Endoplasmic Reticulum Stress and Oxidative Stress in Inflammatory Diseases

Abstract

Endoplasmic reticulum (ER) stress and oxidative stress (OS) are often related states in cells as part of normal physiology but more frequently manifested in the pathophysiology of many diseases, particularly diseases involving acute or chronic inflammation. In this study, we reviewed recent findings about the role of ER stress and OS in the pathogenesis of inflammatory diseases.

Introduction to the Endoplasmic Reticulum Stress and Oxidative Stress

The endoplasmic reticulum (ER) is the largest organelle of eukaryotic cells, comprising the rough ER constituted by sheets, and the smooth ER constituted by tubules, each structure is related to the type of processes that takes place at the site (Oakes and Papa, 2015). ER performs various cellular functions such as protein folding, post-translational modifications, fatty acid and sterol biosynthesis, xenobiotic detoxification, and intracellular calcium storage (Riaz et al, 2020). When ER encounters a substantial increase in workload, some proteins cannot be folded properly and natively leading to aggregation and accumulation of the unfolded proteins in the ER lumen. Such a scenario is known as ER stress (Burman et al, 2018). Severe and prolonged ER stress is thought to drive the pathology of many chronic disorders owing to its potential to elicit aberrant inflammatory signaling and facilitate cell death.

In response to ER stress, cells initiate the unfolded protein response (UPR) that involves a series of signaling and transcriptional events in an attempt to restore ER homeostasis by ways of increasing protein folding capacity, diminishing translation rate, and degrading unfolded and misfolded proteins (Chen and Cubillos-Ruiz, 2021). The canonical UPR signaling is triggered by activation of three ER membrane-bound transducers: (1) the endoribonucleases inositol requiring enzyme 1 (IRE1α) (ubiquitously expressed) and IRE1β (confined to mucosal secretory cells, which splice the X-box-binding protein (XBP1) mRNA leading to translation of the sXBP1 transcription factor that drives expression of chaperones and other ER-resident proteins required for folding; (2) the ER-resident protein kinase RNA-like ER kinase (PERK) that inhibits translation through eIF2a and induces transcriptional responses by activating transcription factor-4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP) resulting in ER stress–induced apoptosis; and (3) the activating transcription factor 6 (ATF6) that also facilitates the generation of proteins for enhancing ER function (Chen and Cubillos-Ruiz, 2021).

Oxidative stress (OS) is a form of cellular stress and damage caused by excess production and accumulation of reactive oxygen species (ROS) that compromises antioxidant defense mechanisms (Ren et al, 2021). ROS are a group of small reactive molecules which could bring some beneficial effects on cellular responses (Kattoor et al, 2017). For an instance, accumulating evidence has suggested that intracellular ROS would act as secondary messengers in intracellular signaling cascades, which induce and maintain physiological responses to protect cells from hypoxia and inflammation (Zepeda et al, 2013). However, abnormal production and accumulation of ROS have detrimental effects on cellular function and homeostasis because it could trigger many cellular signaling pathways and induce damage to DNA, proteins, and cells (Henriksen et al, 2011, Tsai et al, 2014). Persistent exposure to ROS upregulates the production of oxidatively modified nucleic acids, lipids, and proteins leading to the development of diseases (Srinivas et al, 2019).

Crosstalk Between ER Stress and OS

Although the association between ER stress and OS remains to be fully elucidated, studies have supported the notion that these two cellular stresses are closely linked in many physiological and pathological conditions (Victor et al, 2021). In ER, redox homeostasis is critical for the protein folding process and disulfide bond formation (Maamoun et al, 2019). Alterations in ER-mediated protein folding pathways can cause an ROS imbalance and enhance ROS production, indirectly disturbing both ER and redox homeostasis (Hasanain et al, 2015). In an ER stress condition, misfolded proteins particularly with aberrant disulfide bond formation and reduction may cause ROS accumulation and diffusion into the cytoplasm leading to cellular OS (Margittai et al, 2012; Mennerich et al, 2019). Conversely, OS from increased production of ROS can induce protein misfolding and ER stress as several oxidants including peroxides, metal ions, and oxidation byproducts can pathologically initiate the UPR (Cao and Kaufman, 2014). It appears that ER stress and OS are intrinsically linked with one process triggering the other in various scenarios encountered by the cell.

ER Stress and OS in Inflammatory Cytokine Production

It has been established that ER stress response is one of the major factors causing inflammatory pathologies through regulation of production of the proinflammatory cytokines. Inflammation is usually triggered when pattern recognition receptors, such as Toll-like receptors (TLRs) or nucleotide-binding oligomeric domain (NOD)-like receptors (NLRs), detect tissue damage or microbial infection. Kevin Shenderov et al (2014) showed that ER stress can promote the secretion of mature interleukin (IL)-1β from macrophages upon TLR4 stimulation through a caspase-8- and TRIF-dependent pathway. Treatment of macrophages with ER stress–inducing reagents tunicamycin or thapsigargin followed by TLR stimulation–induced IL-1β and TNF-α production (Komura et al, 2013). Intriguingly, ER stress has recently been reported to associate with inflammasomes in inflammatory signaling pathways (Chen et al, 2019; Lebeaupin et al, 2015).

The inflammasome is a signaling protein complex composed of NLR including caspase 1 and NLR family pyrin domain containing 3 (NLRP3) and takes a crucial part in different inflammation-induced autoimmune and metabolic disorders (de Torre-Minguela et al, 2017; Gong et al, 2017; Perera et al, 2017; Ralston et al, 2017). Upon activation, inflammasome can convert procaspase 1 into active caspase 1 that subsequently activates pro-IL1β into active IL-1β, one of the key mediators of the inflammatory response. The hypothesis that ER stress is strongly associated with inflammasome during inflammation has now been clarified from several studies demonstrating that ER stress is involved in the activation of pro-IL1β and NLRP3 (Lerner et al, 2012; Menu et al, 2012) (Fig. 1).

FIG. 1.

Crosstalk between ER stress, NLRP3 inflammasome, and inflammation. ASC, apoptosis-associated speck-like protein containing a caspase-1 recruitment domain; ER, endoplasmic reticulum; IL-1β, interleukin-1β; NLRP3, NLR family pyrin domain-containing protein 3; Pro-IL1β, pro-interleukin-1β; TLRs, Toll-like receptors; TRIF, Toll/IL-1R domain-containing adapter-inducing IFN-β.

In parallel with ER stress, when the redox equilibrium is disturbed owing to the excessive accumulation or depletion of ROS, many cellular signaling pathways are influenced, which confers to the cellular dysfunction and subsequently the development of various pathologies. ROS act as second messengers and activate numerous signal transduction pathways including PI3K/Akt, p38 MAPK, ERK, JNK, PKC, Src family kinases, and growth factor tyrosine kinase receptor pathways (Zhang et al, 2016), all of which could lead to the production of proinflammatory cytokines.

