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Ferroptosis: A potential target of macrophages in plaque vulnerability

  • Yu Li , Ji-Qing Ma , Chao-Chen Wang , Jian Zhou , Yu-Dong Sun EMAIL logo , Xiao-Long Wei EMAIL logo and Zhi-Qing Zhao EMAIL logo
Published/Copyright: October 2, 2023
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Open Life Sciences
From the journal Open Life Sciences Volume 18 Issue 1

Abstract

Plaque vulnerability has been the subject of several recent studies aimed at reducing the risk of stroke and carotid artery stenosis. Atherosclerotic plaque development is a complex process involving inflammation mediated by macrophages. Plaques become more vulnerable when the equilibrium between macrophage recruitment and clearance is disturbed. Lipoperoxides, which are affected by iron levels in cells, are responsible for the cell death seen in ferroptosis. Ferroptosis results from lipoperoxide-induced mitochondrial membrane toxicity. Atherosclerosis in ApoE(−/−) mice is reduced when ferroptosis is inhibited and iron intake is limited. Single-cell sequencing revealed that a ferroptosis-related gene was substantially expressed in atherosclerosis-modeled macrophages. Since ferroptosis can be regulated, it offers hope as a non-invasive method of treating carotid plaque. In this study, we discuss the role of ferroptosis in atherosclerotic plaque vulnerability, including its mechanism, regulation, and potential future research directions.

Keywords: atherosclerosis; ferroptosis; macrophage; plaque vulnerability

1 Introduction

Ischemic cerebral strokes, a major cause of severe morbidity and mortality, are caused primarily by vulnerable atherosclerotic plaque in the carotid artery [1,2]. Ischemic stroke rates have fallen worldwide over the past decade, but they have increased dramatically in East Asia, especially China [3,4,5]. Thus, plaque vulnerability has become an increasingly central issue in the treatment and prevention of carotid artery stenosis and stroke [1,6]. Atherosclerosis complications are more strongly linked to plaque stability than to plaque size [7]. Plaque characteristics are more reliable than symptoms and stenosis for predicting strokes and choosing surgical interventions [8]. Most ischemic strokes are brought on by plaque rupture, which is characterized by a necrotic core, intraplaque hemorrhage, immunocyte infiltration, and the rupture of thin fibrous caps [9,10].

Increased macrophages relative to lipids in the plaque make the plaque more susceptible to rupture [11]. Macrophage death is linked to inflammation, oxidative stress, and lipid metabolism [12]. Macrophage death from recruitment due to pro-inflammatory factors [13], hypoxia from inadequate blood supply [14], and foam cell formation due to lipoprotein retention [15] are all hallmarks of advanced plaques. Plaque necrosis and rupture are facilitated by factors such as a necrotic core, a weakened fibrous cap, and increased inflammation. Defects in macrophage recruitment and clearance lead to these characteristics of plaque vulnerability [16,17,18].

Sullivan proposed a theory in 1981 that iron buildup was associated with the onset of cardiovascular disease [19]. However, contradictory findings have been found in clinical studies and animal experiments. Increased levels of the ubiquitous ferritin (FTN) storage protein serum FTN are not always associated with an increased risk of cardiovascular disease [20,21]. Macrophages in atherosclerotic plaques have been found to undergo ferroptosis, a form of iron-dependent cell programmed death that differs from apoptosis, cell necrosis, and autophagy, and explains the effect of iron overload on atherosclerotic vascular disease leading to cell death [22]. The systemic use of ferroptosis agents on plaques should be approached with caution, despite the fact that ferroptosis may hold promise in the treatment of cancer and other diseases[23]. Macrophage ferroptosis causes lipid peroxidation [24], inflammation [25], and phenotypic changes [26] that are all closely related to plaque, though its precise role in carotid plaque vulnerability is not well defined. Nonetheless, its role in macrophages has been shown to be crucial in determining plaque vulnerability [27]. Due to their dual role in inflammation and necrotic core, macrophage ferroptosis in plaques warrants a re-evaluation. This review provides an overview of ferroptosis and its regulatory mechanisms, discusses the link between macrophage ferroptosis and plaque vulnerability, and points researchers in a new direction in their study of carotid atherosclerotic plaques, which may ultimately lead to the discovery of novel therapeutic targets.

