDL) and deceased high density lipoproteins (HDL). Hypertriglyceridemia is attributable to abnormalities in the synthesis and catabolism of triglyceride-rich lipoproteins (TRL), such as very low density lipoprotein (VLDL) and chylomicrons. Structural protein of TRL is apoB100 or apoB48. ApoB100 is produced in the liver parenchymal cells and apoB48 is produced in intestinal enterocytes. Overproduction of TRL is mainly associated with hepatic VLDL production. Insulin resistance is an important factor that regulates hepatic TRL production. Under normal condition, hepatic apoB100 synthesis is regulated by intracellular degradation that limits the level of VLDL assembly and secretion[11]. Intracellular degradation of apoB100 is controlled by insulin action. In insulin resistance state, overproduction of apoB100-VLDL occurs and, as a consequence, hypertriglyceridemia ensures. There are two types of VLDL produced by human liver, namely VLDL1 and VLDL2[55]. Hepatic overproduction of VLDL in insulin resistant state, such as diabetes and metabolic syndrome, is strongly related to VLDL1, whereas the level of VLDL2 production remains relatively normal under this condition. The observed VLDL1 overproduction could at least be partially attributable to increased blood glucose levels[57].
Postprandial hypertriglyceridemia is a state in which the peak of TG increase after meals is high as well as a state where TG does not return to pre-meal levels. The chylomicron remnant concentration is increased in postprandial hyperlipidemia as compared with that in the fasting state. The association between increased and prolonged postprandial hypertriglyceridemia and coronary artery disease has been reported[58-59].
Analysis of Multiple Risk Factor Intervention Trial showed that greater prevalence of hypertriglyceridemia with nonfasting than fasting values, and similarly increased risk with each indicates that nonfasting TG levels may be more useful than fasting ones for risk stratification[60]. Iso et al. also reported that in the group with high TG under non-fasting condition, there is high risk of cardiovascular disease, coronary artery disease such as myocardial infarction and onset of sudden death[6].
Recently, the apoC-Ⅲ functionality has resurged as a main topic in lipid and lipoprotein metabolism[61]. ApoC-Ⅲ is a small protein (79 amino acids) abundantly presented in the plasma as a component of TRLs and HDL. The plasma triglyceride and apoC-Ⅲ concentrations are positively correlated with each other in normoand hypertriglyceridemic subjects. ApoC-Ⅲ has been shown to slow down the clearance of TRLs by inhibiting the activity of LPL and by interfering with binding to cell-surface receptors. Human studies with familial hyperchylomicronemia patients (averaging TG at 1406 to 2083 mg/dl) have shown that introducing mRNA of apoC-Ⅲ resulted in reduction in serum triglyceride levels[62-64]. Patients with loss-of-function mutations in the APOC3 gene exhibited low risk of cardiovascular events compare with wild type control subjects[65]. The risk of CHD with carriers of any APOC3 mutations was 40% lower than the risk of the non-carriers. The low risk of cardiovascular events in patients with loss-of-function mutations in the APOC3 gene is strongly related to serum low triglyceride levels.
A recent study has reported a positive correlation between apoC-Ⅲ protein levels and plasma fasting glucose level and glucose excursion in overweight patients[66]. It was also shown that high blood glucose concentration plays a role in rat and human apoC-Ⅲ expression through the action of transcription factors ChREBP and HNF-4α[66]. These data suggest that apoC-Ⅲ may be one of the regulatory factors contributing to hypertriglyceridemia (overproduction of TRL) under elevated glucose concentration conditions.
Biosynthesis of TRL requires MTP (microsomal transfer protein), which is an endoplasmic reticulum resident heterodimeric complex. The expression of apoB gene and its serum level under diabetic condition are related to upregulated MTP, which has been demonstrated in various animal models[67-69]. In human T2D, increased expression of MTP mRNA in intestinal biopsies was shown[70-71]. T2D patients who were in statins had lower MTP mRNA compared to the controls. Hepatic MTP mRNA expression is negatively regulated by insulin. Insulin might also directly inhibit apoB48 secretion even though it is probable that upregulation of MTP stimulates apoB secretion[72-73].
Elevation of serum triglyceride is not caused by insulin deficiency, but is often associated with a relative decrease in insulin action (i.e. insulin resistance). Insulin resistance mainly shows that the insulin action in liver and skeletal muscle is lower than that in healthy subjects. In insulin resistance state, overproduction of apoB100-VLDL occurs and hypertriglyceridemia ensures.
Diabetic patients have a high probability of becoming dyslipidemia, and when diabetes and dyslipidemia are merged, they increase the risk of cardiovascular disease. A meta-analysis showed that the relative risk of developing coronary artery disease due to diabetes is 2.0 and the risk of developing cerebral infarction is 2.3[74]. According to NIPPONDATA 80, the relative risk of death in coronary artery disease patients with diabetes is 2.8[75]. In Hisayama-chyo study, the relative risk of developing coronary artery disease after diversification of confounding factor in diabetic patients is 2.6 and the relative risk of developing cerebral infarction is 3.2, which is higher than those of normal glucose tolerance group[76].
Hyperglycemia can be a factor that triggers hypertriglyceridemia in diabetic patients. When the blood glucose level rises in diabetic patients, the liver uses excess glucose to make triglyceride. Since lipoprotein lipase (LPL) is activated by insulin, triglycerides tend to accumulate when secretion of insulin deteriorates due to diabetes. On the other hand, hypertriglyceridemia exacerbates insulin action (insulin resistance), and blood glucose level further exacerbates diabetes. Diabetes promotes arteriosclerosis, but arteriosclerosis progresses faster when dyslipidemia is combined.
Many epidemiological, experimental and clinical studies have been performed to determine the incidence of cardiovascular disease and metabolic disorders related to hyperglycemia and hyperlipidemia[6, 48, 77-83]. Dyslipidemia is strongly related to and an important risk factor of cardiovascular disease in T2D. Result of the STENO2 study (a long-term follow-up for incidence of vascular complications in diabetic patients)[84] have indicated that not only blood sugar control but also optimal blood pressure and lipid control is needed to achieve the reduction of cardiovascular events. Hyper-triglyceridemia contributes indirectly to arteriosclerosis progression through increase in sdLDL and lowered HDL.
Cardiovascular risk factors are present in overlap with those in patients with T2D, such as obesity, hypertension, and hypertriglyceridemia. Moreover, the presence of postprandial abnormalities, namely postprandial hyperglycemia and postprandial hypertriglyceridemia, are the most important inter-related risk factors for the development of cardiovascular disease in patients with T2D.
Insulin resistance is closely related to both postprandial excursion of blood glucose and lipid profile. Clinical manifestation of insulin resistant status is obesity or metabolic syndrome. Inflammatory process is present in these conditions. IL1β and IL6 are the major inflammatory cytokines that stimulate expression of sterol regulatory element binding protein 2 (SREBP2) and 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) in HepG2 cells[85-87]. Upregulation of SREBP2 through extracellular signal regulated pathways involves the kinases ERK-1 and -2.
There is a strong relationship between metabolism of free fatty acid (FFA) in adipocytes and that in liver cells. Histological view of adipose tissue in patients with obesity shows crown-like structures (CLS) that are the appearances of fat cells and surrounding macrophages. Interaction between enlarged fat cell and macrophages evoked chronic inflammatory response, resulting in overproduction of FFA. Increase influx of FFA into the liver can lead to fatty liver and non-alcoholic steatohepatitis (NASH)[88-89].
Macrophages in the liver can be activated by degenerated hepatocyte. Phagocytosis and digestion of degenerated hepatocyte by macrophages may result in chronic inflammatory change and liver fibrosis. Deposition of FFA in the liver is also the cause of insulin resistance and postprandial hyperglycemia[90].
Currently, various antidiabetic agents are being developed for the treatment. Since onset of cardiovascular disease can be prevented by suppressing postprandial excursions of blood glucose level, various drugs have been used clinically. There is some evidence showing that suppression of cardiovascular events can be achieved by using a single antidiabetic agent. For instance, the STOP-NIDDM study[91] has shown that cardiovascular events can be reduced by the treatment of acarbose, an α-glucosidase inhibitor.