Moreover, ROS could also stimulate redox-sensitive transcription factors such as NF-κB, NRF2, and hypoxia-inducible factor (HIF)-1 that all play important roles in inflammatory responses (Lee and Yang, 2012). NF-κB transcription factor, which is critical for a wide range of processes, such as immunity, inflammation, cell development, growth, and survival, can also regulate ROS production and degradation (Wang et al, 2019b). NRF2 is a transcription factor that primarily regulates the antioxidant protein expression in response to oxidative damage can lead to inflammatory signaling as well (Kudo et al, 2020; Nishimoto et al, 2017). Under the normoxic condition, NRF2 is retained in the cytoplasm and degraded by Kelch-like ECH-associated protein 1 (KEAP1) and Cullin3 protein to prevent the activation of associated downstream signaling pathways (Guo et al, 2022). During oxidative damage, KEAP1-Cullin3-induced NRF2 degradation is inhibited as such NRF2 translocates to the nucleus where it binds to the antioxidant response element promoter to upregulate the gene expressions for antioxidant proteins (Cullinan and Diehl, 2006). It has also been shown that knockout of HIF-1α in the myeloid cells increases the survival rates in a murine LPS-induced sepsis model and decreases serum levels of proinflammatory cytokines TNF-α, IL-1α, IL-1β, and IL-12 (Peyssonnaux et al, 2007) (Fig. 2).

FIG. 2.

Crosstalk between ER stress, OS, and inflammatory cytokine production. Akt, protein kinase B; ARE, antioxidant response element; ERK, extracellular regulated protein kinases; HIF-1, hypoxia-inducible factor 1; JNK, c-Jun N-terminal kinase; KEAP1, Kelch-like ECH-associated protein 1; MAPK, mitogen-activated protein kinases; Mit, mitochondria; NF-κB, nuclear factor-kappa B; NRF2, nuclear factor erythroid-2-related factor (NF-E2-related factor 2); OS, oxidative stress; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PTK, receptor tyrosine kinase; Ras, rat sarcoma protein; RNS, reactive nitrogen species; ROS, reactive oxygen species; SS, disulfide bond; Src, src protein.

ER Stress and OS in Inflammatory Diseases

ER stress and OS have been shown to contribute to the pathogenesis of inflammatory disorders in various tissue or organ systems such as inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), chronic kidney disease, viral hepatitis, pancreatitis, rheumatoid arthritis (RA), and others (He et al, 2018; Laudisi et al, 2019; Lee et al, 2018; Liong and Lappas, 2016; Wang et al, 2019a; Zha et al, 2015). Their respective targets and mechanisms have been described in many reviews. This review briefly summarizes the target organs/tissues of ER stress and the target genes and effects of activation of hypoxia-inducible factor (HIF)-1, an important molecule involved in OS. The following part mainly focuses on their crosstalk in a variety of inflammatory diseases (Tables 1 and 2).

Table 1.

Target Organs/Tissues of Endoplasmic Reticulum Stress and Inflammation Crosstalk

Organ(s)/tissue(s)	Lesion type	Target cell(s)	The role of ER stress (pathologic mechanism)	Main mechanism pathway
Central nervous system	Neurodegenerative diseases	Microglia, astrocytes	The accumulation of misfolded proteins within the ER of neurons and neuroglia leads to neurodegenerative diseases (Valgimigli et al, 2002). Encourage an inflammatory M1-like phenotype in microglia (Meares et al, 2014). TNF-α autocrine signaling during ER stress enhances the apoptotic signals of the UPR (Hu et al, 2006)	PERK-dependent eIF2α phosphorylation (PERK-eIF2α pathway) (Guthrie et al, 2016; Halliday et al, 2015; Moreno et al, 2013; Valgimigli et al, 2002)
Heart	Viral myocarditis	Cardiomyocytes	Promote the expression of proinflammatory cytokines and chemokines (Zha et al, 2015). Induce cell apoptosis (Liu et al, 2012; Zhang et al, 2010)	IRE1-associated NF-κB pathway
Lung	Sepsis-induced lung inflammation	Human pulmonary epithelial cell	Induce the release of proinflammatory cytokines (Wang et al, 2019a). Induce OS inside cells (Cheresh et al, 2013; Wang et al, 2019a)	ER stress–mediated TLR signaling (Wang et al, 2019a) IRE1α/NF-κB pathway (Wang et al, 2019a)
Kidney	Renal inflammation, Inflammation associated with lipid-induced injury of HMCs (Yang et al, 2017)	Renal cortical cells, HMCs	ER stress–mediated apoptosis (Jaikumkao et al, 2018) ER stress participates in inflammation associated with lipid-mediated injury to HMCs (ER stress induced in lipid-loaded HMCs) (Yang et al, 2017)	ER-calcium leak-induced apoptosis (Jaikumkao et al, 2018; Tabas and Ron, 2011) CHOP protein-related apoptosis pathway 14 (Jaikumkao et al, 2018) PERK-eIF2α-NF-κB pathways
Intestine	Gut inflammation	Gut epithelial cells (Eri et al, 2011)	Decreasing mucin-2 output resulting from ER stress diminishes the mucus barrier and ultimately trigger inflammation (Eri et al, 2011)	p38 MAPK-IRE1β
Adipose tissue	Adipose tissue inflammation	Stromal cells. Macrophages. Adipocytes	Increased production of proinflammatory cytokine by the adipose tissue (Ghosh et al, 2015)	ATF6-XBP1 pathway (Ghosh et al, 2015) IRE1-JNK-NF-κB pathway (Ghosh et al, 2015)
Skeletal muscle	Skeletal muscle inflammation	Skeletal muscle tissue	Propagate the production of proinflammatory cytokines	IRE1α-XBP1s pathway
Bone joint	Rheumatoid arthritis	Osteoclasts, synovial fibroblasts, synovial macrophages	Initiate inflammation and involved in RANKL-mediated osteoclast formation, enhancing osteoclastogenesis in inflammatory conditions	RANKL-induced pathways in the osteoclasts, NF-κB pathway

ATF6, activating transcription factor 6; eIF2α, eukaryotic translation initiation factor 2α; ER, endoplasmic reticulum; HMCs, human glomerular mesangial cells; IRE1, inositol-requiring enzyme 1α; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-kappa B; OS, oxidative stress; PERK, pancreatic endoplasmic reticulum kinase; RANKL, nuclear factor-kappa B ligand; TLR, Toll-like receptor; UPR, unfolded protein response; XBP1, X-box protein 1.

Table 2.

