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Published in final edited form as: Cell Biochem Funct. 2024 Dec;42(8):e70007. doi: 10.1002/cbf.70007

Endothelial Unfolded Protein Response-Mediated Cytoskeletal Effects

Joy T Folahan 1, Saikat Fakir 1, Nektarios Barabutis 1
PMCID: PMC11528298  NIHMSID: NIHMS2031766  PMID: 39449673

Abstract

The endothelial semipermeable monolayers ensure tissue homeostasis, are subjected to a plethora of stimuli, and their function depends on cytoskeletal integrity and remodeling. The permeability of those membranes can fluctuate to maintain organ homeostasis. In cases of severe injury, inflammation or disease, barrier hyperpermeability can cause irreparable damage of endothelium-dependent issues, and eventually death. Elucidation of the signaling regulating cytoskeletal structure and barrier integrity promotes the development of targeted pharmacotherapies towards disorders related to the impaired endothelium (e.g., acute respiratory distress syndrome, sepsis). Recent reports investigate the role of unfolded protein response in barrier function. Herein we review the cytoskeletal components, the unfolded protein response function; and their interrelations on health and disorder. Moreover, we emphasize on unfolded protein response modulators, since they ameliorate illness related to endothelial leak.

Keywords: ARDS, growth hormone, heat shock protein 90, lungs

1 |. Introduction

The cytoskeleton is a vital network of filaments essential in maintaining cell shape and facilitating cell division across bacteria, archaea, and eukaryotes [1]. In eukaryotic cells, it forms a network that spans from the nucleus to the cell membrane [2]. It is composed of three primary components (actin filaments, microtubules, and intermediate filaments [IFs]) which form a complex network to provide structural support (Figure 1).

FIGURE 1 |.

FIGURE 1 |

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Protein misfolding due to endoplasmic reticulum (ER) stress leads to lung, eye, and BBB endothelial barrier dysfunction, associated with cytoskeletal remodeling.

2 |. Actin Filaments

Actin filaments, also known as microfilaments, are a vital part of the cytoskeleton in eukaryotic cells [3]. In non-muscle cells, actin plays a crucial role in cell motility [4]. This dynamic network determines the shape, structure, and mechanical properties of the cells [5]. Accessory proteins regulate actin filament formation and localization.

3 |. Microtubules

Microtubules are long, cylindrical filaments consisting of 13–15 protofilament strands. Those highly polar biopolymeric formations are composed of globular tubulin subunits to form a hollow tube-like structure [6]. They are involved in cell configuration, spreading, polarization, division, cytoplasmic vesicle transportation, and signaling [7, 8]. Microtubules are the most rigid cytoskeletal component and synergize with actin filaments to regulate cell stiffness, mechanical properties, and overall rigidity [9]. They act to transport membrane-bound vesicles within the cell, in coordination with kinesin and dynein [10]. Kinesins typically travel in the direction of the microtubule’s plus end, while dyneins move toward the minus end [11]. In the neurons, this microtubule-based transport mechanism enables the delivery of vital components at the extremities of their lengthy extensions [12].

4 |. Intermediate Filaments (IFs)

IFs are a common component of various cell types [13]. They are thicker than the actin filaments and thinner than the microtubules or the muscle myosin filaments [14]. IFs form a network which links the nucleus and cell membrane to actin filaments and microtubules. They are essential for maintaining cell shape and structural integrity [15]. IFs subunits are elon-gated rather than globular and are arranged in an antipolar manner, giving the filament an overall lack of polarity [16]. Consequently, motor proteins do not move along IFs [17]. IFs play a key role in bridging the cell membrane and the nuclear interior and interact with the actin filaments, microtubules, as well as the nucleoskeleton/cytoskeleton complex [18]. This connection enables the integration of the nuclear interior with the cytoskeleton; facilitating communication and mechanical support between cell structural components [19] (Figure 1).

