count	source_label	source_id	relationship	target_label	target_id	entity_type	solr_id	publication_id	sentences
8	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:Q9NR97	Protein	eff2e4d6-04c0-11f0-bb39-0050569a791b	10.1016/j.sbi.2024.102913	SLC29A3 mutations lead to abnormal nucleoside storage within lysosomes, resulting in the constitutive activation of TLR7 and TLR8 by nucleosides.
8	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:Q9NYK1	Protein	eff2e4d6-04c0-11f0-bb39-0050569a791b	10.1016/j.sbi.2024.102913	SLC29A3 mutations lead to abnormal nucleoside storage within lysosomes, resulting in the constitutive activation of TLR7 and TLR8 by nucleosides.
3	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:P42345	Protein	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	ENT3-related gene accumulation was found to activate the mTOR signal pathway, the star oncogene MYC, the DNA repair process, and so on.|||Knockdown of ENT3 inhibits the activation of the AKT/mTOR signaling pathway in vitro We utilized RStudio to normalize the original data of TCGA-LIHC in the liver and intrahepatic bile ducts from the TCGA-GDC database, and the GSEA software package was employed to analyze the single gene correlation enrichment of ENT3.|||Data showed that an increase in ENT3-related genes activates the mTOR signaling pathway (Fig. 6A, B).
3	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D006528	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	Therefore, the ENT3 expression may promote tumorigenesis by promoting the migration and invasion of hepatoma cells.|||A Transwell invasion test was performed in a chamber containing matrix glue, and the knockdown of ENT3 inhibited the ability of hepatoma cells to invade (Fig. 5E, F).|||Therefore, we inferred that ENT3 knockdown inhibits the proliferation and promotes apoptosis of hepatoma cells.
2	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:P11279	Protein	dc805798-c47a-11e5-8491-001a4ae51247	22174130	ENT3–/–splenic macrophages had increased numbers of lysosomal-associated membrane protein 1 (lamp-1)+vesicles (Fig. 2Aand fig.
2	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:P42858	Protein	4e5f7b76-0541-11f0-8fe6-0050569a1f61	10.1016/j.bbi.2024.06.021	Notably, the distinct localization of ENTs imposes differential biological functions – while both ENT1 and ENT2 are membrane-targeting transporters that modulate the nucleoside dynamics between the cell and its residing microenvironment, the current study on the endosomal/lysosomal ENT3 reveals the importance of intracellular nucleoside balance mediated by ENT3 and its protective role under HD setting.
2	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0042592	Phenotype	4e5f7b76-0541-11f0-8fe6-0050569a1f61	10.1016/j.bbi.2024.06.021	ENT3 ameliorates HD-induced microglial stress The disturbed microglial homeostasis phenotypes in the R6/2 ENT3−/−mice prompted us to hypothesize that these microglia may be dysfunctional.
2	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D006863	Phenotype	961718a6-c678-11ee-ae05-0050569a1f61	10.1016/j.yexcr.2023.113892	Mutations of SLC29A3 caused the abnormal transport of nucleosides in the cytoplasmic pool will increase the pH of the lysosome [41], thereby blocking several critical cellular pathways [36,41].
2	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0015031	Phenotype	919bbe94-bbfa-11e5-8abe-001a4ae51246	10.1016/j.bbalip.2006.06.015	The ENTH domains of yeast Ent3 and Ent5, which are thought to mediate protein transport in the late endosomal compartment (multivesicular bodies), but not endocytosis at the plasma membrane, bind almost exclusively to PI(3,5)P2[131–133].
2	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0032238	Phenotype	b45ce294-aba2-11e6-9646-001a4ae51246	26163994	The possibility that the alterations in cellular bioenergetics following ENT3 disruption is associated with enhanced β-cell apoptosis was investigated using dipyridamole, a global ENT inhibitor that reduces hENT3-mediated adenosine transport[7,11].
2	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0008152	Phenotype	4e5f7b76-0541-11f0-8fe6-0050569a1f61	10.1016/j.bbi.2024.06.021	Our study suggests that ENT3-mediated metabolism is an integral part of HD's compensatory energy generation module.
2	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D013577	Phenotype	6f518f5a-5d87-11e7-8c5f-001a4ae51246	PMC5461533	Conclusion:PHID syndrome is associated with recessive mutations inSLC29A3which encodes for the equilibrative nucleoside transporter hENT3 expressed in mitochondria, causing PHID and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy-plus syndrome.
