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Allogeneic hematopoietic stem cell transplantation (HSCT) is the solitary therapeutic therapy for many types of hematological cancers. The benefits of this procedure are challenged by graft vs. host disease (GVHD), causing significant morbidity and mortality. Recent advances in the metabolomics field have revolutionized our understanding of complex human diseases, clinical diagnostics and allow to trace the
Metabolomics is an extensively used set of techniques designed to analyze metabolomic profiles in bio-fluids and tissue extracts. Metabolomics helps to understand biomarkers and phenotypic biochemical changes caused by a disease or its therapeutic intervention ( Multi-omics workflow. Metabolomics analysis involves tissue collection which needs to be snap frozen in liquid Nitrogen. Frozen tissues are minced and subjected to polar and non-polar metabolites, DNA, Protein extraction according to the requirement for target and processed further for respective approach. Collected data is subjected to metabolites detection, data reduction and analysis, which may help to generate or prove a hypothesis.
Allogeneic hematopoietic cell transplantation (allo-HSCT) is a potential therapeutic course of action for patients with a diversity of acquired and inherited malignant and nonmalignant disorders to establish marrow and immune function. Currently there are more than 25,000 procedures performed annually and increasing regularly. Allo-HSCT involves the infusion of donor hematopoietic stem and progenitor cells into the patient. Interactions between the donor immune system and the recipient tissue result in a devastating complicated disease, called graft vs. host disease (GVHD), which is significantly linked with mortality and morbidity ( Schematic overview of graft vs. host disease (GVHD) pathophysiology with immunoregulatory aspects: Conditioning regimen at the time of transplant causes damage to the host tissues. This leads secretion of pro-inflammatory cytokines like tumor necrosis factor interleukin-6 and interleukin-1. These pro-inflammatory cytokines induce antigen presenting cell activation. Conditioning regimen also disturbs the homeostasis at intestinal mucosal Frontier due to damage caused to epithelial barrier injury and the microbiome niche. This causes increased movement of bacteria, MAMPs (microbe-associated molecular patterns), and polysaccharides to the mucosa. This consist phase-I of GVHD development. During phase 2, activated antigen presenting cells induce T cell maturation and proliferation. The effector T cells and an inflammatory cytokine storm together affect the host tissue causing further damage and perpetuating the cycle that aggravates GVHD, considering phase III. Figure modified from (
Metabolic regulation is important for immunoregulation and GVHD, and pretransplant cytokine profiles and metabolic status of allotransplant recipients are shown to be associated with a risk of later a GVHD development (
Scientific reports suggest a valid possibility of inhibiting glycolysis to treat GVHD while not affecting the graft-versus- tumor (GVT) effect after allo-HSCT. Inhibition of Hexokinase-2, a glucose-metabolizing enzyme reduced activation and function of allogeneic T cells. Lower levels of glycolysis would support the generation of long-lived CD8 T cells which are important in maintaining the GVT effect (
Michoneau D.
Previous work has shown that T effector cells (Teff) cells may show reprogramming of metabolic phenotypes induced by varying levels of oxygen tension among tissues. These changes in metabolic phenotypes are regulated by hypoxia-inducible factors (HIFs) (
Immune cells metabolism have been shown to differ during GVHD pathophysiology and associate significantly (
Naïve T cells solely depend on oxidative phosphorylation (OXPHOS) to meet their energy requirements (
Metabolism of Teff shows shift to anaerobic glycolysis as a main energy source (
Quiescent T cells (i.e., naive or memory T cells) follow a catabolic metabolism where nutrients are broken down to support cell survival. On the contrary, activated T cells acquire an anabolic metabolism, where nutrients are used to form the molecular building blocks that are integrated into cellular biomass to continue proliferation. The balance of catabolic and anabolic reactions in a cell decides the amount of ATP generated vs. consumed (
T cells in aGVHD patients have been shown to be polarized toward pro-inflammatory T cells and have higher glycolytic activity in contrast to T cells of non-aGVHD patients. Importantly,
Activated B cells share a few metabolic phenotype with T cells and show increased glucose uptake and induction of glycolysis (
Assmann et al. showed that higher glycolytic activity diagnosed by hyperpolarized 13C-pyruvate MRI of the liver showing high conversion of pyruvate to lactate, could differentiate allogeneic from syngeneic HSCT recipients, before chronic GVHD developed clearly. Authors observed similar metabolic changes on single cell sequencing of T cells obtained from patients undergoing allogeneic HSCT. Their finding indicated the value for using this imaging technique in the clinical post-HSCT setting which may allow early, non-invasive diagnosis of GVHD (
The naïve T cells expanding into Teff cells can alternatively obtain a Treg phenotype.