Drug | Target | Clinical effects/availability | Effect for PPHG/PPHL |
Limitation | Refs |
Metformin | Unclear; involves complex I & mGPD | Extensively used | Fasting HG | GI side effect Nausea, Diarrhea |
|
α-glucosidase inhibitor | Intestinal α-glucosidase | Reduction of CVD | PPHG | GI side effect Constipation, Farting | 49, 91, 93 |
Glinides | β cells Pancreas | Short duration of action | PPHG | Use every meal time | 98 |
DPP4inhibitor | Intestinal DPP4 | Suppression of glucagon | Fasting/PPHG | GI side effect Nausea, Constipation | 100-102 |
Thiazolidinedione | Liver, Fat PPARg | Increase in insulin sensitivity | Fasting HG | Edema, Bone fracture | |
Sulfonylureas | β cells pancreas | Insulin stimulator | Fasting HG | Prolonged hypoglycemia | 96, 97 |
SGLT2 inhibitor | Renal tubular SGLT2 | Decrease CVD outcome Mild body weight reduction | Fasting HG | Urogenital infection Dehydration | |
Insulin (Insulin analogue) |
Insulin receptor | Robust glucose reduction Extensively used | Fasting/PPHG | Increase body weight Injection | 44 |
GLP1 agonist | a/b cells pancreas | Reduce satiety Mild body weight reduction |
PPHG | Nausea, Vomiting Injection |
99 |
mGPD: mitochondrial glycerol-3-phosphate dehydrogenase; HG: hyperglycemia; GI: gastro intestinal; CVD: cardiovascular disease; PPHG: post prandial hyperglycemia; DPP4: dipeptidyl peptidase 4; PPARg: peroxisome oroliferator-activated receptor γ. |
Intestinal absorption of the glucose depends on total gut function. α-Glucosidase (maltase, α-glucopyranosidase, α-glucoside hydrolase, α-1, 4-glucosidase) is a glycoside hydrolase located in the brush border of the small intestine. α-Glucosidase breaks down complex carbohydrates such as starch and glycogen into their monomers, thus plays a role in glucose absorption. The cleavage occurs at α-1, 4-glycosidic bond between individual glucosyl residues from various glycoconjugates, including α- or β-linked polymers of glucose.
In humans, the pancreas and salivary gland synthesize amylase (α-amylase) that hydrolyses dietary starch into disaccharides and trisaccharides. The secretion from the Lieberkuhn glands of the small intestine contains the digestive enzymes maltase, lactase, and sucurase. These digestive enzymes are abundantly distributed in the vicinity of microvilli of intestinal epithelial cells. Thus, nutrients that have been digested near microvilli can be absorbed efficiently by the cells. Starch blockers are substances that inhibit amylase. It has been demonstrated that concentrated starch blocker extracts from white bean (Phaseolus vulgaris), when given with a starchy meal, can reduce the usual rise in blood glucose levels of both healthy subjects and diabetics[92].
Clinically, only α-glucosidase inhibitors (e.g. acarbose, voglibose and miglitol) are used to inhibit postprandial blood glucose excursion. Daily dose of voglibose at 0.2mg orally can reduce 2 h postprandial blood glucose excursion by 2.0 +/- 2.15 μmol/L in T2D patients[93]. Adverse events associated with the use of these compounds include diarrhea, constipation and farting.
Postprandial hyperglycemia is partially dependent of the rate of insulin secretion during postprandial period, which is believed to be associated with genic predisposition of T2D patients. Insulin secretion from the pancreatic β- cells is composed of two phases, the first fast phase is followed by a second relatively slow phase in response to rapid rise in blood glucose concentrations[94]. The early phase of insulin secretion is important for the rapid and efficient suppression of endogenous glucose production after a meal.[95] In patients with T2D, the first phase of insulin secretion is reduced, and the reactivity of the second phase is delayed.
Sulfonylureas stimulate insulin secretion from pancreatic beta cells mediated by the sulfonylurea receptor that displays a high affinity toward sulfonylureas. Glibenclamide is the most powerful among the sulfonylurea agents. At daily dose of 1.25-2.5 mg of oral administration, the duration of glibenclamide action is 12-18 hours and halflife (T1/2) is 2.7 hours. On the other hand, Glimepiride is a relatively weak insulin secretagouge, thus exerting a mild hypoglycemic effect, yet its insulin sensitivity enhancing effect is almost the same as glibenclamide. Duration of glimepiride action is 6-24 h (T1/2 = 1.5 hours). However, these compounds are not specifically effective for reducing postprandial glucose excursion[96-97].
Glinides, a group of drug that lead to insulin secretion in an immediate and short-term, bind to the sulfonylurea receptor transiently. Although the glucose lowering effect of glinides is weak compared to the other sulfonylurea agents, the effect appears in about 15 min after taking and reaches maximum blood concentration in about 30 min. Therefore, glinides can reduce postprandial hyperglycemia and improve the first phase insulin secretion[98].
Incretin hormones, such as GLP-1 and GIP, not only are insulin secretagouge but also exert other actions in regulation of blood glucose level, such as decreasing motility of GI tract that can delay gastric emptying. GLP- 1 can also suppress inappropriate glucagon secretion by pancreatic α-cells and therefore decrease endogenous hepatic glucose production by approximately 50%. The glucagon secretion may otherwise contribute to reduction of postprandial glucose excursion.
A pharmacological approach to control blood glucose level in T2D patients is the use of dipeptidyl peptidase 4 (DPP-4) inhibitor and GLP-1 receptor agonist. These agents are strongly effective for reduction of postprandial glucose excursion. GLP-1 receptor agonists (e. g. exenatide, liragrutide, lixisenatide) are synthetic DPP-4 resistant form of endogenous GLP-1. For example, exenatide has 53% homology with endogenous GLP-1 and longer circulating halflife than that of endogenous GLP-1[99]. Exenatide binds to the GLP-1 receptors on pancreatic β-cells and augments glucoseinduced insulin secretion.
DPP-4 inhibitors decrease the metabolism of GLP-1 and GIP through inhibition of the enzyme DPP-4. In normal physiologic conditions, the DPP4 enzyme rapidly inactivates GLP-1 and GIP by cleaving the two end-terminal amino acids of these incretin hormones. DPP-4 inhibitors increase prandial insulin secretion and suppress glucagon secretion. Postprandial glucose level of patients with T2D decreases by decreasing hepatic glucose production and improving peripheral glucose uptake. DPP-4 inhibitors (e.g. alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin and vildagliptin) are currently approved for treatment of T2D[100-102].
Drug | Target | Clinical effects/availability | Effect for TC/TG | Limitation | Refs |
Statin | HMG-CoA | Extensively used | Both | Increase CK | 5, 104, 105 |
reductase | Reduction of CVD | Rhabdomyolysis | |||
Fibrate | PPARα | Reduction of CVD | TG | Rhabdomyolysis | 107 |
Ezetimibe | intestinal NPC1L1 | Short duration of action | TC | GI side effect | |
PPARδ/β | |||||
Ecolocumab | PCSK9 | Familial hypercholesterolemia or high risk CVD patients | TC | Need regular injection | 108, 109 |
ISIS 304801 | Antisense inhibition ApoC-Ⅲ | TG reduction 31.3-70.9% Under clinical trial | TG | Need regular injection | 62, 63 |
CP-346086 | MTP inhibitor | Underdevelopment | TG | 110, 111 | |
JTT-130 | |||||
Ginko biloba | Lipoprotein(a) synthesis inhibition |
Supplementary use | TC | 114-117 | |
Tocilizumab | IL6 inhibition | Patients for rheumatoid arthritis | TC | 118-121 | |
Torcetrapib Anacetrapib, Evacetrapib |
CETP inhibitor | Underdevelopment (anacetrapib, evacetrapib) |
TC | Blood pressure and bserum aldosterone increased | 122 |
List of the drugs for hyperlipidemia in diabetes mellitus. Only Statin, Fibrate, Ezetimibe and Evolocumabhave already widely in clinical use. TC: total cholesterol; TG: triglyceride; CVD: cardiovascular disease; CK: creatinine kinase; GI: gastro intestinal tract. |
Long-term blood glucose control can prevent the onset of microvascular complications such as diabetic nephropathy and diabetic retinopathy, as well as inhibit the worsening of microvascular complications. Strict blood glucose control per se, however, cannot reduce the incidence of the onset of cardiovascular disease[103].However, a large number of evidence showed that lipidimproving drugs, especially cholesterol-lowering, can achieve cardiovascular disease prevention[5, 104-105].
Although cardiovascular prevention studies suggests that both statins and fibrate can improve lipid profiles, a clear clinical evidence that treatments focusing on postprandial triglyceride rise can prevent cardiovascular disease remains to be established[106]. Currently, there is no new agent specifically effective for postprandial excursion of triglycerides. The combination therapy of fibrate and statin for total serum lipid profile improvement has been studied. The effectiveness of statins in the prevention of cardiovascular diseases has been widely recognized. Studies examining the lipid improvement effect of fibrates have demonstrated that reduction in frequency of cardiovascular diseaseas compare with control group[107].
The results of epidemiological studies conducted in Japan indicate that the triglyceride levels, along with the blood glucose level, are significant cardiovascular risk factors in Japanese diabetic patients[4]. However, despite management of triglyceride level is important in patients with T2D, evidence on the effectiveness of management standards and drug therapy is scarce.
Type Ⅱb dyslipidemia, a combination of hypercholesterolemia and hypertriglyceridemia, has been treated with statin in conjunction with lifestyle modification. Combination therapy of fibrates and statins has not been widely used in general clinical situation because of the risk of rhabdomyolysis or elevation of serum creatin kinase.