5 |. Lung Endothelium

The endothelium is a vital layer of cells lining the inner surface of blood vessels and lymphatic vessels. It serves to maintain vascular homeostasis and regulate various physiological processes [20]. The lung endothelium acts as an interface between the blood and lymphatic vessels [21]; and is involved in the regulation of immune responses, inflammation, angiogenesis, blood fluidity, platelet aggregation, and vascular tone [22]. Deregulation of the endothelial barrier results in the passage of fluid and cells into the lung interstitium and air spaces; leading to respiratory disorders [23]. Adherens and tight junctions provide endothelial mechanical stability [7]. The integrity of the pulmonary EC monolayer is dependent upon the EC cytoskeleton. Cytoskeletal remodeling leads to increased endothelial permeability [24]. Endothelial barrier integrity is maintained by cytoskeletal competing forces, intercellular junctions, and cell–matrix interactions [25].

Transforming growth factor beta 1 stimulation of endothelial cells (ECs) changes the architecture of the actin cytoskeleton, the degree of MLC phosphorylation, and cell-cell interactions, which compromises the EC barrier [26, 27]. Distraction of the cytoskeleton network leads to the formation of paracellular gaps and increased permeability [23]. Vascular EC contains gap, adherens, and tight junctions which involve vascular endothelial-cadherin (VE-cadherin), occludins, and claudins. At the cytoplasmic side, they are interconnected to cytoskeletal filaments through intracellular linker proteins such as catenins, α-actinin, and zonula occludens proteins [28]. VE-cadherin enhances homophilic adhesion by creating zipper-like AJs along cell contacts and interacts with p120, α, β, and γ-catenins to connect with the cytoskeleton [29].

The endothelial cells coordinate the passage of molecules across the alveolar-capillary barrier and maintain the balance of fluids and electrolytes in the lung [30]. They produce surfactant—a lipid-protein complex that reduces surface tension in the alveoli—to facilitate gaseous exchange [31]. Furthermore, the endothelial cells produce nitric oxide—a potent vasodilator—involved in pulmonary vascular tone and blood flow regulation [20, 30]. The clearance of inflammatory mediators and excess fluid from the alveolar space depend on endothelial cells [30, 31].

Dysfunction of the lung endothelium contributes to various pulmonary diseases, including acute respiratory distress syndrome (ARDS), pulmonary hypertension, and chronic obstructive pulmonary disease (COPD) [32, 33]. In ARDS, increased permeability and inflammation lead to fluid accumulation in the alveolar space, causing respiratory failure [33]. In pulmonary hypertension, endothelial dysfunction leads to vasoconstriction and vascular remodeling, resulting in increased pulmonary arterial pressure [34].

6 |. Blood–Brain Barrier (BBB) Endothelium

The BBB endothelium forms a tight, impermeable barrier between the bloodstream and the central nervous system (CNS), regulating the passage of molecules and maintaining CNS homeostasis [35, 36]. BBB endothelial cells express tight junction, adherens junctions, and transport proteins [35, 37]; as well as they produce growth factors and cytokines to support the survival and function of neighboring neurons and glial cells [37]. BBB dysfunction contributes to various neurological disorders, including multiple sclerosis, Alzheimer’s, and Parkinson’s disease [37–39]. In multiple sclerosis, BBB disruption allows autoimmune cell passage into the CNS, leading to demyelination and axonal dysfunction [40]. In Alzheimer’s disease, increased permeability of the BBB allows toxic substances to enter the CNS, contributing to neurodegeneration [41].

7 |. Eye Endothelium

Corneal endothelial cells are vital for maintaining corneal clarity, as they regulate fluid balance and prevent edema through their pump function [42]. Retinal endothelial cells line the tiny blood vessels that supply and drain the neural retina [43]. They also produce nitric oxide, which regulates blood flow and maintains retinal function [42]. Across the blood–retina barrier, the eye endothelium regulates the transport of essential nutrients and waste products. Eye endothelial cells produce growth factors and cytokines that promote the survival and function of neighboring retinal cells [43], and their dysfunction has been associated with diabetic retinopathy, age-related macular degeneration (AMD), and glaucoma [43–45]. In diabetic retinopathy, endothelial dysfunction leads to increased permeability and inflammation, resulting in retinal damage and vision loss [46]; whereas in AMD it contributes to the accumulation of toxic substances and inflammation, leading to retinal degeneration [47].