Target Genes and Effects of Activation of Hypoxia-Inducible Factor-1 and Inflammatory Response

Up/downregulate	Target genes/proteins	Effects	Reference(s)
Upregulate	TNF-α, IL-6, IL-1β, osteopontin	Proinflammation	Jain et al (2018)
	MCP-1	Proinflammatory Promote cell migration	Nakayama et al (2013)
	iNOS, COX4-2	Increase NO production and lead to vascular vasodilation. Increase blood and oxygen supply to cells	Jain et al (2018)
	iNOS	Positively regulate VEGF expression	Van der Wall and Palmer (2006)
	ENG, LEP	Angiogenesis	Jain et al (2018)
	EPO	Erythropoiesis	Kim et al (2013)
	Glycolytic enzymes		Sajid et al (2000)
	MMP-1, MMP-2, MMP-3	Matrix metabolism	Jain et al (2018)
	Cyclin G2, IGF2	Cell proliferation	Jain et al (2018)
	PHD2		Jain et al (2018)
	PDGF	Endothelial cell dysfunctionEndothelial cell proliferationAngiogenesis and proinflammation	Jain et al (2018)
	THBS1	Promote cell migration	Osada-Oka et al (2008)
	MIF	Promote foam cell transformation along with vascular remodeling, preventing migration	Jain et al (2018)
	SDF-1α	Control the recruitment of progenitor cells that attempt to repair the ischemic tissue	Marsch et al (2013)
	VEGF	Enhance cell permeability and angiogenesisPromote cell proliferation and migration	Tang et al (2004)
Downregulate	ABCA1	Reduce the efflux of cholesterol	Parathath et al (2013)
Downregulate	PTPs	Enhance ligand-induced PDGFR phosphorylationCellular proliferation and migration	ten Freyhaus et al (2011)

ABCA1, ATP-binding cassette transporters A1; COX4-2, cytochrome c oxidase4–2; EPO, erythropoietin; HIF-1, hypoxia-inducible factor 1; IGF2, insulin-like growth factor 2; IL, interleukin; iNOS, inducible nitric oxide synthase; LEP, leptin; MCP-1, monocyte chemoattractant protein-1; MIF, macrophage migration inhibitory factor; MMP-1, MMP-2, MMP-3, matrix metalloproteinases 1–3; NO, nitric oxide; PDGF, platelet-derived growth factors; PDGFR, platelet-derived growth factor (PDGF)/PDGFR receptor; PHD2, prolyl hydroxylase domain protein 2; PTPs, protein tyrosine phosphatases; SDF-1α, stromal cell–derived factor-1α; THBS1, thrombospondin 1; VEGF, vascular endothelial–derived growth factor.

Inflammatory bowel disease

The intestinal epithelium is constantly exposed to a microbial environment and is highly susceptible to extracellular and intracellular challenges (Kaser et al, 2013). IBD, including Crohn's disease and ulcerative colitis, is a group of inflammatory pathologies in the gastrointestinal tract. Ample evidence indicates that intestinal epithelial cells (IECs), particularly Paneth and goblet cells, are susceptible to changes in ER protein folding homeostasis as a consequence of environmental challenge and/or genetic defects (Cao et al, 2013; Gagliardi et al, 2021; McGuckin et al, 2011). Both in the mucosal tissues of patients with IBD and several murine models of colitis and Crohn's ileitis, ER stress markers are frequently identified (Engevik et al, 2021; Rees et al, 2020; Xu et al, 2020). Mice expressing a misfolding-prone mutant of MUC2 mucin, the major mucin in the large intestine, are manifested with ER stress, goblet cell dysfunction, and spontaneous colitis (Heazlewood et al, 2008).

Of interest, glucocorticoids, a family of drugs used in clinics for the treatment of IBD for decades, were found to attenuate ER stress in colonic epithelial cells via a mechanism of transactivating ER chaperones and ERAD components (Das et al, 2013). In animal models, the deletion of the UPR component XBP1 impairs the ability of intestinal epithelium to resolve ER stress ultimately leading to spontaneous intestinal inflammatory disorder with characteristics of human IBD (Kaser et al, 2013; Kaser et al, 2008). In fact, XBP1 malfunction is regarded as a genetic risk factor for both Crohn's disease and ulcerative colitis (Glas et al, 2012; Kaser et al, 2008). Although the precise molecular mechanism of how ER stress and the UPR regulate inflammation in IECs and inflammatory cells during IBD development and progression is yet to be elucidated, those prior studies support the overall conclusion that ER stress–induced epithelial dysfunction may be sufficient enough to inflict intestinal inflammation through impairment of mucosal homeostasis and barrier function in the gut.

It has been demonstrated that ROS is increased in the mucosal tissues of both chemical-induced and genetic models of IBD as well as in patients with IBD (Aviello and Knaus, 2017; Wendland et al, 2001). In the course of IBD initiation and progression, multiple cell types in the gut such as neutrophils, macrophages, and IEC can produce a large amount of superoxide. Overproduction of ROS, such as superoxide anion, which results in hydrogen peroxide and oxygen, contributes to intestinal inflammation by inducing epithelial cell death and mucosal tissue injury as well as igniting cell-autonomous inflammation in both IEC and inflammatory cells (Balmus et al, 2016; Zhu and Li, 2012). The depletion of antioxidants was also observed in inflamed mucosal tissues in both human and animal models (Esworthy et al, 2001; Khor et al, 2006). The concept that endogenous antioxidative stress defense plays an important role in the homeostasis of the intestinal mucosa was supported by studies of mice deficient in glutathione peroxidase-1/2 or Nrf2 (Esworthy et al, 2001; Khor et al, 2006).

It should be realized that although ER stress and OS may coexist in inflammatory mucosa, it is still unclear whether the two cellular stresses reciprocally induce each other in the gut or whether either one is adequate to initiate and promote IBD.

Infectious respiratory disease

ER stress and OS have been reported to participate in the pathophysiology of several nonmalignant diseases of lung including infections, cystic fibrosis, idiopathic pulmonary fibrosis, and asthma (Chen et al, 2018). In the case of infections, ER and OS could arise from direct effects of the pathogen on infected cells or as a consequence of the immune response to the pathogen. For instance, infection of respiratory epithelial cells with influenza A virus activates the UPR, which is driven by IRE1, but against the backdrop of PERK and ATF6 suppression (Hassan et al, 2012). As with chronic inflammatory lung diseases (such as COPD and chronic bronchitis), another mechanism by which infection leads to respiratory oxidation and ER stress is through the activation of immune system mediators such as cytokines and ROS (mainly hydrogen peroxide) (Barreiro et al, 2019; Wiegman et al, 2020). COPD and chronic bronchitis are characteristic of OS, inflammation, and mucus hypersecretion, all of which could drive ER stress under these circumstances (Tawiah et al, 2018).