Recently, new approaches that target the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been developed to increase the removal of atherogenic lipoproteins from plasma[108]. The PCSK9 inhibitor (e.g. evolocumab) can markedly reduce serum LDL cholesterol concentrations. No severe adverse event has occurred in the clinical trial of evolocumab therapy. But there is the necessity of subcutaneous injection of evolocumab every 1-2 weeks[109].
New type of intervention using antisense inhibition of apoC-Ⅲ is effective for reduction of serum triglyceride level from 31.3% to 70.9% in a dose-dependent manner[63-64].
Other agents are under development, such as inhibition of the synthesis of apo B, inhibition of MTP[110-111], inhibition of adenosine triphosphate citrate lyase to inhibit the synthesis of cholesterol[112-113], inhibition of the synthesis of lipoprotein(a) by inhibition of Interleukin-6 (IL-6) signaling with natural compounds (e.g. Ginko biloba)[114-117] or the IL-6 receptor antibody Tocilizumab[118-121].
Inhibition of cholesteryl ester transfer protein (CETP) has the potential of reduction of serum lipid level[122]. These agents are developed for general dyslipidemia patients and not for specific dyslipidemia patients with diabetes, nor are they developed for postprandial hyperlipidemia patients.
Agents that target at the stage of gluconeogenesis and glycolysis in the liver have been developed as new antidiabetic drugs. Many of them (e.g. sulfonylurea, biguanide) show effects on reducing the fasting blood glucose level. However, whether or not they specifically suppress postprandial hyperglycemia is not clear. Some of the agents (e.g. thiazolidinedione) are also associated with triglyceride metabolism, thus improving effect on postprandial hyperlipidemia is expected. The antidiabetic agents act upon one of the three aspects in the liver: (ⅰ) glucose metabolism, (ⅱ) pyruvate flux[123], and (ⅲ) gluconeogenesis enzymes. The compounds under development, yet not in clinical use, for modulating liver glucose metabolism include activator of glucokinase[124-125], inhibitors of FBPase[126], inhibitor of PTP-1B[127], inhibitors of glycogen phosphorylase[128-129], and glucagon receptor antagonist[130]. Glucagon receptor antagonists lead to a blood sugar lowering effect by suppressing excessive glucagon secretion in T2D. There is a possibility that glucagon receptor antagonists can suppress postprandial hyperglycemia.
Insulin has been found to decrease hepatic glucose production by suppressing pyruvate flux through inhibition of adipose lipolysis[131].
Pyruvate carboxylase inhibition is one the targets of reduce hyperglycemia. Experimental model of the diabetic rats resulted in lowered blood glucose level and rates of gluconeogenesis. It also revealed decreased adiposity and hepatic steatosis[123].
Another approach to inhibit pyruvate flux is blocking pyruvate transport across the inner mitochondrial membrane into the mitochondrial matrix, which is facilitated by the transport complex composed of mitochondrial pyruvate carrier 1 (MPC1) and MPC2. The MPC inhibitor UK-5099 can suppress glucose production in primary hepatocytes and increase glucose uptake in myocytes.[132-133]
Targeting gluconeogenesis enzyme, such as phosphoenolpyruvate carboxylase (PEPCK) and glucose-6- phosphatase (G6Pase), is another approach to reduce blood glucose level. Pyruvate is converted to oxaloacetate by pyruvate carboxylase in mitochondria. PEPCK catalyzes conversion of oxaloacetate to phosphoenolpyruvate (PEP) in cytosol. Gluconeogenesis substrates include lactate (which is changed to pyruvate by lactate dehydrogenase) and amino acids. Glycerol can also enter gluconeogenesis pathway through conversion to fructose-1, 6-bisphosphate. PEP is converted into fructose- 1, 6-bisphosphate, which is then converted into fructose- 6-phosphate (catalyzed by fructose-1, 6-biphosphatase (FBPase)) and subsequently into glucose-6-phosphate (catalyzed by phosphohexose isomerase). G6Pase catalyzes the conversion of glucose-6-phosphate to glucose. PEPCK expression is dysregulated and increased in diabetes. PEPCK is the rate-limiting enzyme for gluconeogenesis and has been implicated as a potential target to reduce blood glucose level. 3-mercaptopicolonic acid inhibits PEPCK and results in hypoglycemia[134]. But patients with T2D do not have elevation in liver PEPCK and G6Pase. Therefore, achieving a complete inhibition of PEPCK or G6Pase per se may not be sufficient to reduce blood glucose levels.
Targeting transcriptional factors and co-activators (e. g. PCG1-α, FOXO, and CREB) could potentially be an effective method for treatments T2D. For example, FOXO proteins have been shown to regulate hepatic lipid metabolism. However, transcription factors are frequently found in multiprotein complexes, and designing small molecules that potently change the activity of these multi-protein complexes can be difficult. Nevertheless, direct FOXO1 inhibition was successful in decreasing fasting blood glucose and triglyceride levels in db/db mice[135]. Thus, modification of transcriptional factors and co-activators is very attractive as pharmacological interventions may achieve both blood glucose level control and lipid profile improvement in T2D patients. However, for clinical use, it is necessary to establish hepatic specificity of these interventions, because these transcriptional factors and co-activators are also involved in many other processes in different cells and tissues.
Another strategy for controlling glucose metabolism in the liver is enhancing glucose utilization through mitochondrial uncoupling that dissipates the proton gradient across the mitochondrial inner membrane. The uncoupling compounds, such as 2, 4-dinitrophenol (DNP), have been developed and tested in animal models. Administration of DNP to diabetic rats decreased fasting plasma levels of glucose, triglycerides, and insulin[136]. Controlled-release mitochondrial protonophore (CRMP) is an orally available version of DNP, which has been shown to effectively lower plasma glucose, triglycerides and insulin in wild type or Zucker diabetic fatty rats fed a high-fat diet[137].
The aforementioned compounds all have the potential to reduce blood glucose and/or triglyceride levels in an experimental setting. However, it remains to be determined whether these substances are effective for suppressing postprandial level of blood glucose or triglycerides.
For patients with insulin resistant status such as obesity and metabolic syndrome, partial agonist for adiponectin receptor is probably effective to suppress postprandial hyperglycemia. AdipoRon (adiponectin receptor agonist) is a small molecular compound that binds to adipoR1 and adipoR2 receptor at a low micromolar concentration[138-140]. Like adiponectin, adipoRon activates 5′-adenosine monophosphate-activated protein kinase (AMPK) in cultured mammalian cells, an enzyme that is involved in many metabolic processes including release of insulin, inhibition of lipid synthesis, and stimulation of glucose uptake. AdipoRon also activates the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α), which boosts mitochondrial proliferation and energy metabolism. These effects are probably useful for improvement in both glucose metabolism and lipid metabolism.
Postprandial hyperglycemia and postprandial hypertriglyceridemia are both contributors to atherosclerotic change of vessels especially in T2D patients, the process mediated by oxidative stress and inflammatory change of adipose tissue, liver and vascular wall. One of the key substrates is free fatty acid in adipose tissue. Deposition of excess fat in adipose tissue depends on over-nutrition and sedentary life style in contemporary civilized situation, which creates a vicious cycle of hyperglycemia and hypertriglyceridemia in postprandial state. Specialized therapeutic approaches of postprandial hyperglycemia and hyperlipidemia have not been sufficient to reduce risk of cardiovascular event and other complication of T2D patients. New types of pharmacological agents are essential to the resolution of this clinical problem.
None.
This work was supported by the National Key Research and Development Program of China (Grant No. 2022YFA1303900 to S.Y.), the National Natural Science Foundation of China (Grant Nos. 32270921 and 82070567 to S.Y., and 82204354 to Y.H.), the Open Project of State Key Laboratory of Reproductive Medicine of Nanjing Medical University (Grant No. SKLRM-2021B3 to S.Y.), the Talent Cultivation Project of "Organized Scientific Research" of Nanjing Medical University (Grant No. NJMURC20220014 to S.Y.), the Natural Science Foundation of Jiangsu Province (Grant No. BK20221352 to B.W.), the Jiangsu Provincial Outstanding Postdoctoral Program (Grant No. 2022ZB419 to Y.H.) and the Postdoctoral Research Funding Project of Gusu School (Grant No. GSBSHKY202104 to Y.H.), and the China Postdoctoral Science Foundation (Grant No. 2023T160329 to Y.H.).
CLC number: R329.25, Document code: A
The authors reported no conflict of interests.