2	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D013577	Phenotype	ef4ecd2a-bc08-11e5-9b9d-001a4ae51247	10.1016/j.ejmg.2010.06.012	Introduction Mutations in theSLC29A3gene, also termed hENT3, have recently been reported to cause two allelic autosomal recessive syndromes, H syndrome and pigmented hypertrichosis with insulin dependent diabetes (PHID)[4,10].
2	SLC29A3	UNIPROT:Q9BZD2	inhibits		FPLX:MAPK	ProteinFamily	2807bb74-1d19-11f0-a2ca-0050569a1f61	10.1182/blood.2023020714	Loss of function of ENT3 leads to inflammatory cytokine secretion through activation of a signaling cascade involving TLR and MAPK Next, we performed gene set enrichment analysis to identify the signaling pathways activated in H syndrome monocytes.
2	SLC29A3	UNIPROT:Q9BZD2	inhibits		FPLX:TLR	ProteinFamily	2807bb74-1d19-11f0-a2ca-0050569a1f61	10.1182/blood.2023020714	Loss of function of ENT3 leads to inflammatory cytokine secretion through activation of a signaling cascade involving TLR and MAPK Next, we performed gene set enrichment analysis to identify the signaling pathways activated in H syndrome monocytes.
2	SLC29A3	UNIPROT:Q9BZD2	inhibits		UNIPROT:P42345	Protein	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	The downregulation of ENT3 inhibited the AKT/mTOR signaling pathway, HCC cell proliferation, migration, and invasion and promoted apoptosis.|||These findings imply that ENT3 downregulation in the hepatoma cells can inhibit the AKT/mTOR signaling pathway.
2	SLC29A3	UNIPROT:Q9BZD2	inhibits		UNIPROT:Q9BYI3	Protein	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	The downregulation of ENT3 inhibited the AKT/mTOR signaling pathway, HCC cell proliferation, migration, and invasion and promoted apoptosis.|||Knockdown of ENT3 inhibits the proliferation and promotes the apoptosis of HCC cells With reference to the foregoing findings, we employed HepG2 and Huh7 cells as in vitro knockdown models to explore the potential biological functions of ENT3 in HCC.
2	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0006810	Phenotype	53eb40fe-c471-11e5-91a7-001a4ae51247	PMC2670673	Second, knockdown of hENT3 was not complete in JAR-hENT3 siRNA cells, and residual expression of any hENT3 could still allow transport of nucleosides in hENT3-silenced conditions.|||Earlier functional characterization of hENT3 transport was performed inXenopusoocytes with hENT3 mutants (Δ36hENT3 and LLAAhENT3) that allowed trafficking of hENT3 to the cell surface and transport of hENT3 substrates (5).
2	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0008283	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	Therefore, we inferred that ENT3 knockdown inhibits the proliferation and promotes apoptosis of hepatoma cells.|||Knockdown of ENT3 inhibits the proliferation and promotes the apoptosis of HCC cells With reference to the foregoing findings, we employed HepG2 and Huh7 cells as in vitro knockdown models to explore the potential biological functions of ENT3 in HCC.
2	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0008283	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	ENT3 knockdown causes cell cycle arrest and inhibits hepatoma cell proliferation.|||The downregulation of ENT3 inhibited the AKT/mTOR signaling pathway, HCC cell proliferation, migration, and invasion and promoted apoptosis.
2	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0008283	Phenotype	961718a6-c678-11ee-ae05-0050569a1f61	10.1016/j.yexcr.2023.113892	However, the overexpression of SLC29A3 impeded cell proliferation in vitro, yet no definitive proof of SLC29A3 inactivation was discovered in breast or bladder malignancies.|||Morgan et al. demonstrated that the inhibition of SLC29A3 expression through siRNA substantially stimulated the proliferation of HeLa cells [20].
2	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0008283	Phenotype	9b3f6ee0-67d9-11e8-8329-001a4a160176	29791845	ENT3 Is Required for Maintaining T Cell Size and Complexity Our data showed that ENT3 is necessary for the survival and proliferation of T cells, but the question of how ENT3 participates in T cell homeostasis remained.|||ENT3 Supports the Survival and Proliferation of Peripheral T Cells Given the significant loss of naive T cells inENT3−/−mice, we hypothesized that ENT3 supports the survival and/or proliferation of mature peripheral T cells.
2	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D009361	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	Therefore, the ENT3 expression may promote tumorigenesis by promoting the migration and invasion of hepatoma cells.|||Knockdown of ENT3 inhibits the migration and invasion of HCC cells The effect of ENT3 on cell migration and invasion was studied by using wound-healing and Transwell experiment.