Effector function of T cells like proinflammatory cytokine production requires aerobic glycolysis, however it is downregulated along with glutamine metabolism during their transition to memory phase. In contrary FAO is induced to help memory T cell function (
It has been revealed that in naive T cells and memory T cells, Adenosine monophosphate-activated protein kinase (AMPK)-mediated oxidative metabolic state plays important role in cell survival and adapting to the energetic needs (
Scientists suggest the necessity of novel approaches that selectively target alloreactive T cells as the approaches known to inhibit the T cell response are not specific and inhibits alloreactive and protective T cells as well. Exploring the unique metabolic profiles of activated T cells could allow one to target and inhibit them in specific manner ( T cells metabolic reprogramming. Naïve T cells are highly dependent on Oxidative Phosphorylation (OXPHOS) and utilize catabolic metabolism which involves breaking down metabolites into smaller units that are either metabolized to produce energy or utilized in anabolic reactions. Upon antigen recognition, naïve T cells differentiate into Teff cells and most of these Teff cells die upon antigen clearance, but a subset of long-lived memory T cells (Tm) sustain. Teff cells show metabolic shift to glycolysis and show increased pentose phosphate pathway activity. Teff cells tend to utilize glutamine instead of glucose as a major lipogenic precursor. Teff cells show hyperpolarized mitochondrial membrane potential, with a simultaneous rise in the production of reactive oxygen species (ROS) that further mediate damage and inflammation. Tm cells show increased fatty acid oxidation. Rapamycin, which inhibits glycolysis, and Metformin which induces AMPK activity, that is involved in glycolysis inhibition, have shown to attenuate GVHD. This is mediated by enhanced fatty acid oxidation (FAO) in donor T cells which may reduce alloreactivity of T cells and enhance regulatory T cell (Treg) function.
In contrast to lymphocytes that proliferate within tissues, Polymorphonuclear leukocytes (PMNs) (neutrophils), macrophages, and dendritic cells, circulate in the bloodstream and are recruited to sites of inflammation during immune response to foreign invaders. During their movement, these cells undergo various changes as they require huge amounts of energy in the form of ATP for actin turnover and migration. Further metabolic changes are needed to perform phagocytosis and microbial killing. PMNs are able to perform at deep inflammatory lesions that usually have low oxygen concentrations (even anoxia) and this is ensured by their primarily glycolytic nature and few mitochondria, and little energy production from respiration. It has been shown that PMNs have unique mitochondrial properties to maintain a transmembrane potential. This is maintained by the glycerol-3-phosphate shuttle that helps to regulate aerobic glycolysis as opposed to producing energy. PMNs develop these unique mitochondrial phenotype during their differentiation from myeloid precursor cells ( Metabolic pathways of other immune cells.