2 Macrophages in vulnerable plaques

Disparities in recruitment and clearance cause macrophages to increase plaque vulnerability [28,29], which is reflected in the aggravation of local inflammation and formation of the necrotic core [16].

2.1 Inflammation-associated macrophages

An initial step in the development of atherosclerosis is the release of chemokines and adhesion factors from the endothelium, which entice monocytes to bind to the endothelium [30]. Upon binding, monocytes enter the subendothelium, where they are induced by chemokines to undergo the irreversible process of macrophage differentiation and begin ingesting lipoproteins [31]. Nonetheless, macrophages are versatile and they are capable of polarization [32]. Within atherosclerotic plaques, various macrophage subtypes perform specialized phagocytic and secretory roles [33]. Macrophages migrate to the plaque because of the pro-inflammatory role played by M1 macrophages, which secrete pro-inflammatory factors to sustain the recruitment of immunocytes [34]. M1 macrophages increase the risk of plaque rupture and thrombosis by secreting pro-inflammatory factors and matrix-degrading enzymes, which in turn induce the proliferation and migration of vascular smooth muscle cell (VSMC)-derived foam cells to the intima via paracrine effects [35].

After ingesting lipoproteins, macrophages transform into foam cells [36]. Foam cells secrete extracellular matrix molecules that retain lipoproteins [37], and the resulting inflammation attracts more monocytes [38]. Meanwhile, macrophage death is the cause of necrotic core and a source of pro-inflammatory factors and damage-associated molecular patterns (DAMPs), contributing to inflammation, which in turn attracts more macrophages and leads to their aggregation and death [39]. In atherosclerosis, macrophages are responsible for secreting the DAMP HMGB1. Secretion and transcription of pro-inflammatory cytokines by NF-κB in response to HMGB1 increase plaque vulnerability. Inhibiting HMGB1 expression is one mechanism by which statins reduce plaque formation [40]. Plaque progression is hastened by inflammation that worsens over time. Consequently, stopping inflammation would have huge clinical implications.

2.2 Necrotic core-associated macrophages

Macrophage death has the potential to reduce inflammation, which could be helpful in the early stages of atherosclerotic plaque formation. However, necrotic core formation, thinning of the fibrous cap, and exacerbated inflammation can result from defects in the recruitment and clearance of dead macrophages, all of which are hallmarks of plaque vulnerability [16,17,18]. Thrombosis and embolization of distal arteries like the coronary, cerebrovascular, or limb arteries can occur if the intima eventually ruptures, exposing tissue factors to coagulation and increasing platelets in the blood [41]. The presence of apoptotic macrophages at the site of plaque rupture provides further evidence that macrophages play a role in the rupturing of advanced plaques. Drug-coated balloons and drug-eluting stents are two methods of preventing plaque progression and reducing the risk of plaque rupture, despite the complexity of the process.

3 Ferroptosis mechanisms

In 2012, Dixon et al. first identified ferroptosis, an iron-dependent form of regulated cell death mediated by elevated lipid peroxidation. Morphologically, biochemically, and genetically, this form of cell death is distinct from apoptosis, necrosis, and autophagy [42]. Mitochondria undergo morphological changes during ferroptosis, including fragmentation and cristae enlargement [42,43]. Ferroptosis, in contrast to other forms of cell death, does not share the same biochemical characteristics of energy depletion and is not regulated by the same compounds [44].