2	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0006915	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	The downregulation of ENT3 inhibited the AKT/mTOR signaling pathway, HCC cell proliferation, migration, and invasion and promoted apoptosis.|||Therefore, we inferred that ENT3 knockdown inhibits the proliferation and promotes apoptosis of hepatoma cells.
2	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0007165	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	These findings imply that ENT3 downregulation in the hepatoma cells can inhibit the AKT/mTOR signaling pathway.|||The downregulation of ENT3 inhibited the AKT/mTOR signaling pathway, HCC cell proliferation, migration, and invasion and promoted apoptosis.
2	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0007165	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	Knockdown of ENT3 inhibits the activation of the AKT/mTOR signaling pathway in vitro We utilized RStudio to normalize the original data of TCGA-LIHC in the liver and intrahepatic bile ducts from the TCGA-GDC database, and the GSEA software package was employed to analyze the single gene correlation enrichment of ENT3.|||Data showed that an increase in ENT3-related genes activates the mTOR signaling pathway (Fig. 6A, B).
2	SLC29A3	UNIPROT:Q9BZD2	inhibits		FPLX:AKT	ProteinFamily	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	These findings imply that ENT3 downregulation in the hepatoma cells can inhibit the AKT/mTOR signaling pathway.|||The downregulation of ENT3 inhibited the AKT/mTOR signaling pathway, HCC cell proliferation, migration, and invasion and promoted apoptosis.
2		UNIPROT:P42858	activates	SLC29A3	UNIPROT:Q9BZD2	Protein	4e5f7b76-0541-11f0-8fe6-0050569a1f61	10.1016/j.bbi.2024.06.021	ENT3 ameliorates HD-induced microglial stress The disturbed microglial homeostasis phenotypes in the R6/2 ENT3−/−mice prompted us to hypothesize that these microglia may be dysfunctional.
2		MESH:D015614	inhibits	SLC29A3	UNIPROT:Q9BZD2	Phenotype	4e5f7b76-0541-11f0-8fe6-0050569a1f61	10.1016/j.bbi.2024.06.021	Loss-of-function of ENT3 drives histiocytosis has been demonstrated in multiple studies.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		UNIPROT:Q9GZU1	Protein	609a2942-dcc0-11e6-876a-001a4ae51247	PMC5336176	ADA−/−cells display impaired TRPML1 activity, which is rescued by increasing ENT3.
1	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:P38731	Protein	2facac94-c473-11e5-9da3-001a4ae51247	PMC2749155	We observed that deletion of Ent3 alone could disrupt Arn1 trafficking.
1	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:P01266	Protein	2facac94-c473-11e5-9da3-001a4ae51247	PMC2749155	These interactions suggest that Ent3 and Ent5 coordinate with Gga1 and Gga2 to mediate sorting of cargo proteins at the TGN.
1	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:P01266	Protein	85f7811a-c46d-11e5-a92e-001a4ae51246	25512335	Ent3 acts principally in the GGA-mediated TGN sorting (Copic et al., 2007;Costaguta et al., 2006) and only the ENTH domain of Ent3 binds to the endosomal SNAREs Vti1, Pep12 and Syn8 (Chidambaram et al., 2004;Chidambaram et al., 2008;Copic et al., 2007).
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		UNIPROT:P04141	Protein	c1086796-352d-11e8-9fbf-001a4a160176	29079714	ENT3 deficiency, through defects in the lysosomal system, caused ineffective apoptotic cell clearance and increased macrophage colony-stimulating factor signaling that contributed to elevated numbers of macrophages and histiocytosis.
1	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:P09603	Protein	dc805798-c47a-11e5-8491-001a4ae51247	22174130	The higher M-CSF concentration was not due to increased production of M-CSF by ENT3–/–splenic and bone marrow stromal cells or macrophages (fig.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		UNIPROT:P09603	Protein	dc805798-c47a-11e5-8491-001a4ae51247	22174130	ENT3 deficiency, through defects in the lysosomal system, caused ineffective apoptotic cell clearance and increased M-CSF signaling that contribute to elevated numbers of macrophages and histiocytosis.
1	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:Q9BYI3	Protein	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	Knockdown of ENT3 inhibits the migration and invasion of HCC cells The effect of ENT3 on cell migration and invasion was studied by using wound-healing and Transwell experiment.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		UNIPROT:P08922	Protein	37ea903c-bbff-11e5-8abe-001a4ae51246	PMC2581432	The bars in Figure 5 represent the ratio of the two signals: 1 indicates no decrease in ROS, <1 indicates a decrease in ROS and >1 indicates an increase in ROS.ARG2, ENT3, HSP82, IDP3 and JEM1 in high copy significantly blocked ROS in cells expressing WT α-syn (Fig. 5A).