8 |. Unfolded Protein Response (UPR) and Endoplasmic Reticulum (ER) Stress

UPR is a complex cellular signaling pathway that aims to maintain ER homeostasis and promotes cell survival under ER stress [48, 49]. It is activated in response to the accumulation of misfolded or unfolded proteins in the ER, which can occur due to various factors such as genetic mutations, environmental stress, or viral infections [49, 50]. ER is a vital organelle responsible for protein synthesis, folding, and transport. Upon stress, protein folding and transport are disrupted [48, 49], and UPR is activated to restore ER homeostasis and survival [49, 50]. UPR is composed of three main branches, namely the PERK (PKR-like ER kinase) pathway, IRE1 (inositol-requiring enzyme 1), and ATF6 (activating transcription factor 6) [49–51].

8.1 |. PERK

PERK is a transmembrane protein kinase localized in the ER membrane. It is activated via phosphorylation under ER stress conditions. The translation initiation factor eIF2α is a downstream PERK target, which is suppressed by PERK activation [52, 53], and reduces protein synthesis. Those events prevent further accumulation of misfolded proteins in the ER.

The activation of PERK is a complex process that involves the dissociation of the chaperone protein binding immunoglobulin protein (BiP) from PERK, allowing PERK to oligomerize and auto-phosphorylate [53, 54]. This leads to the activation of PERK’s kinase activity, which phosphorylates and inhibits eIF2α [52, 54]. Additionally, PERK activation induces the expression of UPR target genes, including chaperones and protein degradation factors, which help to restore ER homeostasis [55]. These target genes include molecular chaperones such as GRP78 and GRP94, which assist in protein folding and assembly; as well as protein degradation factors such as endoplasmic reticulum-associated degradation (ERAD) components, which remove misfolded proteins from the ER [53, 55].

PERK activation can also initiate proapoptotic signaling pathways, leading to cell death if ER stress is severe or prolonged [55, 56]. Those effects are achieved through the activation of C/EBP homologous protein (CHOP) and c-Jun NH2-terminal kinase (JNK), which regulate the expression of proapoptotic genes and induce apoptosis [56]. Additionally, PERK activates the transcription factor ATF4, which modulates the expression of genes involved in amino acid metabolism, redox reactions, and ER stress responses. ATF4 target genes include those involved in the synthesis of amino acids, such as asparagine synthetase, as well as genes involved in redox reactions, such as glutathione reductase [57, 58].

The PERK pathway interacts with IRE1 and ATF6 to regulate ER homeostasis and mitigate ER stress. PERK phosphorylation leads to IRE1 activation, which regulates the splicing of X-box binding protein 1 (XBP1) and the expression of UPR target genes [51, 59]. Additionally, PERK-mediated ATF6 activation regulates UPR target genes involved in protein folding and degradation [60].

In addition to its role in regulating ER homeostasis, PERK pathway also plays a critical role in regulating cellular metabolism and redox reactions [61]. PERK activation can lead to the regulation of genes involved in amino acid metabolism (e.g., asparagine synthetase) as well as proteins involved in redox reactions (e.g., glutathione reductase) [61]. PERK dysfunction can lead to various diseases, including cancer, neurodegeneration, and metabolic disorders [53, 62, 63] (Figure 2).

FIGURE 2 |.

FIGURE 2 |

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Elements involved in ER stress-induced unfolded protein response (UPR) activation; UPR-related signaling pathways (PERK-eIF2α, IRE1α-XBP1, ATF6); and their impact on cell function and barrier integrity.

8.2 |. IRE1

The activation of IRE1 involves the dissociation of the chaperone protein BiP from IRE1, allowing IRE1 to oligomerize and auto-phosphorylate [51, 54, 64]. This leads to the activation of IRE1’s kinase activity, which phosphorylates and activates the ribonuclease activity of IRE1 [51, 54]. XBP1 is a critical transcription factor involved in the regulation of ER stress response genes and it is the downstream target of IRE1 [65]. XBP1 splicing leads to the removal of a 26-nucleotide intron, resulting in the generation of a frameshifted XBP1 protein [65]. This is a potent transcriptional activator that regulates the expression of genes involved in ER stress response, protein folding, and degradation [65, 66]. XBP1 target genes include molecular chaperones (e.g., GRP78 and GRP94), as well as protein degradation factors such as ERAD components, which remove misfolded proteins from the ER [67, 68].