Macrophages may show differential metabolism depending on their extreme: a pro-inflammatory (M1) and an anti-inflammatory/pro-resolving (M2). M1 macrophages depend solely on glycolysis and present two stops on the TCA cycle that result in collection of itaconate and succinate. Itaconate is a microbicide compound and succinate has been considered to be involved various immune responses. In contrast, M2 cells are mainly dependent on OXPHOS, and do not show any break in TCA cycle that provides the substrates for the complexes of the electron transport chain (ETC) (
Dendritic cells (DCs), on stimulation, show decreased OXPHOS, with simultaneous increase in glycolysis and pentose phosphate pathway activity, similar to M1 macrophages. Upon stimulation with lipopolysaccharides (LPS) and other pathogen-associated molecular patterns (PAMPs), both DCs and macrophages show mitochondrial collapse (meaning a decrease in ATP production) resulted from nitric oxide (NO) production from arginine (
Allo-HSCT recipients developing aGVHD manifest alteration of preconditioning/pretransplant levels of various immunoregulatory metabolites. This observation suggests that these altered metabolite may serve as biomarkers for GVHD prediction (
Energy or ATP generation in cells involves fundamental cellular processes such as Glycolysis and OXPHOS (
Krebs cycle intermediates such as succinate, fumarate and citrate succinate are involved in physiological reaction related to immunity and inflammation, considering both innate and adaptive immune cells (
Macrophages use the metabolite itaconate to control excessive ROS production and hyperinflammation by which they can limit SDH function and proinflammatory response. The amount of itaconate is increased in LPS-activated M1 macrophages because of reduced expression of isocitrate dehydrogenase, as this enzyme distracts citrate away from itaconate. M1 macrophages and LPS-induced macrophages show increased expression of the enzyme Irg1, that carry out the decarboxylation of aconitate (produced from citrate) to Itaconate (
The decreased amount of isocitrate dehydrogenase results in accumulation of itaconate and citrate as well, which initiates an inflammatory response in M1 macrophages (
Histone acetylation regulates transcriptional activation, histone acetyltransferase enzymes acetylate amino- terminus of histone H3 and H4. Histone deacetylase (HDAC) inhibitors can result in altered pattern of gene expression and may show anti-inflammatory and immunoregulatory effects (
Activity of some of the enzymes regulating histone and DNA demethylation, for example the
In murine models of GVHD, alloantigen-activated T cells indicate increased PPP activity (
Amino acid metabolism is shown to be linked with inflammation (
p-Cresol is soaked up from the intestine and detoxified in the liver by conjugation (sulfatation and glucuronidation), producing
Tryptophan metabolism plays a significant role in immunoregulation. For example, indoleamine 2,3-dioxygenase, the rate-limiting enzyme of tryptophan degradation in the kynurenine pathway, acts in a potent immune regulatory loop and participate in the GVHD pathophysiology (
Patients with cGVHD showed a significantly higher levels of phenylacetate, 3-(4-hydroxyphenyl) lactate, phenylalanine, and tyramine
Significant interaction of host and microbial metabolism is seen, and the microbiome has been shown to be capable of metabolizing drugs and thus modulating host response. Production of bioactive indole-containing metabolites such as indoxyl sulfate and the antioxidant indole-3-propionic acid (derived from tryptophan metabolism) and multiple organic acids containing phenyl groups are impacted by presence of gut microbes and composition (
The preceding disease conditions and the necessity for conditioning therapy for allo-HSCT may result in oxidative stress. The increased level of intracellular levels of ROS can destruct lipids, proteins and DNA and has been linked to various disease pathologies (
A study conducted by Reikvam and his team suggested altered protein metabolism associated with disturbed redox homeostasis in cGVHD patients, and hierarchical clustering analyses for “oxidative stress” metabolites resulted in two main clusters with high frequency of cGVHD patients in subset showing high levels of these metabolites. These metabolites increased in cGVHD patients were gamma-glutamyl amino acids (e.g., gamma-glutamylglutamate, gamma-glutamyltryptophan, gamma-glutamylphenylalanine, and gamma-glutamylthreonine) and their activity that is critical for recycling and regeneration of the antioxidant glutathione and other oxidative stress markers, considering alpha-tocopherol, cysteine sulfonic acid, and methionine sulfoxide, were also seen in cGVHD patients (
NO production has various detrimental effects which associates with increased levels of NO synthesis via the inducible form of iNOS. Detrimental effects are mainly carried out by tissue injury due to NO mediated by direct interplay of NO with target tissues. The indirectl detrimental effects of No production take place via proinflammatory functions of NO like apoptosis in intestinal epithelial cells, killing of alveolar type II epithelial cells, mediating expression of the chemokine macrophage Inflammatory Protein-2 and hereby encouraging the movement of immune cells into tissues with increased NO production.