Iron chelators were discovered to prevent cell death during a systematic study of lethal compounds, leading to the discovery of ferroptosis. Ferroptosis is strongly correlated with intracellular iron concentration [42]. Several proteins, such as transferrin receptor 1 (TFR1), divalent metal transporter 1 (DMT1), FTN, and ferroportin (FPN), regulate iron homeostasis in cells. The prevalence of ferroptosis is significantly affected by the amount of iron consumed daily. The stomach acid converts ingested Fe3+ to the more absorbable form Fe2+. Ceruloplasmin converts ferrous ion (Fe2+) to Fe3+, allowing it to bind with transferrin (TF) and be internalized via endocytosis [45]. Plasma TF is involved in the TF cycle, which transports iron from the blood, lymph, and cerebrospinal fluid to cells [46]. The enzyme ferrireductase reduces Fe3+ to Fe2+ [47]. DMT1, a transmembrane responsible for transporting various divalent metal cations into cells, then releases the unstable Fe2+ and transports it into the cytoplasm [48]. FTN can act as a reservoir for Fe2+, while FPN can secrete it [49]. FTN, a major iron storage protein, is made up of the heavy chain (FTH1) and the light chain (FTL) [50]. The iron content is regulated to maintain intracellular iron homeostasis. Iron is stored in a variety of proteins, including FTN, where it is in a form that is both non-toxic and bioavailable [51]. However, the labile iron pool (LIP) increases when the iron overload is greater than the storage capacity [52]. This causes ferroptosis by disrupting intracellular iron homeostasis, catalyzing the Fenton reaction to generate reactive oxygen species (ROS) [53], and subsequently peroxidizing polyunsaturated fatty acids [54]. Changes in mitochondrial morphology, such as mitochondrial fragmentation and cristae enlargement, are linked to the cytotoxicity of lipid peroxidation and occur during the process of ferroptosis [55] (Figure 1).

Figure 1 Macrophage ferroptosis regulation in atherosclerotic plaques. The SLC7A11-GSH-GPX4 and GCH1-BH4-PL cytoplasmic pathways, the FSP1-CoQ-NAD(P)H cell membrane pathway, and the DHODH-CoQ mitochondrial pathway all play roles in regulating macrophage ferroptosis.
Figure 1

Macrophage ferroptosis regulation in atherosclerotic plaques. The SLC7A11-GSH-GPX4 and GCH1-BH4-PL cytoplasmic pathways, the FSP1-CoQ-NAD(P)H cell membrane pathway, and the DHODH-CoQ mitochondrial pathway all play roles in regulating macrophage ferroptosis.

4 Ferroptosis regulation

4.1 Ferroptosis in cytoplasm

Inhibiting lipid peroxide production is central to controlling ferroptosis, which occurs because lipid peroxides are toxic to mitochondria. The production of lipid peroxides is controlled in the cytoplasm by two distinct pathways: SLC7A11-GSH-GPX4 and GCH1-BH4-PL.

Glutathione (GSH) is a tripeptide made up of glycine, cysteine, and glutamic acid that serves as the body’s primary antioxidant [56]. Loss of GSH has been linked to cell death since the 1970s [57]. GSH inhibits ROS production and keeps the cellular environment reduced [58]. SLC7A11 is a catalytic subunit of System Xc-, which regulates intracellular glutathione levels via the intercellular exchange of cysteine and glutamate [59]. Systemic Xc- is activated by the Nrf2-Keap1 pathway, and either increased expression of Nrf2 or decreased expression of Keap1 improves the resistance of ferroptosis in atherosclerosis [60]. By targeting System Xc selectively, erastin reduces GSH levels by depleting cysteine, a precursor for GSH [61]. Depletion of intracellular cysteine caused by SLC7A11 inhibition reduces GSH synthesis, which in turn reduces glutathione peroxidase 4 (GPX4) expression [62]. ATF3 inhibits SLC7A11, causing lipid peroxidation and ferroptosis by consuming GSH [63]. The GSH-dependent enzyme GPX4 regulates ferroptosis by binding to lipid hydroperoxides and reducing them to lipid alcohols in the cytosol and mitochondria (Figure 1) [64]. Overexpression of GPX4 significantly reduces lipoperoxide and atherosclerosis progression in ApoE(−/−) mice [65]. Since RSL3 inhibits GPX4 activity without causing a decrease in GSH levels, it acts through a mechanism distinct from that of erastin [66]. Notably, statins, the lipid-lowering drugs commonly used in atherosclerosis, can inhibit GPX4, a type of selenoprotein [67], leading to plaque progression [68]. By degrading hydroperoxides and lipoxygenases (LOXs), GPX4 not only acts as an intracellular antioxidant enzyme, but it also directly scavenges for phospholipid (PL) hydroperoxides on membranes [69].