1	SLC29A3	UNIPROT:Q9BZD2	increases		UNIPROT:P08922	Protein	9b3f6ee0-67d9-11e8-8329-001a4a160176	29791845	Notably,ENT3−/−T cells also have increased levels of ROS.
1	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:P01106	Protein	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	ENT3-related gene accumulation was found to activate the mTOR signal pathway, the star oncogene MYC, the DNA repair process, and so on.
1	SLC29A3	UNIPROT:Q9BZD2	activates		UNIPROT:Q8N350	Protein	0ef2a3bf-dc35-11ea-8913-001a4a160176	PMC6507048	Notably, DOS caused by the mutations of <ce:italic>SLC29A3</ce:italic> and <ce:italic>TNFRSF11A</ce:italic> do not exhibit the neural degeneration and brain malformations.
1	SLC29A3	UNIPROT:Q9BZD2	activates		CHEBI:29101	Chemical	e597d362-bc08-11e5-8abe-001a4ae51246	10.1016/j.ejmg.2011.06.009	SLC29A3encodes the equilibrative nucleoside transporter, ENT3, a member of nucleoside transporter family which mediates passive sodium-independent transport of nucleosides.
1	SLC29A3	UNIPROT:Q9BZD2	activates		CHEBI:63534	Chemical	f3d632ca-c8e7-11e5-9ad8-001a4ae51247	17379602	hENT3 mediates nucleoside transport across lysosomal membranes, whereas the more distantly related hENT4, also known as the plasma membrane monoamine transporter, transports monoamine neurotransmitters and adenosine (at acidic pH) in brain and heart tissue (8–11).
1	SLC29A3	UNIPROT:Q9BZD2	activates		CHEBI:52211	Chemical	53eb40fe-c471-11e5-91a7-001a4ae51247	PMC2670673	The robust transport activity of Δ36hENT3 measured inXenopusoocytes at pH 6.5 and substantial localization of endogenous hENT3 in the mitochondria support a physiological role for hENT3 in transporting nucleosides/deoxynucleosides into the mitochondria.
1	SLC29A3	UNIPROT:Q9BZD2	activates		CHEBI:18282	Chemical	53eb40fe-c471-11e5-91a7-001a4ae51247	PMC2670673	This is possible ifXenopusoocytes exhibit high levels of endogenous concentrative nucleobase transport activity and the presence of hENT3 allows efflux of the nucleobase (37).
1	SLC29A3	UNIPROT:Q9BZD2	activates		CHEBI:30746	Chemical	c261f52a-bbeb-11e5-9b9d-001a4ae51247	10.1016/j.tet.2012.11.097	General procedure for the aldol intramolecular reaction catalyzed by ent-3 To the catalystent-3(0.06 mmol, 200 mg) and benzoic acid (0.015 mmol, 2 mg) at 25 °C was added the ketone 8 or 11 (0.3 mmol).
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0042592	Phenotype	9b3f6ee0-67d9-11e8-8329-001a4a160176	29791845	Here, we show that the nucleoside transporter ENT3 contributes to the homeostasis of T cells at multiple levels.
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0042592	Phenotype	372453cc-8d86-11e7-955b-001a4ae51246	PMC5592659	"Consistently,
                      gene deletion of hENT3 impairs lysosomal homeostasis (42)."
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0006810	Phenotype	e597d362-bc08-11e5-8abe-001a4ae51246	10.1016/j.ejmg.2011.06.009	SLC29A3encodes the equilibrative nucleoside transporter, ENT3, a member of nucleoside transporter family which mediates passive sodium-independent transport of nucleosides.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0006810	Phenotype	61fa1f46-c46f-11e5-8491-001a4ae51247	PMC4148870	"Indeed, any minor side chain substitution, including alanine, at the Gly-427 position in hENT3 will completely disrupt
                               substrate transport (14)."
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0006810	Phenotype	be66ffc0-bc3a-11e5-8d2d-001a4ae51247	10.1016/j.mam.2012.05.007	Unlike ENT1/2, ENT3-mediated transport is markedly enhanced at acid pH, a characteristic similar to ENT family H+/nucleoside cotransporters from kinetoplastid protozoa, suggesting that ENT3 may also be H+-coupled.
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0006810	Phenotype	357d82b8-3552-11e8-b868-001a4a160176	19889517	TheSLC29A3gene encodes the human equilibrative nucleoside transporter (hENT3), which mediates passive sodium-independent transport of nucleosides[5].