[1] |
Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060–1072. doi: 10.1016/j.cell.2012.03.042
|
[2] |
Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells[J]. Chem Biol, 2008, 15(3): 234–245. doi: 10.1016/j.chembiol.2008.02.010
|
[3] |
Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer[J]. Nat Rev Cancer, 2022, 22(7): 381–396. doi: 10.1038/s41568-022-00459-0
|
[4] |
Reichert CO, de Freitas FA, Sampaio-Silva J, et al. Ferroptosis mechanisms involved in neurodegenerative diseases[J]. Int J Mol Sci, 2020, 21(22): 8765. doi: 10.3390/ijms21228765
|
[5] |
Ni L, Yuan C, Wu X. Targeting ferroptosis in acute kidney injury[J]. Cell Death Dis, 2022, 13(2): 182. doi: 10.1038/s41419-022-04628-9
|
[6] |
Tang D, Chen X, Kang R, et al. Ferroptosis: molecular mechanisms and health implications[J]. Cell Res, 2021, 31(2): 107–125. doi: 10.1038/s41422-020-00441-1
|
[7] |
Wang Y, Liu Y, Liu J, et al. NEDD4L-mediated LTF protein degradation limits ferroptosis[J]. Biochem Biophys Res Commun, 2020, 531(4): 581–587. doi: 10.1016/j.bbrc.2020.07.032
|
[8] |
Dolma S, Lessnick SL, Hahn WC, et al. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells[J]. Cancer Cell, 2003, 3(3): 285–296. doi: 10.1016/S1535-6108(03)00050-3
|
[9] |
Yang WS, Kim KJ, Gaschler MM, et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis[J]. Proc Natl Acad Sci U S A, 2016, 113(34): E4966–E4975. doi: 10.1073/pnas.1603244113
|
[10] |
Chen X, Kang R, Kroemer G, et al. Ferroptosis in infection, inflammation, and immunity[J]. J Exp Med, 2021, 218(6): e20210518. doi: 10.1084/jem.20210518
|
[11] |
Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk[J]. Cell Death Differ, 2019, 26(1): 99–114. doi: 10.1038/s41418-018-0212-6
|
[12] |
Bertheloot D, Latz E, Franklin BS. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death[J]. Cell Mol Immunol, 2021, 18(5): 1106–1121. doi: 10.1038/s41423-020-00630-3
|
[13] |
Chen X, Comish PB, Tang D, et al. Characteristics and biomarkers of ferroptosis[J]. Front Cell Dev Biol, 2021, 9: 637162. doi: 10.3389/fcell.2021.637162
|
[14] |
Xie Y, Hou W, Song X, et al. Ferroptosis: process and function[J]. Cell Death Differ, 2016, 23(3): 369–379. doi: 10.1038/cdd.2015.158
|
[15] |
Cui S, Ghai A, Deng Y, et al. Identification of hyperoxidized PRDX3 as a ferroptosis marker reveals ferroptotic damage in chronic liver diseases[J]. Mol Cell, 2023, 83(21): 3931–3939.e5. doi: 10.1016/j.molcel.2023.09.025
|
[16] |
Friedmann Angeli JP, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice[J]. Nat Cell Biol, 2014, 16(12): 1180–1191. doi: 10.1038/ncb3064
|
[17] |
Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor[J]. Nature, 2019, 575(7784): 693–698. doi: 10.1038/s41586-019-1707-0
|
[18] |
Mao C, Liu X, Zhang Y, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer[J]. Nature, 2021, 593(7860): 586–590. doi: 10.1038/s41586-021-03539-7
|
[19] |
Soula M, Weber RA, Zilka O, et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers[J]. Nat Chem Biol, 2020, 16(12): 1351–1360. doi: 10.1038/s41589-020-0613-y
|
[20] |
Wang Y, Wei Z, Pan K, et al. The function and mechanism of ferroptosis in cancer[J]. Apoptosis, 2020, 25(11-12): 786–798. doi: 10.1007/s10495-020-01638-w
|
[21] |
Vila IK, Chamma H, Steer A, et al. STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses[J]. Cell Metab, 2022, 34(1): 125–139.e8. doi: 10.1016/j.cmet.2021.12.007
|
[22] |
Yu X, Zhu D, Luo B, et al. IFNγ enhances ferroptosis by increasing JAK-STAT pathway activation to suppress SLCA711 expression in adrenocortical carcinoma[J]. Oncol Rep, 2022, 47(5): 97. doi: 10.3892/or.2022.8308
|
[23] |
Wei T, Zhang M, Zheng X, et al. Interferon-γ induces retinal pigment epithelial cell Ferroptosis by a JAK1-2/STAT1/SLC7A11 signaling pathway in Age-related Macular Degeneration[J]. FEBS J, 2022, 289(7): 1968–1983. doi: 10.1111/febs.16272
|
[24] |
Song SH, Han D, Park K, et al. Bone morphogenetic protein-7 attenuates pancreatic damage under diabetic conditions and prevents progression to diabetic nephropathy via inhibition of ferroptosis[J]. Front Endocrinol, 2023, 14: 1172199. doi: 10.3389/fendo.2023.1172199
|
[25] |
Louandre C, Ezzoukhry Z, Godin C, et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib[J]. Int J Cancer, 2013, 133(7): 1732–1742. doi: 10.1002/ijc.28159
|
[26] |
Lachaier E, Louandre C, Godin C, et al. Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors[J]. Anticancer Res, 2014, 34(11): 6417–6422. https://ar.iiarjournals.org/content/34/11/6417.long
|
[27] |
Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J]. Hepatology, 2016, 63(1): 173–184. doi: 10.1002/hep.28251
|
[28] |
Chen D, Fan Z, Rauh M, et al. ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner[J]. Oncogene, 2017, 36(40): 5593–5608. doi: 10.1038/onc.2017.146
|
[29] |
Lu Y, Qin H, Jiang B, et al. KLF2 inhibits cancer cell migration and invasion by regulating ferroptosis through GPX4 in clear cell renal cell carcinoma[J]. Cancer Lett, 2021, 522: 1–13. doi: 10.1016/j.canlet.2021.09.014
|
[30] |
Duce JA, Tsatsanis A, Cater MA, et al. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease[J]. Cell, 2010, 142(6): 857–867. doi: 10.1016/j.cell.2010.08.014
|
[31] |
Bao W, Pang P, Zhou X, et al. Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer's disease[J]. Cell Death Differ, 2021, 28(5): 1548–1562. doi: 10.1038/s41418-020-00685-9
|
[32] |
Mahoney-Sánchez L, Bouchaoui H, Ayton S, et al. Ferroptosis and its potential role in the physiopathology of Parkinson's disease[J]. Prog Neurobiol, 2021, 196: 101890. doi: 10.1016/j.pneurobio.2020.101890
|
[33] |
Xu M, Tao J, Yang Y, et al. Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis[J]. Cell Death Dis, 2020, 11(2): 86. doi: 10.1038/s41419-020-2299-1
|
[34] |
Xu J, Liu S, Cui Z, et al. Ferrostatin-1 alleviated TNBS induced colitis via the inhibition of ferroptosis[J]. Biochem Biophys Res Commun, 2021, 573: 48–54. doi: 10.1016/j.bbrc.2021.08.018
|
[35] |
Shou Y, Yang L, Yang Y, et al. Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation[J]. Cell Death Dis, 2021, 12(11): 1009. doi: 10.1038/s41419-021-04284-5
|
[36] |
Li P, Jiang M, Li K, et al. Glutathione peroxidase 4–regulated neutrophil ferroptosis induces systemic autoimmunity[J]. Nat Immunol, 2021, 22(9): 1107–1117. doi: 10.1038/s41590-021-00993-3
|
[37] |
Cheng Y, Song Y, Chen H, et al. Ferroptosis mediated by lipid reactive oxygen species: a possible causal link of neuroinflammation to neurological disorders[J]. Oxid Med Cell Longev, 2021, 2021: 5005136. https://www.hindawi.com/journals/omcl/2021/5005136/
|
[38] |
Kirtonia A, Sethi G, Garg M. The multifaceted role of reactive oxygen species in tumorigenesis[J]. Cell Mol Life Sci, 2020, 77(22): 4459–4483. doi: 10.1007/s00018-020-03536-5
|
[39] |
Yan B, Ai Y, Sun Q, et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1[J]. Mol cell, 2021, 81(2): 355–369.e10. doi: 10.1016/j.molcel.2020.11.024
|
[40] |
Zhang C, Zhang F. Iron homeostasis and tumorigenesis: molecular mechanisms and therapeutic opportunities[J]. Protein Cell, 2015, 6(2): 88–100. doi: 10.1007/s13238-014-0119-z
|
[41] |
Wang Y, Yu L, Ding J, et al. Iron metabolism in cancer[J]. Int J Mol Sci, 2018, 20(1): 95. doi: 10.3390/ijms20010095
|
[42] |
Mancias JD, Wang X, Gygi SP, et al. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy[J]. Nature, 2014, 509(7498): 105–109. doi: 10.1038/nature13148
|
[43] |
Gao M, Monian P, Pan Q, et al. Ferroptosis is an autophagic cell death process[J]. Cell Res, 2016, 26(9): 1021–1032. doi: 10.1038/cr.2016.95
|
[44] |
Hou W, Xie Y, Song X, et al. Autophagy promotes ferroptosis by degradation of ferritin[J]. Autophagy, 2016, 12(8): 1425–1428. doi: 10.1080/15548627.2016.1187366
|
[45] |
Liu Z, Lv X, Yang B, et al. Tetrachlorobenzoquinone exposure triggers ferroptosis contributing to its neurotoxicity[J]. Chemosphere, 2021, 264: 128413. doi: 10.1016/j.chemosphere.2020.128413
|
[46] |
Ingold I, Berndt C, Schmitt S, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis[J]. Cell, 2018, 172(3): 409–422.e21. doi: 10.1016/j.cell.2017.11.048
|
[47] |
Angeli JPF, Conrad M. Selenium and GPX4, a vital symbiosis[J]. Free Radical Biol Med, 2018, 127: 153–159. doi: 10.1016/j.freeradbiomed.2018.03.001
|
[48] |
Ursini F, Maiorino M. Lipid peroxidation and ferroptosis: the role of GSH and GPx4[J]. Free Radical Biol Med, 2020, 152: 175–185. doi: 10.1016/j.freeradbiomed.2020.02.027
|
[49] |
Griffith OW. Biologic and pharmacologic regulation of mammalian glutathione synthesis[J]. Free Radical Biol Med, 1999, 27(9-10): 922–935. doi: 10.1016/S0891-5849(99)00176-8
|
[50] |
Griffith OW, Mulcahy RT. The enzymes of glutathione synthesis: γ-glutamylcysteine synthetase[M]//Purich DL. Advances in Enzymology and Related Areas of Molecular Biology: Mechanism of Enzyme Action, Part A. New York: Wiley, 1999: 209–267.