The production of tetrahydrobiopterin (BH4) and dihydrobiopterin (BH2) is limited by the enzyme GTP cyclohydrolase-1 (GCH1) (Figure 1) [70]. The oxidized low-density lipoprotein (ox-LDL) present in hypercholesterolemia downregulates the mRNA expression of GCH1 and BH4, which in turn leads to NO-induced endothelial damage in atherosclerosis [71]. The involvement of GCH1 and its metabolic derivative BH4/BH2 in the regulation of ferroptosis was discovered through a genome-wide activation screen [72]. BH4 selectively inhibits PL oxidation and speeds up the production of CoQ10, both of which require dihydrofolate reductase [73].

Increased levels of BH4 caused by overexpression of GCH1 induce lipid remodeling and inhibit ferroptosis by selectively blocking phospholipid peroxidation [72]. Additionally, GCH1 protects cells from ferroptosis by regulating the oxidative balance of macrophages and BH4 [36], making it a potent antioxidant. The GCH1-BH4-PL axis regulates the endogenous generation of the antioxidant BH4 and CoQ10, as well as the peroxidation of polyunsaturated phospholipids, and is linked to ROS production as a regulator against ferroptosis [74]. In contrast to the SLC7A11-GSH-GPX4 pathway, the GCH1-BH4-PL axis is involved in ferroptosis resistance against GPX4-independent ferroptosis [72].

4.2 Ferroptosis in mitochondria

Mitochondrial DHODH-CoQ and SLC7A11-GSH-GPX4 have similar roles. SLC7A11-GSH-GPX4 functions similarly to its cytoplasmic counterpart.

Dihydroorotate dehydrogenase (DHODH) has been shown to inhibit ferroptosis and decrease mitochondrial lipid peroxidation [75], effects that are thought to be unrelated to its nucleotide production function [76]. DHODH catalyzes the formation of dihydroorotate and orotate (OA), and, like ferroptosis suppressor protein 1 (FSP1), prevents the production of peroxide by reducing CoQ to CoQH2 (Figure 1) [77]. DHODH substrate supplementation has been shown to have a significant effect on ferroptosis induced by GPX4 inhibition [75].

DHODH inhibition does not affect GPX4 and SLC7A11 activity or GSH content but does sensitize cells to ferroptosis inducers. Overexpression or knockout of FSP1 does not affect RSL3-induced ferroptosis in DHODH(−/−) cells. Ferroptosis is not stimulated by the inhibition of DHODH in FSP1(−/−) cells. In contrast, inhibition of DHODH makes wild-type cells more susceptible to RSL3-induced ferroptosis. Mitochondrial DHODH inhibits peroxidation similar to that of GPX4 and FSP1 [75].