NO production also has beneficial effects like inhibition of P-selectin expression by platelets and neutrophils, inhibition of the activation of cyclooxygenase and the production of superoxide anion by leukocytes, inhibition of Ag presentation and T cell proliferation and immunosuppression of alveolar macrophages in the lung. The balance between the detrimental and beneficial effects in inflammatory disease settings is most likely determining the effect of NO and reactive nitrogen intermediates and may be influenced by the phase and intensity of inflammatory diseases, like GVHD and idiopathic pneumonia syndrome (
The early oxidation of plasma glutathione and its oxidized form (GSH/GSSG) redox couple along with significant increase in hepatic protein oxidative damage and ROS production has been observed irrespective of radiation conditioning treatment. Authors also suggested the requirement of future studies to understand the mechanisms for these alterations and examine the importance of antioxidant intervention approaches to prevent GVHD (
Recent research advancement and attention have increased the understanding of lipid metabolism considered in the improvement of inflammation and responses at mucosal Frontier. Dyslipidemia (abnormal amount of lipids) commonly occurs post-HSCT and use of effective lipid lowering therapy in this setting suggests role of lipids metabolism in modulating graft-versus-host disease (GVHD) (
The regulators of fatty acid uptake and FAO are known to reduce crucially after autologous or allogeneic HSCT, in comparison to resting T cells. It has been shown in both human and mouse models that inhibition of ACC1, a potential mediator for
In addition to upregulation of FAS associated enzymes, alloreactive T cells show a propensity for the stacking up of long-chain fatty acids. Interference of acetyl-CoA carboxylase 1 (TACC1) inhibiting the FAS halted clonal expansion of alloreactive T cells
Enhanced lipid synthesis promotes the proinflammatory Teff phenotype while lipid oxidation favors iTreg differentiation, validating the role of FAS in GVHD development (
Saturated fatty acids are known to induce inflammation in part by mimicking the actions of lipopolysaccharide (
Polyunsaturated fatty acids (PUFAs) are essential to tissue homeostasis and cannot be synthesized by the body and need to be obtained through dietary sources. w-6 PUFAs leads to proinflammatory lipids, whereas v-3 PUFAs are metabolized to anti-inflammatory lipid mediators (
Analysis of lipidome and metabolome in blood samples taken prior to transplant suggested a crucial pro-inflammatory metabolic profile in patients who later developed GVHD (
Polyunsaturated fatty acids are the precursor metabolites of the eicosanoid family, such as leukotriene or prostaglandin (PG) (
Isobutyrylcarnitine and propyonylcarnitine levels which are crucial for the transport of fatty acids and the release of immunoregulatory cytokines, were altered pretransplant samples of patients who later developed GVHD (
It is suggested that systemic steroid treatment of patients with cGVHD, alters the fatty acid/triglyceride metabolism including phospholipid, lysolipid, plasmalogen, metabolites. However several of them are also increased during inflammation (
Sterol lipids (ST) serves as a component of membrane lipids and as hormones and signaling molecules regulate T cell function (
Sphingolipids (SP) are an crucial class of lipids that play fundamental roles in cell life and play various roles in foundational phases of the acute inflammatory response and are able to induce lipotoxicity and inflammation and regulate cell death (
Sphingolipid altered metabolism is seen in the alveolar compartment, i.e., the important lung functional unit involved in gas exchange, and is associated with inflammatory reaction and ceramide increase, especially, responsible for the shift to pathological hyperinflammation (
Previous studies demonstrated that alloreactive Teff cells use fatty acids (FAs) as a power origin to assist their
FTY720 (fingolimod) is a high-affinity agonist for four of five known Sphingosine 1-phosphate (S1P) receptors and decreases aGVHD mortality without loss of GVT effects. This effect is exerted by its immunomodulatory effects specifically by sequestering lymphocytes within secondary lymphoid organs, inhibiting circulation to peripheral sites of inflammation (
Reikvam et al. reported that the presence of cGVHD was associated with significantly higher levels of (1) the three lysolipid metabolites 1-linoleoyl- GPC (18:2), 1-oleoyl-GPC (18:1), 1-palmitoleoyl-GPC (16:1), 2) the eicosanoid 12-HETE; and 3) the sphingolipid sphingosine consistent with ongoing inflammation, which could be a metabolic signature (
In addition to shift in host metabolism, variation in microbiota-derived metabolites may contribute significantly to GVHD pathophysiology. The microbiota metabolome, considering the products produced by host metabolism, microbial metabolism, and mammalian–microbial co-metabolism in the intestines, affects the GVHD pathophysiology and development. Microbial metabolites like SCFA generated by microbial fermentation of dietary fibers, are able to induce H3 acetylation in the locus of Foxp3; therefore increasing the counts of Tregs directly and TGF-B production in the intestine, the recruitment of Treg, epithelial barrier protection while protecting against danger associated molecular patterns and PAMPs release and decreased apoptosis in gut, all have been shown able to mitigate GVHD. These effects of SCFA are mediated by signaling through various G protein receptors (
At the onset of aGVHD, especially aryl hydrocarbon receptor (AhR) ligands, bile acids and plasmalogens has been shown to vary, which may affect the allogeneic immune response during aGVHD. The reduced production of AhR ligands by microbiota could impair indoleamine 2,3-dioxygenase (IDO) stimulation and is known to affect allogeneic T cell reactivity (
IDO regulates immune metabolism by catalyzing Tryptophan (TRP) catabolism and that generates kynurenine pathway metabolites. These metabolites are biologically active, both as natural immunologically-active ligands for the AhR and by depleting TRP to trigger amino-acid sensing signal-transduction pathways, and serving as direct intracellular signaling molecule in DCs ( Metabolic pathways and their possible therapeutic approach in graft vs. host disease (GVHD). Energy or ATP generation in cells involve fundamental cellular processes glycolysis and OXPHOS. Glycolysis interconnects with Kreb’s cycle and the PPP, which is necessary for fundamental metabolic process, and NADPH regeneration. Metabolic changes in a pathway may consequently affects others as they are all interconnected.