Chronic kidney disease

The mechanism underlying nephrotoxicity by patulin (PAT), a metabolite produced by several species of the genera of Penicillium, Aspergillus, and Byssochlamys, has been linked to the induction of ER stress and production of excessive ROS, such as superoxide anion and hydrogen peroxide (Boussabbeh et al, 2016). Consistently, the two common dietary compounds quercetin (a natural flavonoid) and crocin (a natural carotenoid) could prevent PAT-induced apoptosis by inhibiting the ROS-mediated ER stress pathway. Some drugs with severe nephrotoxic side effects such as acetaminophen cause renal tubular injury via ROS-mediated ER stress as evidenced by PERK pathway activation, CHOP induction, and caspase-12 cleavage (Lorz et al, 2004; Ściskalska et al, 2015).

ER stress is also involved in age-related renal fibrosis. It has been reported that the age-linked aggregation of oxidative carbonylated Bip/Grp78 or PDI could lead to ER stress–induced kidney dysfunction (Naidoo, 2009). Likewise, the ER marker Bip/Grp78 was highly expressed in kidney biopsy specimens of patients with uromodulin-linked renal disease (Adam et al, 2012). These findings implicate that both ER stress and OS are key mediators for chemical-induced renal disease and that these two cellular stresses may also serve as protective mechanisms against kidney injury.

Viral hepatitis

ER stress–mediated ROS, free radicals, and superoxide anion are involved in the pathogenesis of different liver diseases including acute and chronic viral hepatitis (Apostolova et al, 2013; Duvigneau et al, 2019; Ríos-Ocampo et al, 2019). It has been shown that HBV and HCV replication and expression of viral proteins could induce cellular stress contributing to the pathogenesis of liver injury and liver fibrogenesis (He et al, 2018; Ke and Chen, 2012). The alterations in cellular homeostasis owing to the infection can lead to an increase of OS and/or ER stress. Increased OS has been found in liver biopsies from patients with chronic HCV infection and the levels of superoxide radicals and hydrogen peroxide were significantly higher in patients infected with HCV compared with other liver diseases (Ivanov et al, 2013; Valgimigli et al, 2002).

Furthermore, the free radical–mediated lipid peroxidation, steatosis, and prooxidant markers were also elevated during chronic HCV infection (Farinati et al, 1995). In acute hepatic disease, the GSH level is significantly decreased and the accumulation of peroxide accelerates protein aggregation and ER stress, which may increase the development of disease and reduce hepatic functional efficiency for chronic progression (Galligan et al, 2012).

In addition, studies have confirmed that ER stress induction by HBV infection has been implicated in liver carcinogenesis and disease progression with chronic inflammation through enhanced inflammation and OS-mediated DNA damage (Choi et al, 2019; Lorz et al, 2004).

Pancreatitis

Acinar cells in the pancreas are specialized in the production, storage, and secretion of various digestive enzymes and other proteins. To ensure this high rate of protein production, acinar cells are evolved to possess extensive ER networks. The role of ER stress responses has been extensively investigated in alcohol-related pancreatitis (Lugea et al, 2011). It is apparent that a functional UPR effectively alleviates ethanol-induced ER stress and protects from ethanol-induced pancreatic damage because partial deletion of XBP1, the essential component of UPR significantly increased pancreatic damage in the XBP1+/− mice fed with ethanol (Lugea et al, 2011). The role of the functional ER responses in other forms of pancreatic injury is currently uncertain (Sah and Saluja, 2011).

Although OS is generally regarded as a detrimental factor in pancreatitis, limited success is achieved in trials using antioxidant agents (Mohseni Salehi Monfared et al, 2009; Sateesh et al, 2009). A study investigating the role of ROS (peroxidation products) in pancreatitis yielded unexpected results (Booth et al, 2011). In this study, peroxide induction in the acinar cells by bile acid promoted apoptosis, whereas inhibition of peroxide generation led to necrosis accompanied by a significant reduction in ATP production, indicating that ROS generation within acinar cells functions as a protective response during pancreatitis. Meanwhile, OS in the neutrophils that were activated in response to acinar injury may be responsible for further dissemination of local and systemic inflammation (Booth et al, 2011). Thus, OS itself appears to have a dual role in the pancreatic injury.

Rheumatoid arthritis

In the synovial fluid of patients with RA, it has been found that the IRE1α/XBP1-mediated UPR branch is activated in macrophages (Qiu et al, 2013). In the animal model of inflammatory RA, IRE1α facilitates the production of proinflammatory cytokines from macrophages including IL-6, TNF-α, IL-1β, and RANTES. In macrophages and neutrophils, TLR interacts with IRE1α via signaling through MyD88 and TNF receptor–associated factor 6 (TRAF6) to activate IRE1α, thus promoting the expression of the genes encoding proinflammatory cytokines (Qiu et al, 2013). TLR-mediated IRE1α activation by TRAF6 acted through catalyzing IRE1α ubiquitination and blocking the recruitment of protein phosphatase 2A (PP2A), a phosphatase known to dephosphorylate and inactivate IRE1α.

OS also executes an essential part in the pathophysiology of RA (Phull et al, 2018). The imbalanced antioxidant system and higher lipid peroxidation levels in serum and synovial fluid have been reported in RA (Mateen et al, 2016). Although it is an indirect confirmation, the role of ROS in ligament degradation is evidenced from the presence of peroxidation products in the cartilage, and modified low-density lipoprotein (LDL), a nitrous type II collagen peptide, and oxidized IgG in the serum and urine of the RA patients (Hitchon and El-Gabalawy, 2004; Phull et al, 2018). Based on the observation that nitrated proteins, nitrotyrosine, and oxidized LDL were aggregated in the cartilage of patients suffering from arthritis, an immediate complication of peroxidation products in chronic arthritis has been proposed (Ahmed et al, 2016; Henrotin et al, 2003). Moreover, it was demonstrated that a low antioxidant status appeared to be a risk factor for initiating and developing RA in a Finnish cohort of 1419 adult men and women (Heliövaara et al, 1994) (Fig. 3).

FIG. 3.

ER stress and OS related to inflammatory diseases.

Conclusions and Perspectives

Over the past few decades, we have witnessed hot and fast advancing research topics on the ER stress response, OS, and inflammation as well as their interactive relationships in the biomedical field. However, an in-depth mechanistic understanding of the crosstalk or relationship between the intracellular stresses and inflammatory responses and their participation in disease progression has not yet been fully accomplished. Future studies are needed to understand the pathophysiology behind cellular stress-mediated alterations in the protein folding and misfolding processes and to dissect the precise mechanism(s) of the interactions between ER stress and OS signaling in the context of inflammation with the hope of making them lucrative targets for therapeutic benefit to curing many dreadful diseases related to inflammation.

Footnotes

Acknowledgment

The authors thank everyone for their help with this review.

Authors' Contributions

All the authors have approved to publish this article. Y.T. and X.Z. wrote the article. T.C., E.C., Y.L., W.L., Y.H., and B.H. revised the article. S.L. critically revised the article for important intellectual content. All authors read and approved the final version of the article.

Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by the National Natural Science Foundation of China (No. 81201331), the Natural Science Foundation of Hunan Province (2022JJ30532) and Hunan Provincial Innovation University of South China Innovation Foundation for Postgraduate (No. 213YXC016).

References

Adam

, Bollée

, Fougeray

, et al. Endoplasmic reticulum stress in UMOD-related kidney disease: A human pathologic study. Am J Kidney Dis, 2012; 59(1):117–121; doi: 10.1053/j.ajkd.2011.08.014.

Ahmed

, Anwar

, Savage

, et al. Protein oxidation, nitration and glycation biomarkers for early-stage diagnosis of osteoarthritis of the knee and typing and progression of arthritic disease. Arthr Res Ther, 2016; 18(1):250; doi: 10.1186/s13075-016-1154-3.

Apostolova

, Gomez-Sucerquia

, Alegre

, et al. ER stress in human hepatic cells treated with Efavirenz: Mitochondria again. J Hepatol, 2013; 59(4):780–789; doi: 10.1016/j.jhep.2013.06.005.

Aviello

, Knaus

. ROS in gastrointestinal inflammation: Rescue or Sabotage?. Br J Pharmacol, 2017; 174(12):1704–1718; doi: 10.1111/bph.13428.

Balmus

, Ciobica

, Trifan

, et al. The implications of oxidative stress and antioxidant therapies in Inflammatory Bowel Disease: Clinical aspects and animal models. Saudi J Gastroenterol, 2016; 22(1):3–17; doi: 10.4103/1319-3767.173753.

Barreiro

, Salazar-Degracia

, Sancho-Muñoz

, et al. Endoplasmic reticulum stress and unfolded protein response profile in quadriceps of sarcopenic patients with respiratory diseases. J Cell Physiol, 2019; 234(7):11315–11329; doi: 10.1002/jcp.27789.

Booth

, Murphy

, Mukherjee

, et al. Reactive oxygen species induced by bile acid induce apoptosis and protect against necrosis in pancreatic acinar cells. Gastroenterology, 2011; 140(7):2116–2125; doi: 10.1053/j.gastro.2011.02.054.

Boussabbeh

, Prola

, Ben Salem

, et al. Crocin and quercetin prevent PAT-induced apoptosis in mammalian cells: Involvement of ROS-mediated ER stress pathway. Environ Toxicol, 2016; 31(12):1851–1858; doi: 10.1002/tox.22185.

Burman

, Tanjore

, Blackwell

. Endoplasmic reticulum stress in pulmonary fibrosis. Matrix Biol, 2018; 128(1):68–69:355–365; doi: 10.1016/j.matbio.2018.03.015.

10.

Cao

, Kaufman

. Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal, 2014; 21(3):396–413; doi: 10.1089/ars.2014.5851.

11.

Cao

, Zimmermann

, Chuang

, et al. The unfolded protein response and chemical chaperones reduce protein misfolding and colitis in mice. Gastroenterology, 2013; 144(5):989.e6–1000.e6; doi: 10.1053/j.gastro.2013.01.023.

12.

Chen

, Burr

, McGuckin

. Oxidative and endoplasmic reticulum stress in respiratory disease. Clin Transl Immunol, 2018; 7(6):e1019; doi: 10.1002/cti2.1019.

13.

Chen

, Cubillos-Ruiz

. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer, 2021; 21(2):71–88; doi: 10.1038/s41568-020-00312-2.

14.

Chen

, Guo

, Ge

, et al. ER stress activates the NLRP3 inflammasome: A novel mechanism of atherosclerosis. Oxidat Med Cell Longev, 2019; 2019:3462530; doi: 10.1155/2019/3462530.

15.

Cheresh

, Kim

, Tulasiram

, et al. Oxidative stress and pulmonary fibrosis. Biochim Biophys Acta, 2013; 1832(7):1028–1040; doi: 10.1016/j.bbadis.2012.11.021.

16.

Choi

, Lee

, Kim

. Naturally occurring hepatitis B virus mutations leading to endoplasmic reticulum stress and their contribution to the progression of hepatocellular carcinoma. Int J Mol Sci, 2019; 20(3):597; doi: 10.3390/ijms20030597.

17.

Cullinan

, Diehl

. Coordination of ER and oxidative stress signaling: The PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol, 2006; 38(3):317–332; doi: 10.1016/j.biocel.2005.09.018.

18.

Das

, Png

, Oancea

, et al. Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins. J Exp Med, 2013; 210(6):1201–1216; doi: 10.1084/jem.20121268.

19.

de Torre-Minguela

, Mesa Del Castillo

, Pelegrín

. The NLRP3 and pyrin inflammasomes: Implications in the pathophysiology of autoinflammatory diseases. Front Immunol, 2017; 8:43; doi: 10.3389/fimmu.2017.00043.

20.

Duvigneau

, Luís

, Gorman

, et al. Crosstalk between inflammatory mediators and endoplasmic reticulum stress in liver diseases. Cytokine, 2019; 124(C):154577; doi: 10.1016/j.cyto.2018.10.018.

21.

Engevik

, Herrmann

, Ruan

, et al. Bifidobacterium dentium-derived y-glutamylcysteine suppresses ER-mediated goblet cell stress and reduces TNBS-driven colonic inflammation. Gut Microb, 2021; 13(1):1–21; doi: 10.1080/19490976.2021.1902717.

22.

Eri

, Adams

, Tran

, et al. An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity. Mucos Immunol, 2011; 4(3):354–364; doi: 10.1038/mi.2010.74.

23.

Esworthy

, Aranda

, Martín

, et al. Mice with combined disruption of Gpx1 and Gpx2 genes have colitis. Am J Physiol Gastrointest Liver Physiol, 2001; 281(3):G848–G855; doi: 10.1152/ajpgi.2001.281.3.G848.

24.

Farinati

, Cardin

, De Maria

, et al. Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol, 1995; 22(4):449–456; doi: 10.1016/0168-8278(95)80108-1.

25.

Gagliardi

, Monzani

, Clemente

, et al. A Gut-ex-vivo system to study gut inflammation associated to inflammatory bowel disease (IBD). Biology, 2021; 10(7):605; doi: 10.3390/biology10070605.

26.

Galligan

, Smathers

, Shearn

, et al. Oxidative stress and the ER stress response in a murine model for early-stage alcoholic liver disease. J Toxicol, 2012; 2012(Pt.II):207594; doi: 10.1155/2012/207594.

27.

Ghosh

, Garg

, Mau

, et al. Elevated endoplasmic reticulum stress response contributes to adipose tissue inflammation in aging. J Gerontol Ser A Biol Sci Med Sci, 2015; 70(11):1320–1329; doi: 10.1093/gerona/glu186.

28.

Glas

, Seiderer

, Czamara

, et al. PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites. PLoS One, 2012; 7(12):e52873; doi: 10.1371/journal.pone.0052873.