4.3 Ferroptosis in the cell membrane

By catalyzing the reduction of ubiquinone (CoQ) to ubiquinol (CoQH2) on the cell membrane, the FSP1, also known as mitochondrial apoptosis-inducing factor 2, acts as a GSH-independent ferroptosis inhibitor (Figure 1). Inhibition of FSP1 leads to elevated lipoperoxides even in the presence of functional GPX4 [78]. An N-terminal hydrophobic sequence and an NADH oxidoreductase domain containing flavoprotein are both present in FSP1, making it an effective inhibitor of ferroptosis. To facilitate the reduction of CoQ by flavoprotein oxidoreductase, N-myristoylation of FSP1 is required in the endoplasmic reticulum, the cell membrane, and the Golgi apparatus. Inhibition of ferroptosis can be attributed to CoQH2, which acts as a free radical that recruits antioxidants on the cell membrane to prevent lipid peroxidation. Meanwhile, NAD(P)H is consumed by FSP1 to catalyze the regeneration of CoQ [79]. FSP1 knockout cells are extremely vulnerable to RSL3-induced ferroptosis, but this sensitivity can be mitigated by the presence of the potent inhibitor iFSP1. The anti-ferroptosis function of FSP1-CoQ10-NAD(P)H is independent of glutathione levels in the cell, suggesting that this antioxidant system plays a role at the membrane level [80].

5 Ferroptosis of macrophages in atherosclerosis

In comparison to iron accumulation in healthy arteries, iron accumulation in atherosclerotic plaques is dramatically higher [20]. There is a correlation between elevated iron levels and the development of oxidative stress, inflammation, and macrophage-derived foam cells [81]. Key features of advanced plaques include iron overload in macrophages, lipid peroxidation, intraplaque hemorrhage, and ROS accumulation [82]. Plaque formation in ApoE(−/−) mice fed a high-fat diet is significantly reduced in the presence of the ferroptosis inhibitor ferrostatin-1. By increasing the expressions of SLC7A11 and GPX4, two key regulators of iron homeostasis, ferrostatin-1 prevents iron accumulation and lipid peroxidation in mice [83]. These results provide further evidence that ferroptosis contributes to atherosclerosis. Ferroptosis may be the cause of macrophage death after recruitment, which in turn stimulates the recruitment of even more macrophages.

The increased risk of plaque rupture is a direct result of the necrotic core formation and atherosclerotic plaque progression induced by macrophage death. Macrophage ferroptosis has been linked to increased atherosclerotic plaque vulnerability. Ferroptosis is triggered by iron, and its primary mechanism is the Fenton reaction, which generates ROS and lipid peroxidation [42]. Ceruloplasmin converts Fe2+ into Fe3+ in vivo, and TFR1 facilitates its entry into cells [84]. Foam cells contribute to the development of human carotid plaque by having an abnormally high level of TFR1, a cell surface receptor involved in transferrin-mediated iron uptake and FTN synthesis [85]. To prevent oxidative stress from the Fe2+-mediated Fenton reaction and to maintain intracellular iron homeostasis and prevent ferroptosis, the major iron-storage protein with ferroxidase activity in cells, FTN, oxidizes Fe2+ to Fe3+ and stores it [86]. Decreases in FTN lead to an increase in LIP, which in turn increases ROS production and makes cells more vulnerable to ferroptosis [87]. Atherosclerotic plaques are associated with iron accumulation. Atherosclerotic plaque macrophage iron and lipid accumulation both play a role in plaque development and progression [27].

Atherosclerotic plaque vulnerability is also associated with the amount of iron present in the body. Iron chelators or dietary iron restriction slowed atherosclerosis development in ApoE(−/−) mice without influencing serum total cholesterol or triglyceride levels [20]. Through its interaction with FPN, hepcidin inhibits iron efflux in macrophages, raises intracellular iron concentration, and stimulates ferroptosis, all of which contribute to the development of inflammation and plaque [88]. Conversely, iron overload is aggravated by iron retention in macrophages via the TLR4/NF-κB pathway [89].

The mitochondrial toxicity of lipid peroxide, which results in mitochondrial changes and cell death, is the physiological basis of ferroptosis. In atherosclerosis, LOXs expressed by macrophages is a key enzyme in ROS production that promotes ferroptosis. Deposition of ox-LDL in the subendothelial space is greatly reduced by 12/15-LOX inhibition [90]. In addition to endothelial cells, foam cells, and VSMC, oxidative phospholipids (ox-PL) induced by ROS in macrophages promote plaque progression. Thus, inhibition of ox-PL in macrophages can reduce inflammation and calcification [27].