Furthermore, the IRE1 pathway is also involved in the regulation of cellular differentiation and development [69]. XBP1 has been shown to modulate the expression of genes involved in cellular differentiation, development, cell cycle progression, and apoptosis [65]. IRE1 regulates cell metabolism, redox reactions, inflammation, and immune responses [69]; and increases PERK expression to activate the ERAD pathway [51]. This pathway is initiated by the recognition of misfolded proteins, which are detected by ER chaperones and lectins, such as calnexin and calreticulin. They bind to immature or misfolded proteins and prevent their aggregation [70, 71] (Figures 1 and 2).

Once recognized, misfolded proteins are retro-translocated from the ER to the cytosol through a process mediated by the Hrd1 E3 ubiquitin-protein ligase and other proteins [72, 73]. In the cytosol, misfolded proteins are ubiquitinated by a cascade of enzymatic reactions involving E1, E2, and E3 ubiquitin-conjugating enzymes. The polyubiquitinated proteins are then recognized by the 26S proteasome, a large protein complex responsible for protein degradation [72, 73]. The 26S proteasome consists of a 20S core particle and two 19S regulatory particles [74]. The 20S core particle contains the proteolytic active sites, while the 19S regulatory particles recognize and bind to polyubiquitinated proteins. Once bound, the misfolded protein is fed into the 20S core particle, where it is degraded into small peptides [74, 75].

Dysregulation of the IRE1 pathway has been implicated in various diseases, including cancer, neurodegeneration, glomerular disease, and metabolic disorders [65, 69]. Mutations in the IRE1 gene have been identified in cancer cells, leading to the activation of XBP1 and the regulation of genes involved in tumorigenesis [65]. IRE1 has also been implicated in the development of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease [76, 77].

8.3 |. ATF6

Activation of the ATF6 pathway occurs through the translocation of ATF6 from the ER to the Golgi apparatus, where it undergoes proteolytic cleavage [50, 54]. In its inactive state, ATF6 is localized to the ER membrane, bound to the molecular chaperone BiP, which maintains ATF6 in an inactive state by masking its Golgi-localization signal. Upon ER stress, BiP dissociates from ATF6, allowing it to translocate to the Golgi apparatus [49, 78].

In the Golgi, ATF6 is cleaved by the proteases S1P (Site-1 Protease) and S2P (Site-2 Protease), resulting in the release of its cytosolic domain [54]. The cleaved ATF6 fragment is translocated to the nucleus, where it binds to specific DNA sequences, known as ER stress response elements (ERSEs), to regulate the expression of target genes [54, 79]. ATF6 activation leads to the upregulation of genes involved in protein folding, degradation, and ER stress mitigation [80]. GRP78 and GRP94 are upregulated to assist in protein folding and assembly [71]. ERAD components are induced to remove misfolded proteins from the ER [70], whereas XBP1 and CHOP are upregulated [80].

ATF6 activation affects IRE1, PERK [50], and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) to modulate inflammation and immune responses [81–83], whereas its dysregulation may contribute to cancer, neurodegeneration, and metabolic disorders [84].

9 |. UPR Regulation and Dysfunction

UPR is tightly regulated to ensure that it is activated only under conditions of ER stress and that it returns to a quiescent state once ER homeostasis is restored [49, 54]. UPR involves multiple mechanisms, such as the negative feedback loop which inhibits UPR activity once ER homeostasis is restored, preventing excessive or prolonged activation. Other mechanisms include phosphatases, such as PP2A and PP1—which dephosphorylate and inactivate PERK, IRE1, and ATF6—to terminate their response [49, 81]. Additionally, BiP and GRP94 play a crucial role in regulating the activity of UPR components and preventing their overactivation. BiP binds to—and inhibits—the activation of PERK and IRE1, whereas GRP94 regulates the ATF6 [54, 71]. UPR has been implicated in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease [48, 50, 79]; and in cancer, where it promotes resistance to chemotherapy [48]. UPR is also involved in the development of metabolic disorders such as diabetes and obesity [54, 85].