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0006810	Phenotype	5d4e329c-375f-11e8-b868-001a4a160176	21816170	Similarly, expression of ENT3 in mitochondria correlates with ENT3-mediated transport of several classes of nucleosides that produce mitochondrial toxicity: the nucleoside reverse transcriptase inhibitors lamivudine, zalcitabine, didanosine, stavudine, and azidothymidine, the anticancer drug gemcitabine, and the anti-hepatitis drugs fialuridine and ribavirin (Baldwin et al., 2005; Govindarajan et al., 2009) (Table 3).
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0006810	Phenotype	961718a6-c678-11ee-ae05-0050569a1f61	10.1016/j.yexcr.2023.113892	Mutation of SLC29A3 and tumorigenesis Disruption of nucleosides metabolism and transport in cells result in various abnormal phenotypes.
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0006810	Phenotype	961718a6-c678-11ee-ae05-0050569a1f61	10.1016/j.yexcr.2023.113892	Some studies have proved that ENT3-mediated transport is greatly enhanced in an acidic environment, similar to the H+/nucleoside cotransporters of the ENT family in kinetoplastid protozoa, suggesting a possible H+-coupling mechanism for ENT3.
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0006810	Phenotype	cd6d4950-67ed-11e8-bbed-001a4a160175	PMC5896370	1, C and D, hENT2 showed a 2.62-fold (P< 0.0001) increased transport activity, consistent with its higher apparent affinity for its natural nucleoside counterpart (inosine), and hENT3 showed a 2.23-fold (P< 0.0001) increased transport activity compared with H2O-injected oocytes in transporting DDI.
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D004194	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	ENT3 mutations increased the susceptibility to lung cancer (19), lysosomal deposition disease, and hereditary diseases[19,23,25,26].
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		MESH:D012871	Phenotype	961718a6-c678-11ee-ae05-0050569a1f61	10.1016/j.yexcr.2023.113892	The deletion of ENT3 in β-cells might underlie the etiology of pigmented hirsute dermatosis in individuals with insulin-dependent diabetes [46].
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D028361	Phenotype	372453cc-8d86-11e7-955b-001a4ae51246	PMC5592659	"Recently, numerous reports from independent laboratories have identified exclusive mutations in hENT3 that cause a wide range
                      of human clinical disorders (H syndrome, PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome)
                      syndrome, SHML (sinus histiocytosis with massive lymphadenopathy)/RDD (Rosai-Dorfman Disease) syndrome, dysosteosclerosis,
                      etc.) with intriguing resemblances to lysosome storage-like and mitochondrial disorders (20–31)."
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		MESH:D006528	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	ENT3 knockdown causes cell cycle arrest and inhibits hepatoma cell proliferation.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0043277	Phenotype	c1086796-352d-11e8-9fbf-001a4a160176	29079714	ENT3 deficiency, through defects in the lysosomal system, caused ineffective apoptotic cell clearance and increased macrophage colony-stimulating factor signaling that contributed to elevated numbers of macrophages and histiocytosis.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0043277	Phenotype	dc805798-c47a-11e5-8491-001a4ae51247	22174130	ENT3 deficiency, through defects in the lysosomal system, caused ineffective apoptotic cell clearance and increased M-CSF signaling that contribute to elevated numbers of macrophages and histiocytosis.
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0006839	Phenotype	9268a796-bc00-11e5-9b9d-001a4ae51247	10.1016/j.bbrc.2012.09.143	ENT3-mediated mitochondrial transport has been suggested to play an important role in basal mitochondrial metabolism[4].
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0006839	Phenotype	961718a6-c678-11ee-ae05-0050569a1f61	10.1016/j.yexcr.2023.113892	ENT3-mediated mitochondrial transport plays a crucial role in the mitochondrial toxicity caused by nucleoside drugs [34].
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0008283	Phenotype	f008e2be-c473-11e5-9cc6-001a4ae51246	PMC4830313	[13] It is possible that mutations in the SLC29A3 gene may induce an abnormal proliferation of histiocytes and thus lead to the immune response, resulting in skin sclerosis and hypertrichosis.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0008283	Phenotype	e7032ea6-bc3d-11e5-8abe-001a4ae51246	PMC2816679	SLC29A3 siRNAinhibitsSLC29A3gene expression and promotes cell proliferation To further investigate the effect ofSLC29A3on cell growth HeLa cells were treated with siRNA againstSLC29A3(120032-siRNA and 26642-siRNA) or with a luciferase control sequence (control-siRNA).
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D009369	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	Based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database and literature, the expression of ENT3 has significantly increased in several tumors such as bladder urothelial carcinoma (BLCA), breast cancer (BRCA), and HCC, albeit the role of ENT3 in these tumors has not been studied[27].