Literature cited on metabolic reprograming after allo-HSCT and during GVHD pathophysiology indicates the substantial involvement of metabolic changes during development and progression of GVHD and provides a growing plethora of mechanistic insights into its complex pathophysiology. The reports outlined in this review warrant the extensive analysis of GVHD target organs and immune cells metabolism involved. The relevant pathway for mitigating GVHD seems reduction of glycolysis, PPP, NO production, fatty acids biosynthesis and GSH/GSSH regulation and activation of fatty acid oxidation and tryptophan metabolites.
Possible potential therapeutic targets used in past or worth to try in future.
Serial. No | Possible targets | Action | Significance/background | References |
---|---|---|---|---|
1 | Hexokinase-2 | Reduced glycolysis | Glucose-metabolizing enzymes reduced activation and function of allogeneic T cells. Lower levels of glycolysis would support the generation of long-lived CD8 T cells which are important in maintaining the GVT effect. | ( |
2 | Glutamine uptake by T cells and thus glutaminolysis | Inhibit lipogenesis | T cells utilize glutamine in lieu of glucose for lipogenesis and may shift from oxidative to reductive metabolism. | ( |
3 | Anaerobic glycolysis | Inhibition | Metabolism of Teff shows shift to anaerobic glycolysis as a main energy source. | ( |
4 | Pentose phosphate pathway (PPP) | Inhibition | In murine models of GVHD, alloantigen-activated T cells indicate increased PPP activity. | ( |
5 | Mitochondrial F1F0-ATPase | Inhibition | Inhibition of the mitochondrial F1F0-ATPase avert GVHD without altering homeostatic reconstitution, thus OXPHOS is required for allo-reactive T cell survival. | ( |
6 | Adenosine monophosphate activated protein kinase (AMPK) | Activation | Metformin activates AMPK therefore promotes FAO and might reduce GVHD by supporting the differentiation of Treg and affecting the balance between T helper (Th)-17 and Treg cells. | ( |
7 | Glycerol-3-phosphate shuttle | Inhibition | PMNs have unique mitochondrial properties to maintain a transmembrane potential. This is maintained by the glycerol-3-phosphate shuttle that helps to regulate aerobic glycolysis as opposed to producing energy. | ( |
8 | Isocitrate dehydrogenase (IDH1) | Induction | IDH1 allows the withdrawal of citrate from the cycle. Cytosolic citrate is broken down by ATP-citrate lyase (ACLY) to oxaloacetate and acetyl-CoA. Acetyl-CoA can be used as a substrate for fatty acid synthesis. | ( |
9 | Succinate dehydrogenase A (SDHA) | Induction | Allogeneic recipients (villin-Cre+SDHAfl/fl), with intestinal epithelial cell (IEC) specific SDHA KO mice, demonstrated significantly greater mortality and gastro-intestinal GVHD. | ( |
10 | Glutathione (GSH) | Inhibition | GSH is known to promote T-cell expansion by driving glycolysis and glutaminolysis, and assisting mTORC1 and c-Myc signaling during inflammation. | ( |
11 | Fatty acid oxidation (FAO) | Inhibition |
|
( |
12 | Tyrosine metabolites (p-cresol sulfate, |
Inhibition | Several metabolites from the cytokine-responsive kynurenine pathway for tryptophan degradation, phenylalanine and tyrosine metabolites derived from the gut microbial flora were increased in patients with cGVHD compared to controls and shown association with inflammation. | ( |
13 | Branched chain amino acids (BCAA) | Inhibition/activation | BCAA have been shown to increase in patients with cGVHD compared to controls, however, they have both pro and anti-inflammatory role. | ( |