|
[51] |
Hao S, Liang B, Huang Q, et al. Metabolic networks in ferroptosis[J]. Oncol Lett, 2018, 15(4): 5405–5411. doi: 10.3892/ol.2018.8066
|
[52] |
Liu L, Liu R, Liu Y, et al. Cystine-glutamate antiporter xCT as a therapeutic target for cancer[J]. Cell Biochem Funct, 2021, 39(2): 174–179. doi: 10.1002/cbf.3581
|
[53] |
Liu M, Zhu W, Pei D. System Xc−: a key regulatory target of ferroptosis in cancer[J]. Invest New Drugs, 2021, 39(4): 1123–1131. doi: 10.1007/s10637-021-01070-0
|
[54] |
Lin Z, Liu J, Long F, et al. The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis[J]. Nat Commun, 2022, 13(1): 7965. doi: 10.1038/s41467-022-35707-2
|
[55] |
Vasan K, Werner M, Chandel NS. Mitochondrial metabolism as a target for cancer therapy[J]. Cell Metab, 2020, 32(3): 341–352. doi: 10.1016/j.cmet.2020.06.019
|
[56] |
Mishima E, Nakamura T, Zheng J, et al. DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition[J]. Nature, 2023, 619(7968): E9–E18. doi: 10.1038/s41586-023-06269-0
|
[57] |
Crabtree MJ, Tatham AL, Hale AB, et al. Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways[J]. J Biol Chem, 2009, 284(41): 28128–28136. doi: 10.1074/jbc.M109.041483
|
[58] |
Kraft VAN, Bezjian CT, Pfeiffer S, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling[J]. ACS Cent Sci, 2019, 6(1): 41–53. doi: 10.1021/acscentsci.9b01063
|
[59] |
Dodson M, Castro-Portuguez R, Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis[J]. Redox Biol, 2019, 23: 101107. doi: 10.1016/j.redox.2019.101107
|
[60] |
Anandhan A, Dodson M, Schmidlin CJ, et al. Breakdown of an ironclad defense system: the critical role of NRF2 in mediating ferroptosis[J]. Cell Chem Biol, 2020, 27(4): 436–447. doi: 10.1016/j.chembiol.2020.03.011
|
[61] |
Hassannia B, Wiernicki B, Ingold I, et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma[J]. J Clin Invest, 2018, 128(8): 3341–3355. doi: 10.1172/JCI99032
|
[62] |
Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal[J]. Oxid Med Cell Longev, 2014, 2014: 360438. https://www.hindawi.com/journals/omcl/2014/360438/
|
[63] |
Lee JY, Nam M, Son HY, et al. Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer[J]. Proc Natl Acad Sci U S A, 2020, 117(51): 32433–32442. doi: 10.1073/pnas.2006828117
|
[64] |
Yamane D, Hayashi Y, Matsumoto M, et al. FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication[J]. Cell Chem Biol, 2022, 29(5): 799–810.e4. doi: 10.1016/j.chembiol.2021.07.022
|
[65] |
Nassar ZD, Mah CY, Dehairs J, et al. Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis[J]. Elife, 2020, 9: e54166. doi: 10.7554/eLife.54166
|
[66] |
Magtanong L, Ko PJ, To M, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state[J]. Cell Chem Biol, 2019, 26(3): 420–432.e9. doi: 10.1016/j.chembiol.2018.11.016
|
[67] |
Liang D, Feng Y, Zandkarimi F, et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones[J]. Cell, 2023, 186(13): 2748–2764.e22. doi: 10.1016/j.cell.2023.05.003
|
[68] |
Küch EM, Vellaramkalayil R, Zhang I, et al. Differentially localized acyl-CoA synthetase 4 isoenzymes mediate the metabolic channeling of fatty acids towards phosphatidylinositol[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2014, 1841(2): 227–239. doi: 10.1016/j.bbalip.2013.10.018
|
[69] |
Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition[J]. Nat Chem Biol, 2017, 13(1): 91–98. doi: 10.1038/nchembio.2239
|
[70] |
Kagan VE, Mao G, Qu F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis[J]. Nat Chem Biol, 2017, 13(1): 81–90. doi: 10.1038/nchembio.2238
|
[71] |
Zhang H, Hu B, Li Z, et al. PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis[J]. Nat cell Biol, 2022, 24(1): 88–98. doi: 10.1038/s41556-021-00818-3
|
[72] |
Conrad M, Pratt DA. The chemical basis of ferroptosis[J]. Nat Chem Biol, 2019, 15(12): 1137–1147. doi: 10.1038/s41589-019-0408-1
|
[73] |
Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease[J]. Nat Rev Mol Cell Biol, 2021, 22(4): 266–282. doi: 10.1038/s41580-020-00324-8
|
[74] |
Singh NK, Rao GN. Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies[J]. Prog Lipid Res, 2019, 73: 28–45. doi: 10.1016/j.plipres.2018.11.001
|
[75] |
Wenzel S E, Tyurina Y Y, Zhao J, et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals[J]. Cell, 2017, 173(3): 628–641.e26. doi: 10.1016/j.cell.2017.09.044
|
[76] |
Tschuck J, Theilacker L, Rothenaigner I, et al. Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis[J]. Nat Commun, 2023, 14(1): 6908. doi: 10.1038/s41467-023-42702-8
|
[77] |
Ablasser A, Goldeck M, Cavlar T, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING[J]. Nature, 2013, 498(7454): 380–384. doi: 10.1038/nature12306
|
[78] |
Sun L, Wu J, Du F, et al. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway[J]. Science, 2013, 339(6121): 786–791. doi: 10.1126/science.1232458
|
[79] |
Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGAS–STING signalling[J]. Nat Rev Mol Cell Biol, 2020, 21(9): 501–521. doi: 10.1038/s41580-020-0244-x
|
[80] |
Cheng Z, Dai T, He X, et al. The interactions between cGAS-STING pathway and pathogens[J]. Signal Transduct Target Ther, 2020, 5(1): 91. doi: 10.1038/s41392-020-0198-7
|
[81] |
Jia M, Qin D, Zhao C, et al. Redox homeostasis maintained by GPX4 facilitates STING activation[J]. Nat Immunol, 2020, 21(7): 727–735. doi: 10.1038/s41590-020-0699-0
|
[82] |
Li C, Liu J, Hou W, et al. STING1 promotes ferroptosis through MFN1/2-dependent mitochondrial fusion[J]. Front Cell Dev Biol, 2021, 9: 698679. doi: 10.3389/fcell.2021.698679
|
[83] |
Santel A, Fuller MT. Control of mitochondrial morphology by a human mitofusin[J]. J Cell Sci, 2001, 114(5): 867–874. doi: 10.1242/jcs.114.5.867
|
[84] |
Qiu S, Zhong X, Meng X, et al. Mitochondria-localized cGAS suppresses ferroptosis to promote cancer progression[J]. Cell Res, 2023, 33(4): 299–311. doi: 10.1038/s41422-023-00788-1
|
[85] |
Fonseca TB, Sánchez-Guerrero Á, Milosevic I, et al. Mitochondrial fission requires DRP1 but not dynamins[J]. Nature, 2019, 570(7761): E34–E42. doi: 10.1038/s41586-019-1296-y
|
[86] |
Wang W, Green M, Choi JE, et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy[J]. Nature, 2019, 569(7755): 270–274. doi: 10.1038/s41586-019-1170-y
|
[87] |
Kong R, Wang N, Han W, et al. IFNγ-mediated repression of system xc− drives vulnerability to induced ferroptosis in hepatocellular carcinoma cells[J]. J Leukoc Biol, 2021, 110(2): 301–314. doi: 10.1002/JLB.3MA1220-815RRR
|
[88] |
Liau NPD, Laktyushin A, Lucet IS, et al. The molecular basis of JAK/STAT inhibition by SOCS1[J]. Nat Commun, 2018, 9(1): 1558. doi: 10.1038/s41467-018-04013-1
|
[89] |
Saint-Germain E, Mignacca L, Vernier M, et al. SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes[J]. Aging (Albany NY), 2017, 9(10): 2137–2162. https://www.aging-us.com/article/101306/text
|
[90] |
Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression[J]. Nature, 2015, 520(7545): 57–62. doi: 10.1038/nature14344
|
[91] |
Chu B, Kon N, Chen D, et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway[J]. Nat Cell Biol, 2019, 21(5): 579–591. doi: 10.1038/s41556-019-0305-6