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0051179	Phenotype	cd6d4950-67ed-11e8-bbed-001a4a160175	PMC5896370	Full-length hENT3 does not show cell surface transport activity in oocytes without the removal of the N-terminal 36 amino acid residues because of the presence of intracellular targeting signals within this region of hENT3 that causes its localization to organelles (Baldwin et al., 2005).
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0051641	Phenotype	f629804c-c8e5-11e5-9624-001a4ae51246	17711502	It is quite likely that the GFP-hENT3 and GFP-hENT4 proteins cause increased accumulation of nucleoside analogs in intracellular organelles because of their cellular localization.
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D015618	Phenotype	372453cc-8d86-11e7-955b-001a4ae51246	PMC5592659	"Recently, numerous reports from independent laboratories have identified exclusive mutations in hENT3 that cause a wide range
                      of human clinical disorders (H syndrome, PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome)
                      syndrome, SHML (sinus histiocytosis with massive lymphadenopathy)/RDD (Rosai-Dorfman Disease) syndrome, dysosteosclerosis,
                      etc.) with intriguing resemblances to lysosome storage-like and mitochondrial disorders (20–31)."
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D015618	Phenotype	6f518f5a-5d87-11e7-8c5f-001a4ae51246	PMC5461533	Conclusion:PHID syndrome is associated with recessive mutations inSLC29A3which encodes for the equilibrative nucleoside transporter hENT3 expressed in mitochondria, causing PHID and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy-plus syndrome.
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0006281	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	ENT3-related gene accumulation was found to activate the mTOR signal pathway, the star oncogene MYC, the DNA repair process, and so on.
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D063646	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	Therefore, the ENT3 expression may promote tumorigenesis by promoting the migration and invasion of hepatoma cells.
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D006983	Phenotype	ef4ecd2a-bc08-11e5-9b9d-001a4ae51247	10.1016/j.ejmg.2010.06.012	Introduction Mutations in theSLC29A3gene, also termed hENT3, have recently been reported to cause two allelic autosomal recessive syndromes, H syndrome and pigmented hypertrichosis with insulin dependent diabetes (PHID)[4,10].
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		MESH:D009361	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	The downregulation of ENT3 inhibited the AKT/mTOR signaling pathway, HCC cell proliferation, migration, and invasion and promoted apoptosis.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0008152	Phenotype	961718a6-c678-11ee-ae05-0050569a1f61	10.1016/j.yexcr.2023.113892	Mutation of SLC29A3 and tumorigenesis Disruption of nucleosides metabolism and transport in cells result in various abnormal phenotypes.
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0046085	Phenotype	961718a6-c678-11ee-ae05-0050569a1f61	10.1016/j.yexcr.2023.113892	Therefore, researchers have explored whether alterations in adenosine metabolism mediated by SLC29A3 could contribute to tumor formation.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0007050	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	ENT3 knockdown causes cell cycle arrest and inhibits hepatoma cell proliferation.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0006915	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	Knockdown of ENT3 inhibits the proliferation and promotes the apoptosis of HCC cells With reference to the foregoing findings, we employed HepG2 and Huh7 cells as in vitro knockdown models to explore the potential biological functions of ENT3 in HCC.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		MESH:D013577	Phenotype	d9996d70-c480-11e5-8491-001a4ae51247	PMC2934698	RESULTS All H and PHID Syndrome Mutations in hENT3 Reduce Nucleoside Transport Activity Positional analyses of H and PHID syndrome mutations in hENT3 show that all mutations except the M116R affect the C terminus of the protein (Fig. 1).
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D013577	Phenotype	53eb40fe-c471-11e5-91a7-001a4ae51247	PMC2670673	In addition, our finding that hENT3 is a mitochondrial transporter is consistent with an important finding that mutations of the hENT3 gene cause an autosomal recessive disorder in humans called the H syndrome (27).
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D013577	Phenotype	cd6d4950-67ed-11e8-bbed-001a4a160175	PMC5896370	Numerous independent laboratories are also reporting monogenic mutations in hENT3 that produce a spectrum of human genetic disorders (e.g., H syndrome, familial Rosai-Dorfman disease, pigmented hypertrichotic dermatosis, sinus histiocytosis with massive lymphadenopathy, etc.) to share many clinical resemblances to mitochondrial and lysosomal storage disorders (Molho-Pessach et al., 2008;Cliffe et al., 2009;Kang et al., 2010;Morgan et al., 2010;Campeau et al., 2012).