6 Future directions and therapeutic implications

6.1 Decreasing iron content

Sullivan proposed a theory in 1981 that iron content is related to cardiovascular disease [19], though he has not been able to confirm this view. However, in atherosclerotic plaques, many studies have found that iron content is higher than that of normal vascular tissue, especially in advanced plaques. Although a few studies provide direct evidence to confirm the correlation between the iron content and plaque vulnerability, this may indicate the direction of future research, that is, the detection of plaque iron content by imaging methods to determine the risk of atherosclerotic plaque complications.

After intraplaque hemorrhage, advanced atherosclerotic plaques have a higher iron content because of the necrotic core and macrophage infiltration [91]. Iron not only accumulates in local plaques but also affects plaque progression via serum iron content [20]. Overloading FTN causes iron homeostasis to be disrupted, leading to an increase in LIP, which is the first step in ferroptosis [92]. Thus, effectively regulating iron content in cells can affect plaques through ferroptosis [93]. Elevated serum FTN concentration, along with high levels of free iron and transferrin saturation, has been linked to an increased risk of cardiovascular disease in humans [94]. Elevated intracellular iron content due to hepcidin enhances inflammation and progression of atherosclerotic plaques [88]. Iron chelators and dietary restrictions slowed plaque progression and decreased inflammation and vascular injury in ApoE(−/−) mice [20]. Heat shock proteins (HSPs) have been found to downregulate TFR1-mediated iron uptake and thereby reduce intracellular iron concentration [95]. HSPs have been reported to inhibit inflammation and the progression of plaques [96], and their role in macrophages provides a direction for future research on plaque stability.

Iron chelators are the most common pharmaceutical agents for reducing iron accumulation [97]. They can penetrate cell membranes and bind to free ferrous iron, thereby preventing the Fenton reaction [98]. Iron chelators are also effective in decreasing LIP and preventing ferroptosis in cancer and neurodegenerative diseases [99,100]. Desferrioxamine, deferiprone, and deferasirox are types of iron chelators that have been found to reduce iron concentrations [101]. An increase in LIP can lead to the progression of atherosclerosis and the accumulation of immune cells [102]. When used together, iron chelators, iron-restricted diets, and anti-inflammatory therapies can inhibit iron-overload-related atherosclerosis [20].

Atherosclerosis risk factors include increased intracellular iron content, which promotes inflammation, lipid oxidation, and necrotic core. By reducing the lipid content, Statins have been shown to be effective in delaying plaque progression but not pathology progression. It is proved that iron content can affect plaque vulnerability by causing ferroptosis in plaque, so reducing blood iron content to improve plaque stability has a good development prospect. Inhibiting ferroptosis, atherosclerosis, and plaque vulnerability can be achieved by reducing intracellular iron content. Although there is currently no concrete evidence for this, it has the potential to be a useful treatment in the near future.

6.2 Inflammation and polarization

Inflammation in the plaque is the main cause of rapid plaque progression, necrosis, and rupture of advanced plaque. At present, researchers need an exact and comprehensive understanding of the causes of inflammation in plaques. Although it has been recognized that macrophage death plays a key role, there are many causes of macrophage death including apoptosis, necrosis, pyroptosis, ferroptosis, and other death modes. Delaying plaque progression and decreasing plaque vulnerability through ferroptosis intervention will be a new direction for the stability of atherosclerotic plaques in the future.