10 |. UPR Activation in the Lung Endothelium

UPR activation exerts protective effects against various forms of lung injury and leads to the upregulation of antioxidant and cytoprotective genes, which helps to mitigate oxidative stress and inflammation [86, 87]. It has been shown to promote endothelial cell survival and maintain endothelial barrier function, thereby preventing vascular leak and edema [88, 89]. Moreover, it suppresses the production of proinflammatory cytokines and reduces the recruitment of immune cells to the lungs [90]. ATF6 modulates barrier function and participates in the protective effects of GHRH antagonists and Hsp90 inhibitors in the endothelium [91–93]. Selective activation of that highly conserved pathway may serve as a potential therapeutic target in lung inflammatory disease [87, 92, 94, 95].

11 |. Protective Effects of UPR Activation in BBB

The BBB is formed by microvascular endothelial cells in the neurovascular unit, serving as a critical boundary between the brain and the bloodstream. This barrier maintains high resistance and prevents harmful substances, blood cells, and pathogens from entering the brain [96]. It regulates the entry of nutrients, vitamins, ions, and other molecules into the brain, and protects from toxins and pathogens [97, 98]. BBB leak is associated with aging and various psychiatric conditions, including schizophrenia, depression, autism spectrum disorder, and mood disorders [99]. ER stress is involved in the progression of CNS disorders, including traumatic brain injury [100]. UPR activates the expression of antioxidant and cytoprotective genes [101], improves endothelial barrier function, inhibits inflammatory responses and immune cell infiltration [86]. GHRH antagonists and Hsp90 inhibitors—which induce UPR—protect human brain microvascular cells against breakdown [102–104]. Therefore, UPR activation in the BBB may reveal new therapeutic possibilities against brain disorders [100, 105].

12 |. UPR Activation on Eye Function

UPR activation has been shown to have protective effects on eye function, particularly in the context of retinal degenerative diseases. It restores ER protein homeostasis by reducing protein translation, increasing protein-folding capacity, and promoting misfolded protein degradation [106, 107]. UPR governs the homeostasis of protein production, modification, trafficking, and degradation; and regulates cell metabolism, mitochondrial function, and calcium levels. Recent studies revealed a significant link between cell processes related to UPR and diabetic retinopathy progression [108, 109]. UPR promotes retinal degeneration and triggers an inflammatory response in the retina. However, it was also suggested that a persistently activated UPR could be responsible for promoting retinal degeneration via the UPR-induced proinflammatory cytokine interleukin 1 [110]. In animal models of retinitis pigmentosa, UPR activation reduces mutant rhodopsin retention in the ER and diminishes rod photoreceptor degeneration [111]. Additionally, UPR protects retinal pigment epithelial cells from ER stress-induced damage [112] and reduces retinal endothelial inflammation and vascular leakage in diabetes [110, 113, 114]. UPR activation may serve as a potential therapeutic strategy in age- and disease-related retinal degeneration [115].

13 |. Effects of Severe ER Stress in the Endothelium

13.1 |. Lung

Prolonged ER stress leads to harmful effects [57]. The lung endothelium is particularly susceptible to ER stress due to its high demand for protein synthesis and folding [116]. It can lead to inflammation, apoptosis, and dysfunction; contributing to pulmonary diseases such as ARDS and COPD [117]. ER stress-induced NF-κB activation and proinflammatory cytokine release may result in caspase-3 activation and DNA fragmentation affecting angiogenesis and exacerbating disease progression [118].

13.2 |. BBB

Severe ER stress in the BBB endothelium disrupts the neurovascular unit, leading to neurological disorders (e.g., multiple sclerosis, Alzheimer’s, and Parkinson’s disease [119–121]. It can also activate astrocytes and microglia, leading to inflammation and disrupted tight junctions and adherens junctions, which in turn allow toxic substances to enter the CNS [120, 122]. In multiple sclerosis, ER stress leads to demyelination and axonal damage [120]. In Alzheimer’s disease, ER stress contributes to amyloid-β accumulation and neurofibrillary tangle formation [121].

13.3 |. Eye

The eye endothelium is susceptible to ER stress due to its high metabolic demand and exposure to oxidative stress, which can contribute to ocular diseases such as dry eye syndrome, diabetic retinopathy, and AMD [106, 123, 124]. In diabetic retinopathy, the disruption of the blood-retina barrier allows vascular leakage and impaired angiogenesis which leads to retinal degeneration [106]. In AMD, ER stress impairs angiogenesis, leading to retinal degeneration and vision loss [125].