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D013577	Phenotype	f008e2be-c473-11e5-9cc6-001a4ae51246	PMC4830313	However, it is noteworthy that in our case the cutaneous lesion is more extended, involving the areas such as buttocks and knees that were previously considered to be uninvolved.H syndrome is caused by mutations in the SLC29A3 gene, which encodes the hENT3.
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D013577	Phenotype	d9996d70-c480-11e5-8491-001a4ae51247	PMC2934698	Although mutations in hENT3 are known to cause H and PHID syndromes, the mechanistic basis of development and pathogenesis of both of these syndromes are completely unknown.
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D013577	Phenotype	372453cc-8d86-11e7-955b-001a4ae51246	PMC5592659	"Recently, numerous reports from independent laboratories have identified exclusive mutations in hENT3 that cause a wide range
                      of human clinical disorders (H syndrome, PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome)
                      syndrome, SHML (sinus histiocytosis with massive lymphadenopathy)/RDD (Rosai-Dorfman Disease) syndrome, dysosteosclerosis,
                      etc.) with intriguing resemblances to lysosome storage-like and mitochondrial disorders (20–31)."
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0061519	Phenotype	78246cfa-34e1-11e9-87c2-001a4a160175	30658162	A hENT3 deficiency in mouse has been shown to perturb lysosome function, macrophage homeostasis and T-cell performance [12,13].
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0060914	Phenotype	ddcd2482-bc14-11e5-8abe-001a4ae51246	10.1016/j.mod.2009.06.279	While the mechanisms by which mutant ENT3 leads to the clinical manifestation observed in H syndrome have yet to be elucidated, preliminary studies in Xenopus suggest that Ent3 is necessary for early development and specifically for heart formation.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0016049	Phenotype	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	In addition, to further understand how ENT3 restricts cell growth, we used flow cytometry to detect the cell growth cycle and apoptosis.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0016049	Phenotype	e7032ea6-bc3d-11e5-8abe-001a4ae51246	PMC2816679	SLC29A3 siRNAinhibitsSLC29A3gene expression and promotes cell proliferation To further investigate the effect ofSLC29A3on cell growth HeLa cells were treated with siRNA againstSLC29A3(120032-siRNA and 26642-siRNA) or with a luciferase control sequence (control-siRNA).
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0015858	Phenotype	d9996d70-c480-11e5-8491-001a4ae51247	PMC2934698	These data, together with the fact that Gly427is highly conserved across species (1), support that Gly427per seis an absolute requirement for facilitating hENT3-mediated nucleoside transport activity.
1	SLC29A3	UNIPROT:Q9BZD2	activates		GO:0015858	Phenotype	f3d632ca-c8e7-11e5-9ad8-001a4ae51247	17379602	hENT3 mediates nucleoside transport across lysosomal membranes, whereas the more distantly related hENT4, also known as the plasma membrane monoamine transporter, transports monoamine neurotransmitters and adenosine (at acidic pH) in brain and heart tissue (8–11).
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		GO:0015858	Phenotype	d9996d70-c480-11e5-8491-001a4ae51247	PMC2934698	RESULTS All H and PHID Syndrome Mutations in hENT3 Reduce Nucleoside Transport Activity Positional analyses of H and PHID syndrome mutations in hENT3 show that all mutations except the M116R affect the C terminus of the protein (Fig. 1).
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		MESH:D015614	Phenotype	961718a6-c678-11ee-ae05-0050569a1f61	10.1016/j.yexcr.2023.113892	Defective SLC29A3 impairs proper clearance of apoptotic cells and increases the activation of macrophage colony-stimulating factors, thereby affecting the lysosomal system and leading to an increased number of macrophages and histiocytosis [37].
1	SLC29A3	UNIPROT:Q9BZD2	activates		MESH:D000241	Phenotype	f3d632ca-c8e7-11e5-9ad8-001a4ae51247	17379602	hENT3 mediates nucleoside transport across lysosomal membranes, whereas the more distantly related hENT4, also known as the plasma membrane monoamine transporter, transports monoamine neurotransmitters and adenosine (at acidic pH) in brain and heart tissue (8–11).
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		MESH:D000241	Phenotype	609a2942-dcc0-11e6-876a-001a4ae51247	PMC5336176	In agreement with this, the loss of either ADA (this study) or ENT3 (7) causes lysosomal adenosine accumulation.
1	SLC29A3	UNIPROT:Q9BZD2	inhibits		PF:PF01733	ProteinFamily	00690f83-f5b2-11eb-9f5f-001a4a160176	30357508	According to our data, this might be particularly important in hypertensive tissues, once ENT3 expression is downregulated, particularly in arteries (Li et al.32), suggesting an indirect role of this nucleoside transporter in the regulation of intracellular adenosine bioavailability in hypertension.