|
[92] |
Dituri F, Mancarella S, Cigliano A, et al. TGF-β as multifaceted orchestrator in HCC progression: signaling, EMT, immune microenvironment, and novel therapeutic perspectives[J]. Semin Liver Dis, 2019, 39(1): 53–69. doi: 10.1055/s-0038-1676121
|
[93] |
Bachman KE, Park BH. Duel nature of TGF-β signaling: tumor suppressor vs. tumor promoter[J]. Curr Opin Oncol, 2005, 17(1): 49–54. doi: 10.1097/01.cco.0000143682.45316.ae
|
[94] |
Kim DH, Kim WD, Kim SK, et al. TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells[J]. Cell Death Dis, 2020, 11(5): 406. doi: 10.1038/s41419-020-2618-6
|
[95] |
Pedrera L, Espiritu RA, Ros U, et al. Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics[J]. Cell Death Differ, 2021, 28(5): 1644–1657. doi: 10.1038/s41418-020-00691-x
|
[96] |
Zhu Y, Zheng B, Wang H, et al. New knowledge of the mechanisms of sorafenib resistance in liver cancer[J]. Acta Pharmacol Sin, 2017, 38(5): 614–622. doi: 10.1038/aps.2017.5
|
[97] |
Lee SY. Temozolomide resistance in glioblastoma multiforme[J]. Genes Dis, 2016, 3(3): 198–210. doi: 10.1016/j.gendis.2016.04.007
|
[98] |
Sehm T, Rauh M, Wiendieck K, et al. Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis[J]. Oncotarget, 2016, 7(46): 74630–74647. doi: 10.18632/oncotarget.11858
|
[99] |
Koppula P, Zhang Y, Zhuang L, et al. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer[J]. Cancer Commun, 2018, 38(1): 12. doi: 10.1186/s40880-018-0288-x
|
[100] |
Rohr-Udilova N, Bauer E, Timelthaler G, et al. Impact of glutathione peroxidase 4 on cell proliferation, angiogenesis and cytokine production in hepatocellular carcinoma[J]. Oncotarget, 2018, 9(11): 10054–10068. doi: 10.18632/oncotarget.24300
|
[101] |
Chen H, Peng F, Xu J, et al. Increased expression of GPX4 promotes the tumorigenesis of thyroid cancer by inhibiting ferroptosis and predicts poor clinical outcomes[J]. Aging (Albany NY), 2023, 15(1): 230–245. https://www.aging-us.com/article/204473/text
|
[102] |
Jones TD, Eble JN, Wang M, et al. Molecular genetic evidence for the independent origin of multifocal papillary tumors in patients with papillary renal cell carcinomas[J]. Clin Cancer Res, 2005, 11(20): 7226–7233. doi: 10.1158/1078-0432.CCR-04-2597
|
[103] |
Xu F, Guan Y, Xue L, et al. The roles of ferroptosis regulatory gene SLC7A11 in renal cell carcinoma: a multi-omics study[J]. Cancer Med, 2021, 10(24): 9078–9096. doi: 10.1002/cam4.4395
|
[104] |
Yu H, Han Z, Xu Z, et al. RNA sequencing uncovers the key long non-coding RNAs and potential molecular mechanism contributing to XAV939-mediated inhibition of non-small cell lung cancer[J]. Oncol Lett, 2019, 17(6): 4994–5004. doi: 10.3892/ol.2019.10191
|
[105] |
Wu H, Liu A. Long non-coding RNA NEAT1 regulates ferroptosis sensitivity in non-small-cell lung cancer[J]. J Int Med Res, 2021, 49(3): 300060521996183. doi: 10.1177/0300060521996183
|
[106] |
Rysman E, Brusselmans K, Scheys K, et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation[J]. Cancer Res, 2010, 70(20): 8117–8126. doi: 10.1158/0008-5472.CAN-09-3871
|
[107] |
King ME, Yuan R, Chen J, et al. Long-chain polyunsaturated lipids associated with responsiveness to anti-PD-1 therapy are colocalized with immune infiltrates in the tumor microenvironment[J]. J Biol Chem, 2023, 299(3): 102902. doi: 10.1016/j.jbc.2023.102902
|
[108] |
Liao P, Wang W, Wang W, et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4[J]. Cancer Cell, 2022, 40(4): 365–378.e6. doi: 10.1016/j.ccell.2022.02.003
|
[109] |
Xue Y, Lu F, Chang Z, et al. Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade[J]. Nat Commun, 2023, 14(1): 4758. doi: 10.1038/s41467-023-40518-0
|
[110] |
Castellani RJ, Plascencia-Villa G, Perry G. The amyloid cascade and Alzheimer's disease therapeutics: theory versus observation[J]. Lab Invest, 2019, 99(7): 958–970. doi: 10.1038/s41374-019-0231-z
|
[111] |
Butterfield DA, Boyd-Kimball D. Oxidative stress, amyloid-β peptide, and altered key molecular pathways in the pathogenesis and progression of Alzheimer's disease[J]. J Alzheimer's Dis, 2018, 62(3): 1345–1367. doi: 10.3233/JAD-170543
|
[112] |
Galante D, Cavallo E, Perico A, et al. Effect of ferric citrate on amyloid-beta peptides behavior[J]. Biopolymers, 2018, 109(6): e23224. doi: 10.1002/bip.23224
|
[113] |
Kalia LV, Lang AE. Parkinson's disease[J]. Lancet, 2015, 386(9996): 896–912. doi: 10.1016/S0140-6736(14)61393-3
|
[114] |
Oñate M, Catenaccio A, Salvadores N, et al. The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease[J]. Cell Death Differ, 2020, 27(4): 1169–1185. doi: 10.1038/s41418-019-0408-4
|
[115] |
Wang B, Ma Y, Li S, et al. GSDMD in peripheral myeloid cells regulates microglial immune training and neuroinflammation in Parkinson's disease[J]. Acta Pharm Sin B, 2023, 13(6): 2663–2679. doi: 10.1016/j.apsb.2023.04.008
|
[116] |
Ward RJ, Zucca FA, Duyn JH, et al. The role of iron in brain ageing and neurodegenerative disorders[J]. Lancet Neurol, 2014, 13(10): 1045–1060. doi: 10.1016/S1474-4422(14)70117-6
|
[117] |
Thomas GEC, Leyland LA, Schrag AE, et al. Brain iron deposition is linked with cognitive severity in Parkinson's disease[J]. J Neurol Neurosurg Psychiatry, 2020, 91(4): 418–425. doi: 10.1136/jnnp-2019-322042
|
[118] |
Devos D, Moreau C, Devedjian JC, et al. Targeting chelatable iron as a therapeutic modality in Parkinson's disease[J]. Antioxid Redox Signal, 2014, 21(2): 195–210. doi: 10.1089/ars.2013.5593
|
[119] |
Hu C, Nydes M, Shanley KL, et al. Reduced expression of the ferroptosis inhibitor glutathione peroxidase-4 in multiple sclerosis and experimental autoimmune encephalomyelitis[J]. J Neurochem, 2019, 148(3): 426–439. doi: 10.1111/jnc.14604
|
[120] |
Baranovicova E, Kantorova E, Kalenska D, et al. Thalamic paramagnetic iron by T2* relaxometry correlates with severity of multiple sclerosis[J]. J Biomed Res, 2017, 31(4): 301–305. doi: 10.7555/JBR.31.20160023
|
[121] |
Luoqian J, Yang W, Ding X, et al. Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis[J]. Cell Mol Immunol, 2022, 19(8): 913–924. doi: 10.1038/s41423-022-00883-0
|
[122] |
Weiland A, Wang Y, Wu W, et al. Ferroptosis and its role in diverse brain diseases[J]. Mol Neurobiol, 2019, 56(7): 4880–4893. doi: 10.1007/s12035-018-1403-3
|
[123] |
Skouta R, Dixon SJ, Wang J, et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models[J]. J Am Chem Soc, 2014, 136(12): 4551–4556. doi: 10.1021/ja411006a
|
[124] |
Jiang Y, Ma C, Hu Y, et al. ECSIT is a critical factor for controlling intestinal homeostasis and tumorigenesis through regulating the translation of YAP protein[J]. Adv Sci, 2023, 10(25): 2205180. doi: 10.1002/advs.202205180
|
[125] |
Garrett WS, Gordon JI, Glimcher LH. Homeostasis and inflammation in the intestine[J]. Cell, 2010, 140(6): 859–870. doi: 10.1016/j.cell.2010.01.023
|
[126] |
Bourgonje AR, von Martels JZH, Bulthuis MLC, et al. Crohn's disease in clinical remission is marked by systemic oxidative stress[J]. Front Physiol, 2019, 10: 499. doi: 10.3389/fphys.2019.00499