29.

Gong

, Wang

, Yang

, et al. Plant lectins activate the NLRP3 inflammasome to promote inflammatory disorders. J Immunol (Baltimore, MD: 1950), 2017; 198(5):2082–2092; doi: 10.4049/jimmunol.1600145.

30.

Guo

, Hu

, Chen

, et al. Cold exposure induces intestinal barrier damage and endoplasmic reticulum stress in the colon via the SIRT1/Nrf2 signaling pathway. Front Physiol, 2022; 13:822348; doi: 10.3389/fphys.2022.822348.

31.

Guthrie

, Abiraman

, Plyler

, et al. Attenuation of PKR-like ER kinase (PERK) signaling selectively controls endoplasmic reticulum stress-induced inflammation without compromising immunological responses. J Biol Chem, 2016; 291(30):15830–15840; doi: 10.1074/jbc.M116.738021.

32.

Halliday

, Radford

, Sekine

, et al. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis, 2015; 6(3):e1672; doi: 10.1038/cddis.2015.49.

33.

Hasanain

, Bhattacharjee

, Pandey

, et al. α-Solanine induces ROS-mediated autophagy through activation of endoplasmic reticulum stress and inhibition of Akt/mTOR pathway. Cell Death Dis, 2015; 6(8):e1860; doi: 10.1038/cddis.2015.219.

34.

Hassan

, Zhang

, Powers

, et al. Influenza A viral replication is blocked by inhibition of the inositol-requiring enzyme 1 (IRE1) stress pathway. J Biol Chem, 2012; 287(7):4679–4689; doi: 10.1074/jbc.M111.284695.

35.

, Qiu

, Han

, et al. ER stress regulating protein phosphatase 2A-B56γ, targeted by hepatitis B virus X protein, induces cell cycle arrest and apoptosis of hepatocytes. Cell Death Dis, 2018; 9(7):762; doi: 10.1038/s41419-018-0787-3.

36.

Heazlewood

, Cook

, Eri

, et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med, 2008; 5(3):e54; doi: 10.1371/journal.pmed.0050054.

37.

Heliövaara

, Knekt

, Aho

, et al. Serum antioxidants and risk of rheumatoid arthritis. Ann Rheum Dis, 1994; 53(1):51–53; doi: 10.1136/ard.53.1.51.

38.

Henriksen

, Diamond-Stanic

, Marchionne

. Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radic Biol Med, 2011; 51(5):993–999; doi: 10.1016/j.freeradbiomed.2010.12.005.

39.

Henrotin

, Bruckner

, Pujol

. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthr Cartil, 2003; 11(10):747–755; doi: 10.1016/s1063-s4584(03)00150-x.

40.

Hitchon

, El-Gabalawy

. Oxidation in rheumatoid arthritis. Arthr Res Ther, 2004; 6(6):265–278; doi: 10.1186/ar1447.

41.

, Han

, Couvillon

, et al. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol, 2006; 26(8):3071–3084; doi: 10.1128/mcb.26.8.3071-3084.2006.

42.

Ivanov

, Bartosch

, Smirnova

, et al. HCV and oxidative stress in the liver. Viruses, 2013; 5(2):439–469; doi: 10.3390/v5020439.

43.

Jaikumkao

, Pongchaidecha

, Chueakula

, et al. Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, slows the progression of renal complications through the suppression of renal inflammation, endoplasmic reticulum stress and apoptosis in prediabetic rats. Diabetes Obes Metab, 2018; 20(11):2617–2626; doi: 10.1111/dom.13441.

44.

Jain

, Nikolopoulou

, Xu

, et al. Hypoxia inducible factor as a therapeutic target for atherosclerosis. Pharmacol Ther, 2018; 183:22–33; doi: 10.1016/j.pharmthera.2017.09.003.

45.

Kaser

, Adolph

, Blumberg

. The unfolded protein response and gastrointestinal disease. Semin Immunopathol, 2013; 35(3):307–319; doi: 10.1007/s00281-013-0377-5.

46.

Kaser

, Lee

, Franke

, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell, 2008; 134(5):743–756; doi: 10.1016/j.cell.2008.07.021.

47.

Kattoor

, Pothineni

NVK

, Palagiri

, et al. Oxidative stress in atherosclerosis. Curr Atheroscler Rep, 2017; 19(11):42; doi: 10.1007/s11883-017-0678-6.

48.

, Chen

. Hepatitis C virus and cellular stress response: Implications to molecular pathogenesis of liver diseases. Viruses, 2012; 4(10):2251–2290; doi: 10.3390/v4102251.

49.

Khor

, Huang

, Kwon

, et al. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res, 2006; 66(24):11580–11584; doi: 10.1158/0008-5472.Can-06-3562.

50.

Kim

, Jeong

, Kim

, et al. Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-κB/HIF-1α signaling pathway. Sci Rep, 2013; 3(1):1142; doi: 10.1038/srep01142.

51.

Komura

, Sakai

, Honda

, et al. ER stress induced impaired TLR signaling and macrophage differentiation of human monocytes. Cell Immunol, 2013; 282(1):44–52; doi: 10.1016/j.cellimm.2013.04.006.

52.

Kudo

, Sugimoto

, Arias

, et al. PKCλ/ι loss induces autophagy, oxidative phosphorylation, and NRF2 to promote liver cancer progression. Cancer Cell, 2020; 38(2):247.e11–262.e11; doi: 10.1016/j.ccell.2020.05.018.

53.

Laudisi

, Di Fusco

, Dinallo

, et al. The food additive maltodextrin promotes endoplasmic reticulum stress-driven mucus depletion and exacerbates intestinal inflammation. Cell Mol Gastroenterol Hepatol, 2019; 7(2):457–473; doi: 10.1016/j.jcmgh.2018.09.002.

54.

Lebeaupin

, Proics

, de Bieville

, et al. ER stress induces NLRP3 inflammasome activation and hepatocyte death. Cell Death Dis, 2015; 6(9):e1879; doi: 10.1038/cddis.2015.248.

55.

Lee

, Yang

. Role of NADPH oxidase/ROS in pro-inflammatory mediators-induced airway and pulmonary diseases. Biochem Pharmacol, 2012; 84(5):581–590; doi: 10.1016/j.bcp.2012.05.005.

56.

Lee

, Jeong

, Lee

, et al. Tacrolimus regulates endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation: In vitro and collagen-induced arthritis mouse model. Cell Biol Int, 2018; 42(4):393–402; doi: 10.1002/cbin.10861.

57.

Lerner

, Upton

, Praveen

, et al. IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab, 2012; 16(2):250–264; doi: 10.1016/j.cmet.2012.07.007.

58.

Liong

, Lappas

. Endoplasmic reticulum stress regulates inflammation and insulin resistance in skeletal muscle from pregnant women. Mol Cell Endocrinol, 2016; 425:11–25; doi: 10.1016/j.mce.2016.02.016.