The polarization of macrophages is a crucial factor of plaque formation and a potential target for atherosclerotic plaque vulnerability [34]. M2 macrophages have strong phagocytosis and anti-inflammation effects and can transform M1 macrophages into M2 macrophages by initiating anti-inflammatory signal transduction [103]. M2 macrophages play a role in tissue repair by activating extracellular matrix synthesis and VSMC proliferation, thereby reducing vulnerability [104]. The role of NO synthase, which inhibits lipid peroxidation in place of GPX4, is associated with the sensitivity of RSL3-induced macrophage ferroptosis in various subtypes [105]. More research is needed on the function of M2 macrophages in preventing ferroptosis, reducing inflammation, preventing necrotic core formation, and enhancing plaque stability. Further, in advanced atherosclerosis, ferroptosis promotes plaque instability, so a better understanding of the molecular and cellular mechanisms involved is necessary.

Although this review focuses on inflammation, oxidative stress, and polarization, the interplay between these molecular effectors remains unclear. Clarifying the mechanism by which defects in macrophages cause ferroptosis and identifying the cellular effectors that are defective are fundamental. Several lines of evidence point to macrophage ferroptosis as a major contributor to atherosclerotic plaque vulnerability. Although the role of ferroptosis in atherosclerosis has been investigated previously, researchers are now focusing on plaque vulnerability instead. Further studies on the correlation between macrophage ferroptosis and plaque vulnerability can provide new insights and therapeutic strategies for stroke prevention and atherosclerotic plaques.

7 Summary and conclusion

Carotid plaque vulnerability is a major factor contributing to cerebral stroke, a leading cause of severe morbidity and mortality. Thus, investigating the molecular mechanisms underlying plaque vulnerability is essential. In this review, we discussed the most up-to-date findings on ferroptosis and provided evidence that iron overload-induced ferroptosis of macrophages occurs in advanced atherosclerotic plaques, resulting in alterations in inflammation and oxidative stress that impact plaque stability. In the future, research on iron content, inflammation, and macrophage polarization of ferroptosis may provide new insights into plaque vulnerability. While ferroptosis may play a role in at least one of the many mechanisms that lead to the destabilization of atherosclerotic plaques, it is important to remember that this is itself a complex process involving the accumulation and defective resolution of inflammation. However, inhibiting ferroptosis may be an effective new strategy for treating carotid plaque. Given the high prevalence of stroke and its associated morbidity and mortality, even incremental improvements in this field could have far-reaching consequences.

# These authors contributed equally to this study.

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Acknowledgements

We are particularly grateful to all people who have helped us on our article.

  1. Funding information: This research was funded by National Natural Science Foundation of China (82270513), National Innovation Talent Promotion Plan (2019RA2132), and Shanghai key clinical specialty – Minimally invasive surgery (shslczdzk06402).

  2. Conflict of interest: Authors state no conflict of interest.

  3. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2023-03-21
Revised: 2023-08-04
Accepted: 2023-08-16
Published Online: 2023-10-02

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
https://doi.org/10.1515/biol-2022-0722
Keywords for this article
atherosclerosis; ferroptosis; macrophage; plaque vulnerability
Creative Commons
BY 4.0