|
[127] |
Balmus IM, Ciobica A, Trifan A, et al. The implications of oxidative stress and antioxidant therapies in inflammatory bowel disease: clinical aspects and animal models[J]. Saudi J Gastroenterol, 2016, 22(1): 3–17. doi: 10.4103/1319-3767.173753
|
[128] |
Banerjee P, Balraj P, Ambhore NS, et al. Network and co-expression analysis of airway smooth muscle cell transcriptome delineates potential gene signatures in asthma[J]. Sci Rep, 2021, 11(1): 14386. doi: 10.1038/s41598-021-93845-x
|
[129] |
Zhao J, O'Donnell VB, Balzar S, et al. 15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells[J]. Proc Natl Acad Sci U S A, 2011, 108(34): 14246–14251. doi: 10.1073/pnas.1018075108
|
[130] |
Wu Y, Chen H, Xuan N, et al. Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation[J]. Thorax, 2020, 75(11): 918–927. doi: 10.1136/thoraxjnl-2020-214764
|
[131] |
Chen Z, Wang W, Abdul Razak SR, et al. Ferroptosis as a potential target for cancer therapy[J]. Cell Death Dis, 2023, 14(7): 460. doi: 10.1038/s41419-023-05930-w
|
[132] |
Huang K, Wei YH, Chiu YC, et al. Assessment of zero-valent iron-based nanotherapeutics for ferroptosis induction and resensitization strategy in cancer cells[J]. Biomater Sci, 2019, 7(4): 1311–1322. doi: 10.1039/C8BM01525B
|
[133] |
Xu J, Zhang H, Zhang Y, et al. Controllable synthesis of variable-sized magnetic nanocrystals self-assembled into porous nanostructures for enhanced cancer chemo-ferroptosis therapy and MR imaging[J]. Nanoscale Adv, 2022, 4(3): 782–791. doi: 10.1039/D1NA00767J
|
[134] |
Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4[J]. Cell, 2014, 156(1-2): 317–331. doi: 10.1016/j.cell.2013.12.010
|
[135] |
Sui X, Zhang R, Liu S, et al. RSL3 drives ferroptosis through GPX4 inactivation and ROS production in colorectal cancer[J]. Front Pharmacol, 2018, 9: 1371. doi: 10.3389/fphar.2018.01371
|
[136] |
Shimada K, Skouta R, Kaplan A, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis[J]. Nat Chem Biol, 2016, 12(7): 497–503. doi: 10.1038/nchembio.2079
|
[137] |
Zhang X, Guo Y, Li H, et al. FIN56, a novel ferroptosis inducer, triggers lysosomal membrane permeabilization in a TFEB-dependent manner in glioblastoma[J]. J Cancer, 2021, 12(22): 6610–6619. doi: 10.7150/jca.58500
|
[138] |
Zhao Y, Li Y, Zhang R, et al. The role of erastin in ferroptosis and its prospects in cancer therapy[J]. Onco Targets Ther, 2020, 13: 5429–5441. doi: 10.2147/OTT.S254995
|
[139] |
Sato M, Kusumi R, Hamashima S, et al. The ferroptosis inducer erastin irreversibly inhibits system xc− and synergizes with cisplatin to increase cisplatin's cytotoxicity in cancer cells[J]. Sci Rep, 2018, 8(1): 968. doi: 10.1038/s41598-018-19213-4
|
[140] |
Yamaguchi H, Hsu JL, Chen C, et al. Caspase-independent cell death is involved in the negative effect of EGF receptor inhibitors on cisplatin in non–small cell lung cancer cells[J]. Clin Cancer Res, 2013, 19(4): 845–854. doi: 10.1158/1078-0432.CCR-12-2621
|
[141] |
Chen L, Li X, Liu L, et al. Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function[J]. Oncol Rep, 2015, 33(3): 1465–1474. doi: 10.3892/or.2015.3712
|
[142] |
Lo M, Ling V, Low C, et al. Potential use of the anti-inflammatory drug, sulfasalazine, for targeted therapy of pancreatic cancer[J]. Curr Oncol, 2010, 17(3): 9–16. doi: 10.3747/co.v17i3.485
|
[143] |
Tang X, Ding H, Liang M, et al. Curcumin induces ferroptosis in non-small-cell lung cancer via activating autophagy[J]. Thorac Cancer, 2021, 12(8): 1219–1230. doi: 10.1111/1759-7714.13904
|
[144] |
Gai C, Yu M, Li Z, et al. Acetaminophen sensitizing erastin-induced ferroptosis via modulation of Nrf2/heme oxygenase-1 signaling pathway in non-small-cell lung cancer[J]. J Cell Physiol, 2020, 235(4): 3329–3339. doi: 10.1002/jcp.29221
|
[145] |
Nakamura T, Hipp C, Santos Dias Mourão A, et al. Phase separation of FSP1 promotes ferroptosis[J]. Nature, 2023, 619(7969): 371–377. doi: 10.1038/s41586-023-06255-6
|
[146] |
Chu J, Liu C, Song R, et al. Ferrostatin-1 protects HT-22 cells from oxidative toxicity[J]. Neural Regen Res, 2020, 15(3): 528. doi: 10.4103/1673-5374.266060
|
[147] |
Sheng X, Shan C, Liu J, et al. Theoretical insights into the mechanism of ferroptosis suppression via inactivation of a lipid peroxide radical by liproxstatin-1[J]. Phys Chem Chem Phys, 2017, 19(20): 13153–13159. doi: 10.1039/C7CP00804J
|
[148] |
Zilka O, Shah R, Li B, et al. On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death[J]. ACS Cent Sci, 2017, 3(3): 232–243. doi: 10.1021/acscentsci.7b00028
|
[149] |
Deschamps JD, Kenyon VA, Holman TR. Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases[J]. Bioorg Med Chem, 2006, 14(12): 4295–4301. doi: 10.1016/j.bmc.2006.01.057
|
[150] |
Gu X, Xu L, Liu Z, et al. The flavonoid baicalein rescues synaptic plasticity and memory deficits in a mouse model of Alzheimer's disease[J]. Behav Brain Res, 2016, 311: 309–321. doi: 10.1016/j.bbr.2016.05.052
|
[151] |
Li Q, Li Q, Jia J, et al. Baicalein exerts neuroprotective effects in FeCl3-induced posttraumatic epileptic seizures via suppressing ferroptosis[J]. Front Pharmacol, 2019, 10: 638. doi: 10.3389/fphar.2019.00638
|
[152] |
Wan Y, Shen K, Yu H, et al. Baicalein limits osteoarthritis development by inhibiting chondrocyte ferroptosis[J]. Free Radical Biol Med, 2023, 196: 108–120. doi: 10.1016/j.freeradbiomed.2023.01.006
|
[153] |
Liu J, Zhou H, Chen J, et al. Baicalin inhibits IL-1β-induced ferroptosis in human osteoarthritis chondrocytes by activating Nrf-2 signaling pathway[J]. J Orthop Surg Res, 2024, 19(1): 23. doi: 10.1186/s13018-023-04483-0
|
[154] |
Dang R, Wang M, Li X, et al. Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway[J]. J Neuroinflammation, 2022, 19(1): 41. doi: 10.1186/s12974-022-02400-6
|
[155] |
Ni H, Song Y, Wu H, et al. 2-Methyl-5H-benzo [d] pyrazolo [5, 1-b][1, 3] oxazin-5-imine, an edaravone analog, exerts neuroprotective effects against acute ischemic injury via inhibiting oxidative stress[J]. J Biomed Res, 2018, 32(4): 270. doi: 10.7555/JBR.32.20180014
|
[156] |
Li Y, Feng D, Wang Z, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion[J]. Cell Death Differ, 2019, 26(11): 2284–2299. doi: 10.1038/s41418-019-0299-4
|
[157] |
Li Q, Liao J, Chen W, et al. NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway[J]. Free Radical Biol Med, 2022, 187: 158–170. doi: 10.1016/j.freeradbiomed.2022.05.024
|
[158] |
Poggiali E, Cassinerio E, Zanaboni L, et al. An update on iron chelation therapy[J]. Blood Transfus, 2012, 10(4): 411–422. doi: 10.2450/2012.0008-12
|
[159] |
Wu Y, Ran L, Yang Y, et al. Deferasirox alleviates DSS-induced ulcerative colitis in mice by inhibiting ferroptosis and improving intestinal microbiota[J]. Life Sci, 2023, 314: 121312. doi: 10.1016/j.lfs.2022.121312
|
[160] |
Yao X, Zhang Y, Hao J, et al. Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis[J]. Neural Regen Res, 2019, 14(3): 532–541. doi: 10.4103/1673-5374.245480
|
[161] |