59.

Liu

, Zhang

, Yuan

, et al. The immunity-related GTPase Irgm3 relieves endoplasmic reticulum stress response during coxsackievirus B3 infection via a PI3K/Akt dependent pathway. Cell Microbiol, 2012; 14(1):133–146; doi: 10.1111/j.1462-5822.2011.01708.x.

60.

Lorz

, Justo

, Sanz

, et al. Paracetamol-induced renal tubular injury: A role for ER stress. J Am Soc Nephrol, 2004; 15(2):380–389; doi: 10.1097/01.asn.0000111289.91206.b0.

61.

Lugea

, Tischler

, Nguyen

, et al. Adaptive unfolded protein response attenuates alcohol-induced pancreatic damage. Gastroenterology, 2011; 140(3):987–997; doi: 10.1053/j.gastro.2010.11.038.

62.

Maamoun

, Benameur

, Pintus

, et al. Crosstalk between oxidative stress and endoplasmic reticulum (ER) stress in endothelial dysfunction and aberrant angiogenesis associated with diabetes: A focus on the protective roles of heme oxygenase (HO)-1. Front Physiol, 2019; 10:70; doi: 10.3389/fphys.2019.00070.

63.

Margittai

, Löw

, Stiller

, et al. Production of H₂O₂ in the endoplasmic reticulum promotes in vivo disulfide bond formation. Antioxid Redox Signal, 2012; 16(10):1088–1099; doi: 10.1089/ars.2011.4221.

64.

Marsch

, Sluimer

, Daemen

. Hypoxia in atherosclerosis and inflammation. Curr Opin Lipidol, 2013; 24(5):393–400; doi: 10.1097/MOL.0b013e32836484a4.

65.

Mateen

, Moin

, Khan

, et al. Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis. PLoS One, 2016; 11(4):e0152925; doi: 10.1371/journal.pone.0152925.

66.

McGuckin

, Eri

, Das

, et al. Intestinal secretory cell ER stress and inflammation. Biochem Soc Trans, 2011; 39(4):1081–1085; doi: 10.1042/bst0391081.

67.

Meares

, Liu

, Rajbhandari

, et al. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Mol Cell Biol, 2014; 34(20):3911–3925; doi: 10.1128/mcb.00980-14.

68.

Mennerich

, Kellokumpu

, Kietzmann

. Hypoxia and reactive oxygen species as modulators of endoplasmic reticulum and golgi homeostasis. Antioxid Redox Signal, 2019; 30(1):113–137; doi: 10.1089/ars.2018.7523.

69.

, Mayor

, Zhou

, et al. ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis, 2012; 3(1):e261; doi: 10.1038/cddis.2011.132.

70.

Mohseni Salehi Monfared

, Vahidi

, Abdolghaffari

, et al. Antioxidant therapy in the management of acute, chronic and post-ERCP pancreatitis: A systematic review. World J Gastroenterol, 2009; 15(36):4481–4490; doi: 10.3748/wjg.15.4481.

71.

Moreno

, Halliday

, Molloy

, et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med, 2013; 5(206):206ra138; doi: 10.1126/scitranslmed.3006767.

72.

Naidoo

. The endoplasmic reticulum stress response and aging. Rev Neurosci, 2009; 20(1):23–37; doi: 10.1515/revneuro.2009.20.1.23.

73.

Nakayama

, Kurobe

, Sugasawa

, et al. Role of macrophage-derived hypoxia-inducible factor (HIF)-1α as a mediator of vascular remodelling. Cardiovasc Res, 2013; 99(4):705–715; doi: 10.1093/cvr/cvt146.

74.

Nishimoto

, Koike

, Inoue

, et al. Activation of Nrf2 attenuates carbonyl stress induced by methylglyoxal in human neuroblastoma cells: Increase in GSH levels is a critical event for the detoxification mechanism. Biochem Biophys Res Commun, 2017; 483(2):874–879; doi: 10.1016/j.bbrc.2017.01.024.

75.

Oakes

, Papa

. The role of endoplasmic reticulum stress in human pathology. Ann Rev Pathol, 2015; 10(1):173–194; doi: 10.1146/annurev-pathol-012513-104649.

76.

Osada-Oka

, Ikeda

, Akiba

, et al. Hypoxia stimulates the autocrine regulation of migration of vascular smooth muscle cells via HIF-1alpha-dependent expression of thrombospondin-1. J Cell Biochem, 2008; 104(5):1918–1926; doi: 10.1002/jcb.21759.

77.

Parathath

, Yang

, Mick

, et al. Hypoxia in murine atherosclerotic plaques and its adverse effects on macrophages. Trends Cardiovasc Med, 2013; 23(3):80–84; doi: 10.1016/j.tcm.2012.09.004.

78.

Perera

, Kunde

, Eri

. NLRP3 inhibitors as potential therapeutic agents for treatment of inflammatory bowel disease. Curr Pharm Des, 2017; 23(16):2321–2327; doi: 10.2174/1381612823666170201162414.

79.

Peyssonnaux

, Cejudo-Martin

, Doedens

, et al. Cutting edge: Essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. J Immunol (Baltimore, MD: 1950), 2007; 178(12):7516–7519; doi: 10.4049/jimmunol.178.12.7516.

80.

Phull

, Nasir

, Haq

, et al. Oxidative stress, consequences and ROS mediated cellular signaling in rheumatoid arthritis. Chem Biol Interact, 2018; 281:121–136; doi: 10.1016/j.cbi.2017.12.024.

81.

Qiu

, Zheng

, Chang

, et al. Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis. EMBO J, 2013; 32(18):2477–2490; doi: 10.1038/emboj.2013.183.

82.

Ralston

, Lyons

, Kennedy

, et al. Fatty acids and NLRP3 inflammasome-mediated inflammation in metabolic tissues. Ann Rev Nutr, 2017; 37:77–102; doi: 10.1146/annurev-nutr-071816-064836.

83.

Rees

, Stahl

, Jacobson

, et al. Enteroids derived from inflammatory bowel disease patients display dysregulated endoplasmic reticulum stress pathways, leading to differential inflammatory responses and dendritic cell maturation. J Crohns Colitis, 2020; 14(7):948–961; doi: 10.1093/ecco-jcc/jjz194.

84.

Ren

, Li

, Yan

, et al. Crosstalk between oxidative stress and ferroptosis/oxytosis in ischemic stroke: possible targets and molecular mechanisms. Oxidat Med Cell Longev, 2021; 2021:6643382; doi: 10.1155/2021/6643382.

85.

Riaz

, Junjappa

, Handigund

, et al. Role of endoplasmic reticulum stress sensor IRE1a in cellular physiology, calcium, ROS signaling, and metaflammation. Cells, 2020; 9(5):1160; doi: 10.3390/cells9051160.