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  125. Crosstalk between lactic acid and immune regulation and its value in the diagnosis and treatment of liver failure
  126. Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma
  127. Traumatic brain injury and rTMS-ERPs: Case report and literature review
  128. Extracellular fibrin promotes non-small cell lung cancer progression through integrin β1/PTEN/AKT signaling
  129. Knockdown of DLK4 inhibits non-small cell lung cancer tumor growth by downregulating CKS2
  130. The co-expression pattern of VEGFR-2 with indicators related to proliferation, apoptosis, and differentiation of anagen hair follicles
  131. Inflammation-related signaling pathways in tendinopathy
  132. CD4+ T cell count in HIV/TB co-infection and co-occurrence with HL: Case report and literature review
  133. Clinical analysis of severe Chlamydia psittaci pneumonia: Case series study
  134. Bioinformatics analysis to identify potential biomarkers for the pulmonary artery hypertension associated with the basement membrane
  135. Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility
  136. Catharanthus roseus (L.) G. Don counteracts the ampicillin resistance in multiple antibiotic-resistant Staphylococcus aureus by downregulation of PBP2a synthesis
  137. Combination of a bronchogenic cyst in the thoracic spinal canal with chronic myelocytic leukemia
  138. Bacterial lipoprotein plays an important role in the macrophage autophagy and apoptosis induced by Salmonella typhimurium and Staphylococcus aureus
  139. TCL1A+ B cells predict prognosis in triple-negative breast cancer through integrative analysis of single-cell and bulk transcriptomic data
  140. Ezrin promotes esophageal squamous cell carcinoma progression via the Hippo signaling pathway
  141. Ferroptosis: A potential target of macrophages in plaque vulnerability
  142. Predicting pediatric Crohn's disease based on six mRNA-constructed risk signature using comprehensive bioinformatic approaches
  143. Applications of genetic code expansion and photosensitive UAAs in studying membrane proteins
  144. HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway
  145. IL-17 in osteoarthritis: A narrative review
  146. Circadian cycle and neuroinflammation
  147. Probiotic management and inflammatory factors as a novel treatment in cirrhosis: A systematic review and meta-analysis
  148. Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review
  149. SPOP regulates the expression profiles and alternative splicing events in human hepatocytes
  150. Knockdown of SETD5 inhibited glycolysis and tumor growth in gastric cancer cells by down-regulating Akt signaling pathway
  151. PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway
  152. Pancreatic ectopic thyroid tissue: A case report and analysis of literature
  153. The prognostic impact of body mass index on female breast cancer patients in underdeveloped regions of northern China differs by menopause status and tumor molecular subtype
  154. Report on a case of liver-originating malignant melanoma of unknown primary
  155. Case report: Herbal treatment of neutropenic enterocolitis after chemotherapy for breast cancer
  156. The fibroblast growth factor–Klotho axis at molecular level
  157. Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations
  158. A case report of diagnosis and dynamic monitoring of Listeria monocytogenes meningitis with NGS
  159. Effect of autologous platelet-rich plasma on new bone formation and viability of a Marburg bone graft
  160. Small breast epithelial mucin as a useful prognostic marker for breast cancer patients
  161. Continuous non-adherent culture promotes transdifferentiation of human adipose-derived stem cells into retinal lineage
  162. Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway
  163. Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report
  164. Case report of atypical undernutrition of hypoproteinemia type
  165. Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer
  166. Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
  167. Research progress of serum eosinophil in chronic obstructive pulmonary disease and asthma
  168. Clinicopathological characteristics of co-existing or mixed colorectal cancer and neuroendocrine tumor: Report of five cases
  169. Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis
  170. Precisional detection of lymph node metastasis using tFCM in colorectal cancer
  171. Advances in diagnosis and treatment of perimenopausal syndrome
  172. A study of forensic genetics: ITO index distribution and kinship judgment between two individuals
  173. Acute lupus pneumonitis resembling miliary tuberculosis: A case-based review
  174. Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
  175. Fractalkine modulates pulmonary angiogenesis and tube formation by modulating CX3CR1 and growth factors in PVECs
  176. Novel risk prediction models for deep vein thrombosis after thoracotomy and thoracoscopic lung cancer resections, involving coagulation and immune function
  177. Exploring the diagnostic markers of essential tremor: A study based on machine learning algorithms
  178. Evaluation of effects of small-incision approach treatment on proximal tibia fracture by deep learning algorithm-based magnetic resonance imaging
  179. An online diagnosis method for cancer lesions based on intelligent imaging analysis
  180. Medical imaging in rheumatoid arthritis: A review on deep learning approach
  181. Predictive analytics in smart healthcare for child mortality prediction using a machine learning approach
  182. Utility of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in predicting acute-on-chronic liver failure survival
  183. A biomedical decision support system for meta-analysis of bilateral upper-limb training in stroke patients with hemiplegia
  184. TNF-α and IL-8 levels are positively correlated with hypobaric hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats
  185. Stochastic gradient descent optimisation for convolutional neural network for medical image segmentation
  186. Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy
  187. Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development
  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
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