14 | Indoleamine 2,3-dioxygenase | Induction | Indoleamine 2,3-dioxygenase, the rate-limiting enzyme of tryptophan degradation in the kynurenine pathway, acts in a potent immune regulatory loop. It is suggested that IDO is capable of decreasing T-cell proliferation and survival at the site of expression, thus diminished colonic inflammation and reduced GVHD severity. | ( |
15 | G-protein coupled receptor trace amine 1 (TAAR1) | Inhibition | Patients with cGVHD showed a significantly higher level of tyramine |
( |
16 | Nitric oxide synthase (NOS) | Inhibition | NO production has proinflammatory functions like apoptosis in intestinal epithelial cells, killing of alveolar type II epithelial cells, mediating expression of the chemokine macrophage inflammatory Protein-2 (MIP-2) and encourage the immune cells migration with increased NO production. | ( |
17 | GSH/GSSG dysregulation | Regulation | The early oxidation of plasma glutathione and its oxidized form (GSH/GSSG) redox couple along with significant increase in hepatic protein oxidative damage and ROS production has been observed irrespective of radiation conditioning treatment. | ( |
18 | Resolvins and maresins | Supplementation | COX-derived lipid mediators named the resolvins and the maresins have been shown to reduce human PMN trans endothelial migration, DC migration, and IL-12 production. | ( |
19 | Acetyl-CoA carboxylase 1 (ACC1) | Inhibition | It has been shown in both human and mouse models that inhibition of ACC1, a potential mediator for |
( |
20 | Lipid oxidation | Activation | Enhanced lipid synthesis promotes the proinflammatory Teff phenotype while lipid oxidation favors iTreg differentiation, validating the role of FAS in GVHD development. | ( |
21 | v-3 PUFAs | Supplementation | Polyunsaturated fatty acids (PUFAs) are essential to tissue homeostasis and cannot be synthesized by the body and need to be obtained through dietary sources. w-6 PUFAs leads to proinflammatory lipids, whereas v-3 PUFAs are metabolized to anti-inflammatory lipid mediators. | ( |
22 | 5-Lipoxygenase (5-LO) | Inhibition | Leukotriene or prostaglandin are known to be associated with generation of pro-inflammatory cytokines like interferon-γ, TNF-α, and IL-17, and gut integrity respectively. Inhibition of 5-lipoxygenase (5-LO) which reduces leukotriene B4 generation from arachidonic acid has been shown to protect mice from aGVHD ( |
( |
23 | L-carnitine acyltransferases | Inhibition | L-Carnitine acyltransferases catalyze the reversible transfer of acyl groups between coenzyme A and L-carnitine, converting acyl-CoA esters into acyl-carnitine esters. Isobutyrylcarnitine and propyonylcarnitine levels which are crucial for the transport of fatty acids and the release of immunoregulatory cytokines, were higher in pretransplant samples of patients who later developed GVHD. | ( |
24 | Palmitic acid | Reduced intake | It is demonstrated that patients with high stearic acid/palmitic acid (SA/PA) ratios on day 7 after HSCT were unlikely to develop II–IV aGVHD compared to patients with low SA/PA ratios. Palmitic acid serves as TLR agonist and in the cell, this is converted into phospholipids, diacylglycerol and ceramides which trigger various signaling pathways, common for LPS-mediated TLR4 activation. | ( |
25 | Sphingosine 1-phosphate receptor | Induction | FTY720 (fingolimod) is a high-affinity agonist for four of five known sphingosine 1-phosphate (S1P) receptors and decreases aGVHD mortality without loss of GVT effects. | ( |
All authors listed, have made substantial, direct and conceptual contribution to the work, and approved it for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.