86.

Ríos-Ocampo

, Daemen

, Buist-Homan

, et al. Hepatitis C virus core or NS3/4A protein expression preconditions hepatocytes against oxidative stress and endoplasmic reticulum stress. Redox Rep Commun Free Radic Rese, 2019; 24(1):17–26; doi: 10.1080/13510002.2019.1596431.

87.

Sah

, Saluja

. Molecular mechanisms of pancreatic injury. Curr Opin Gastroenterol, 2011; 27(5):444–451; doi: 10.1097/MOG.0b013e328349e346.

88.

Sajid

, Lele

, Stouffer

. Autocrine thrombospondin partially mediates TGF-beta1- induced proliferation of vascular smooth muscle cells. Am J Physiol Heart Circ Physiol, 2000; 279(5):H2159–H2165; doi: 10.1152/ajpheart.2000.279.5.H2159.

89.

Sateesh

, Bhardwaj

, Singh

, et al. Effect of antioxidant therapy on hospital stay and complications in patients with early acute pancreatitis: A randomised controlled trial. Trop Gastroenterol, 2009; 30(4):201–206.

90.

Ściskalska

, Śliwińska-Mossoń

, Podawacz

, et al. Mechanisms of interaction of the N-acetyl-p-aminophenol metabolites in terms of nephrotoxicity. Drug Chem Toxicol, 2015; 38(2):121–125; doi: 10.3109/01480545.2014.928722.

91.

Shenderov

, Riteau

, Yip

, et al. Cutting edge: Endoplasmic reticulum stress licenses macrophages to produce mature IL-1β in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway. J Immunol (Baltimore, MD: 1950), 2014; 192(5):2029–2033; doi: 10.4049/jimmunol.1302549.

92.

Srinivas

, Tan

BWQ

, Vellayappan

, et al. ROS and the DNA damage response in cancer. Redox Biol, 2019; 25(C):101084; doi: 10.1016/j.redox.2018.101084.

93.

Tabas

, Ron

. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol, 2011; 13(3):184–190; doi: 10.1038/ncb0311-184.

94.

Tang

, Wang

, Esko

, et al. Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell, 2004; 6(5):485–495; doi: 10.1016/j.ccr.2004.09.026.

95.

Tawiah

, Cornick

, Moreau

, et al. High MUC2 mucin expression and misfolding induce cellular stress, reactive oxygen production, and apoptosis in goblet cells. Am J Pathol, 2018; 188(6):1354–1373; doi: 10.1016/j.ajpath.2018.02.007.

96.

ten Freyhaus

, Dagnell

, Leuchs

, et al. Hypoxia enhances platelet-derived growth factor signaling in the pulmonary vasculature by down-regulation of protein tyrosine phosphatases. Am J Respir Crit Care Med, 2011; 183(8):1092–1102; doi: 10.1164/rccm.200911-201663OC.

97.

Tsai

, Huang

, Wu

, et al. Antioxidant, cell-protective, and anti-melanogenic activities of leaf extracts from wild bitter melon (Momordica charantia Linn. var. abbreviata Ser.) cultivars. Bot Stud, 2014; 55(1):78; doi: 10.1186/s40529-014-0078-y.

98.

Valgimigli

, Valgimigli

, Trerè

, et al. Oxidative stress EPR measurement in human liver by radical-probe technique. Correlation with etiology, histology and cell proliferation. Free Radic Res, 2002; 36(9):939–948; doi: 10.1080/107156021000006653.

99.

Van der Wall

, Palmer

. On the AJR viewbox. Monomelic spread of metastatic disease due to proximal deep venous thrombosis. Am J Roentgenol, 2006; 186(6):1797–1799; doi: 10.2214/ajr.04.0930.

100.

Victor

, Sarada

, Ramkumar

. Crosstalk between endoplasmic reticulum stress and oxidative stress: Focus on protein disulfide isomerase and endoplasmic reticulum oxidase 1. Eur J Pharmacol, 2021; 892:173749; doi: 10.1016/j.ejphar.2020.173749.

101.

Wang

, Yang

, Peng

, et al. Ginsenoside Rg1 regulates SIRT1 to ameliorate sepsis-induced lung inflammation and injury via inhibiting endoplasmic reticulum stress and inflammation. Mediat Inflamm, 2019a;2019:6453296; doi: 10.1155/2019/6453296.

102.

Wang

, Hu

, Yin

, et al. TLR4 participates in sympathetic hyperactivity Post-MI in the PVN by regulating NF-κB pathway and ROS production. Redox Biol, 2019b;24:101186; doi: 10.1016/j.redox.2019.101186.

103.

Wendland

, Aghdassi

, Tam

, et al. Lipid peroxidation and plasma antioxidant micronutrients in Crohn disease. Am J Clin Nutr, 2001; 74(2):259–264; doi: 10.1093/ajcn/74.2.259.

104.

Wiegman

, Li

, Ryffel

, et al. Oxidative stress in ozone-induced chronic lung inflammation and emphysema: A facet of chronic obstructive pulmonary disease. Front Immunol, 2020; 11:1957; doi: 10.3389/fimmu.2020.01957.

105.

, Tao

, Yang

, et al. Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis. Cell Death Dis, 2020; 11(2):86; doi: 10.1038/s41419-020-2299-1.

106.

Yang

, Cui

, Shi

, et al. Endoplasmic reticulum stress participates in inflammation-accelerated, lipid-mediated injury of human glomerular mesangial cells. Nephrology (Carlton, Vic.), 2017; 22(3):234–242; doi: 10.1111/nep.12748.

107.

Zepeda

, Pessoa

Jr. , Castillo

, et al. Cellular and molecular mechanisms in the hypoxic tissue: Role of HIF-1 and ROS. Cell Biochem Funct, 2013; 31(6):451–459; doi: 10.1002/cbf.2985.

108.

Zha

, Yue

, Dong

, et al. Endoplasmic reticulum stress aggravates viral myocarditis by raising inflammation through the IRE1-associated NF-κB pathway. Canadian J Cardiol, 2015; 31(8):1032–1040; doi: 10.1016/j.cjca.2015.03.003.

109.

Zhang

, Ye

, Su

, et al. Coxsackievirus B3 infection activates the unfolded protein response and induces apoptosis through downregulation of p58IPK and activation of CHOP and SREBP1. J Virol, 2010; 84(17):8446–8459; doi: 10.1128/jvi.01416-09.

110.

Zhang

, Wang

, Vikash

, et al. ROS and ROS-mediated cellular signaling. Oxidat Med Cell Longev, 2016; 2016:4350965; doi: 10.1155/2016/4350965.

111.

Zhu

, Li

. Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: Updated experimental and clinical evidence. Exp Biol Med (Maywood, NJ), 2012; 237(5):474–480; doi: 10.1258/ebm.2011.011358.