14 |. UPR Inducers as Therapeutic Agents

UPR inducers have been explored as therapeutic agents in cancers and inflammatory disease, including arthritis, colitis, and autoimmune disorders [126–131], and can trigger cancer cell death. CP-d/n-ATF5-S1, a cell-penetrating peptide, inhibits tumor growth by inducing apoptosis and has demonstrated anticancer effects against malignancies [128]. Low-dose of pharmacological UPR activators induce differentiation in myeloma cells, a promising therapeutic strategy for myeloma treatment [129]. By inducing UPR, GHRH antagonists activate signaling pathways that inhibit cell proliferation, induce apoptosis (cell death), and increase protein degradation, while reducing protein synthesis. GHRH antagonists ameliorate endothelial injury [132]—at least in part due to UPR activation [86], and counteract sepsis in mice [132]. This UPR-inducing effect has been investigated as a potential therapeutic strategy for various diseases, including cancer [133–135], neurodegenerative disorders [136, 137], and metabolic disorders [138, 139].

HSP90 inhibitors are effective inducers of HSPs, presumably by releasing the major heat shock gene transcription factor, HSF1, which is held inactive in HSP90 complexes. This allows it to translocate to the nucleus, bind to heat shock promoter elements (HSE), and activate heat shock genes [140]. HSP90 inhibitors, such as 17-AAG and radicicol, induce apoptosis in multiple myeloma cell lines and have been shown to induce UPR [141]. HSP90 inhibition disrupts client-chaperone interactions leading to an inability to handle immunoglobulin production [142] and activate UPR in endothelial cells and mouse lungs [143, 144]. Additionally, those compounds suppress calcium-mediated stress signals and confer cell death resistance to cancer cells [145]. The effects of HSP90 inhibition appear to be tissue-specific and depend on the presence of other sensors [146]. Overall, HSP90 inhibitors activate UPR and have the potential to be used as therapeutic agents for cancer treatment [147–149].

15 |. Conclusions and Future Directions

Endothelial dysfunction contributes to various diseases, including acute respiratory distress syndrome, pulmonary hypertension, chronic obstructive pulmonary disease, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, diabetic retinopathy, age-related macular degeneration, and glaucoma. UPR modulates endothelial-specific activities, suggesting that its targeted modulation may serve as a therapeutic possibility in disorders related to barrier dysfunction. Future research could focus on the underlying mechanisms by which ATF6, PERK, and IRE1 modulate endothelial-dependent tissues, cell–cell interactions, immune responses, aging, NEK [150], and P53 regulation [95, 151, 152] (Figures 1 and 2). The new knowledge should be utilized to develop new targeted pharmacotherapies towards devastating diseases associated with reduced life quality (e.g., eye disease) and high mortality rates (e.g., sepsis).

Acknowledgments

Nektarios Barabutis is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R03AI176433. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.

Abbreviations:

AMD

age-related macular degeneration

ARDS

acute respiratory distress syndrome

ATF4

activating transcription factor 4

ATF6

activating transcription factor 6

BBB

blood–brain barrier

BiP

binding immunoglobulin protein

CHOP

C/EBP homologous protein

CNS

central nervous system

COPD

chronic obstructive pulmonary disease

EC

endothelial cells

eIF2α

eukaryotic initiation factor 2 alpha

ER

endoplasmic reticulum

ERAD

endoplasmic reticulum-associated degradation

GHRH

growth hormone releasing hormone

GRP78

78 kDa glucose-regulated protein

GRP94

94 kDa glucose-regulated protein

Hrd1

β-hydroxy β-methylglutaryl-coenzyme A (HMG-CoA) reductase degradation protein 1

HSF1

heat shock factor 1

HSP90

heat shock protein 90

IFs

intermediate filaments

IRE1α

inositol-requiring enzyme 1 alpha

JNK

c-Jun NH2-terminal kinase

MLC

myosin light chain

NF-κB

nuclear factor kappa-light-chain-enhancer of activated B cells

PERK

protein kinase R (PKR)-like endoplasmic reticulum kinase

UPR

unfolded protein response

VE-cadherin

vascular endothelial cadherin

XBP1

X-box binding protein 1

Footnotes

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

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Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

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