Yang W, Mu B, You J, et al. Non-classical ferroptosis inhibition by a small molecule targeting PHB2[J]. Nat Commun, 2022, 13(1): 7473. doi: 10.1038/s41467-022-35294-2
|
[162] |
Grootjans S, Vanden Berghe T, Vandenabeele P. Initiation and execution mechanisms of necroptosis: an overview[J]. Cell Death Differ, 2017, 24(7): 1184–1195. doi: 10.1038/cdd.2017.65
|
[163] |
Cai Z, Jitkaew S, Zhao J, et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis[J]. Nat cell Biol, 2014, 16(1): 55–65. doi: 10.1038/ncb2883
|
[164] |
Fadok VA, Voelker DR, Campbell PA, et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages[J]. J Immunol, 1992, 148(7): 2207–2216. doi: 10.4049/jimmunol.148.7.2207
|
[165] |
Ellis RE, Yuan J, Horvitz HR. Mechanisms and functions of cell death[J]. Annu Rev Cell Biol, 1991, 7: 663–698. doi: 10.1146/annurev.cb.07.110191.003311
|
[166] |
Chen X, He W, Hu L, et al. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis[J]. Cell Res, 2016, 26(9): 1007–1020. doi: 10.1038/cr.2016.100
|
[167] |
Liu X, Zhang Z, Ruan J, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores[J]. Nature, 2016, 535(7610): 153–158. doi: 10.1038/nature18629
|
[168] |
Edinger AL, Thompson CB. Death by design: apoptosis, necrosis and autophagy[J]. Curr Opin Cell Biol, 2004, 16(6): 663–669. doi: 10.1016/j.ceb.2004.09.011
|
[1] | Izzatullo Ziyoyiddin o`g`li Abdullaev, Ulugbek Gapparjanovich Gayibov, Sirojiddin Zoirovich Omonturdiev, Sobirova Fotima Azamjonovna, Sabina Narimanovna Gayibova, Takhir Fatikhovich Aripov. Molecular pathways in cardiovascular disease under hypoxia: Mechanisms, biomarkers, and therapeutic targets[J]. The Journal of Biomedical Research. DOI: 10.7555/JBR.38.20240387 |
[2] | Zheng Qiao, Pan Lihong, Ji Yong. H2S protects against diabetes-accelerated atherosclerosis by preventing the activation of NLRP3 inflammasome[J]. The Journal of Biomedical Research, 2020, 34(2): 94-102. DOI: 10.7555/JBR.33.20190071 |
[3] | Stella Briggs, Uchechukwu L Osuagwu, Essam M AlHarthi. Manifestations of type 2 diabetes in corneal endothelial cell density, corneal thickness and intraocular pressure[J]. The Journal of Biomedical Research, 2016, 30(1): 46-51. DOI: 10.7555/JBR.30.20140075 |
[4] | Shangyong Feng, Yan Zhu, Caifeng Yan, Yan Wang, Zhenweng Zhang. Retinol binding protein 4 correlates with and is an early predictor of carotid atherosclerosis in type 2 diabetes mellitus patients[J]. The Journal of Biomedical Research, 2015, 29(6): 451-455. DOI: 10.7555/JBR.29.20140087 |
[5] | Hui Liang, Wei Guan, Yanling Yang, Zhongqi Mao, Yijun Mei, Huan Liu, Yi Miao. Roux-en-Y gastric bypass for Chinese type 2 diabetes mellitus patients with a BMI<28 kg/m2: a multi-institutional study[J]. The Journal of Biomedical Research, 2015, 29(2): 112-117. DOI: 10.7555/JBR.29.20140109 |
[6] | Sonali Ganguly, Hong Chang Tan, Phong Ching Lee, Kwang Wei Tham. Metabolic bariatric surgery and type 2 diabetes mellitus: an endocrinologist’ s perspective[J]. The Journal of Biomedical Research, 2015, 29(2): 105-111. DOI: 10.7555/JBR.29.20140127 |
[7] | Ankit Mahajan, Swarkar Sharma, Manoj K. Dhar, Rameshwar N.K. Bamezai. Risk factors of type 2 diabetes in population of Jammu and Kashmir, India[J]. The Journal of Biomedical Research, 2013, 27(5): 372-379. DOI: 10.7555/JBR.27.20130043 |
[8] | Ravi Prakash Rao, Ansima Singh, Arun K Jain, Bhartu Parsharthi Srinivasan. Dual therapy of rosiglitazone/pioglitazone with glimepiride on diabetic nephropathy in experimentally induced type 2 diabetes rats[J]. The Journal of Biomedical Research, 2011, 25(6): 411-417. DOI: 10.1016/S1674-8301(11)60054-7 |
[9] | Guanhua Su, Kun Liu, Yan Wang, Jue Wang, Xiaowei Li, Wenzhu Li, Yuhua Liao, Zhaohui Wang. Fibrinogen-like protein 2 expression correlates with microthrombosis in rats with type 2 diabetic nephropathy[J]. The Journal of Biomedical Research, 2011, 25(2): 120-127. DOI: 10.1016/S1674-8301(11)60015-8 |
[10] | Juan Du, Hui Shi, Ying Lu, Wencong Du, Yuanyuan Cao, Qian Li, Jianhua Ma, Xinhua Ye, Jinluo Cheng, Xiaofang Yu, Yanqin Gao, Ling Zhou. Tagging single nucleotide polymorphisms in the PPAR-γ and RXR-α gene and type 2 diabetes risk: a case-control study of a Chinese Han population[J]. The Journal of Biomedical Research, 2011, 25(1): 33-41. DOI: 10.1016/S1674-8301(11)60004-3 |
Drug | Target | Clinical effects/availability | Effect for PPHG/PPHL |
Limitation | Refs |
Metformin | Unclear; involves complex I & mGPD | Extensively used | Fasting HG | GI side effect Nausea, Diarrhea |
|
α-glucosidase inhibitor | Intestinal α-glucosidase | Reduction of CVD | PPHG | GI side effect Constipation, Farting | 49, 91, 93 |
Glinides | β cells Pancreas | Short duration of action | PPHG | Use every meal time | 98 |
DPP4inhibitor | Intestinal DPP4 | Suppression of glucagon | Fasting/PPHG | GI side effect Nausea, Constipation | 100-102 |
Thiazolidinedione | Liver, Fat PPARg | Increase in insulin sensitivity | Fasting HG | Edema, Bone fracture | |
Sulfonylureas | β cells pancreas | Insulin stimulator | Fasting HG | Prolonged hypoglycemia | 96, 97 |
SGLT2 inhibitor | Renal tubular SGLT2 | Decrease CVD outcome Mild body weight reduction | Fasting HG | Urogenital infection Dehydration | |
Insulin (Insulin analogue) |
Insulin receptor | Robust glucose reduction Extensively used | Fasting/PPHG | Increase body weight Injection | 44 |
GLP1 agonist | a/b cells pancreas | Reduce satiety Mild body weight reduction |
PPHG | Nausea, Vomiting Injection |
99 |
mGPD: mitochondrial glycerol-3-phosphate dehydrogenase; HG: hyperglycemia; GI: gastro intestinal; CVD: cardiovascular disease; PPHG: post prandial hyperglycemia; DPP4: dipeptidyl peptidase 4; PPARg: peroxisome oroliferator-activated receptor γ. |
Drug | Target | Clinical effects/availability | Effect for TC/TG | Limitation | Refs |
Statin | HMG-CoA | Extensively used | Both | Increase CK | 5, 104, 105 |
reductase | Reduction of CVD | Rhabdomyolysis | |||
Fibrate | PPARα | Reduction of CVD | TG | Rhabdomyolysis | 107 |
Ezetimibe | intestinal NPC1L1 | Short duration of action | TC | GI side effect | |
PPARδ/β | |||||
Ecolocumab | PCSK9 | Familial hypercholesterolemia or high risk CVD patients | TC | Need regular injection | 108, 109 |
ISIS 304801 | Antisense inhibition ApoC-Ⅲ | TG reduction 31.3-70.9% Under clinical trial | TG | Need regular injection | 62, 63 |
CP-346086 | MTP inhibitor | Underdevelopment | TG | 110, 111 | |
JTT-130 | |||||
Ginko biloba | Lipoprotein(a) synthesis inhibition |
Supplementary use | TC | 114-117 | |
Tocilizumab | IL6 inhibition | Patients for rheumatoid arthritis | TC | 118-121 | |
Torcetrapib Anacetrapib, Evacetrapib |
CETP inhibitor | Underdevelopment (anacetrapib, evacetrapib) |
TC | Blood pressure and bserum aldosterone increased | 122 |
List of the drugs for hyperlipidemia in diabetes mellitus. Only Statin, Fibrate, Ezetimibe and Evolocumabhave already widely in clinical use. TC: total cholesterol; TG: triglyceride; CVD: cardiovascular disease; CK: creatinine kinase; GI: gastro intestinal tract. |