1	SLC29A3	UNIPROT:Q9BZD2	activates		FPLX:Caspase	ProteinFamily	961718a6-c678-11ee-ae05-0050569a1f61	10.1016/j.yexcr.2023.113892	ENT3 inhibition and depletion by dipyridamole and siRNA increased the activity of caspase 3/7 in β-cells [46].
1	SLC29A3	UNIPROT:Q9BZD2	activates		FPLX:AKT	ProteinFamily	b427b008-c82b-11ee-b346-0050569a791b	10.1016/j.ijbiomac.2023.124323	Knockdown of ENT3 inhibits the activation of the AKT/mTOR signaling pathway in vitro We utilized RStudio to normalize the original data of TCGA-LIHC in the liver and intrahepatic bile ducts from the TCGA-GDC database, and the GSEA software package was employed to analyze the single gene correlation enrichment of ENT3.
1		UNIPROT:Q99808	inhibits	SLC29A3	UNIPROT:Q9BZD2	Protein	87dea368-c47d-11e5-91a7-001a4ae51247	PMC2962464	Nitrobenzylthioinosine (NBTI) rapidly inhibits both ENT1 and ENT2 at 10 μmand likely also inhibits ENT3 and ENT4 (26).
1		MESH:D006863	activates	SLC29A3	UNIPROT:Q9BZD2	Phenotype	cd6d4950-67ed-11e8-bbed-001a4a160175	PMC5896370	In the mammalian cell context, the acidic pH-activated transport activity of hENT3 facilitates transport of permeants from lower pH to higher pH such as from the lysosome to the cytosol and from intermembrane mitochondrial spaces to the mitochondrial matrix (Govindarajan et al., 2009;Kang et al., 2010;Singh and Govindarajan, 2017).
1		MESH:D006863	activates	SLC29A3	UNIPROT:Q9BZD2	Phenotype	f71e6cf6-f589-11eb-8baa-001a4a160175	30537558	It resides in the luminal loop between transmembrane domains 1 and 2, which plays a role in pH activation of ENT3 [29].
1		CHEBI:6426	activates	SLC29A3	UNIPROT:Q9BZD2	Chemical	d9996d70-c480-11e5-8491-001a4ae51247	PMC2934698	Treatment of leupeptin increased the staining intensity of hENT3 and displayed a more vesicular staining pattern for hENT3 compared with the vehicle-treated cells (Fig. 6A).
1		CHEBI:138859	inhibits	SLC29A3	UNIPROT:Q9BZD2	Chemical	f70fb602-ea47-11ee-9aaa-0050569a1f61	10.1016/j.ijpharm.2022.122044	NBMPR is a selective ENT1 inhibitor, and has been reported to inhibit ENT2 and ENT3 at high concentrations (100 µM) (Baldwin et al., 2005, Nishimura et al., 2012).
1		MESH:D004176	inhibits	SLC29A3	UNIPROT:Q9BZD2	Phenotype	961718a6-c678-11ee-ae05-0050569a1f61	10.1016/j.yexcr.2023.113892	ENT3 inhibition and depletion by dipyridamole and siRNA increased the activity of caspase 3/7 in β-cells [46].
1		UNIPROT:P09603	inhibits	SLC29A3	UNIPROT:Q9BZD2	Protein	dc805798-c47a-11e5-8491-001a4ae51247	22174130	To understand why M-CSF blockade rescued only partially the ENT3–/–histiocytosis phenotype, we investigated factors that may be affected by impaired macrophage functions and found accumulation of apoptotic cells in the spleen after anti–M-CSF treatment (fig.
1		UNIPROT:Q14542	inhibits	SLC29A3	UNIPROT:Q9BZD2	Protein	87dea368-c47d-11e5-91a7-001a4ae51247	PMC2962464	Nitrobenzylthioinosine (NBTI) rapidly inhibits both ENT1 and ENT2 at 10 μmand likely also inhibits ENT3 and ENT4 (26).
1		UNIPROT:O01737	deribosylatesProtein	SLC29A3	UNIPROT:Q9BZD2	Protein	7028382a-c463-11e5-85e4-001a4ae51246	PMC4688390	As inosine cannot be converted to xanthosine directly (Dahncke and Witte,2013), it first has to become deribosylated to hypoxanthine either in the apoplast by NSH3 or after import via ENT3 by NSH1 to become further catabolized to xanthine by xanthine dehydrogenase (Hesberg et al.,2004).
1		CHEBI:16234	inhibits	SLC29A3	UNIPROT:Q9BZD2	Chemical	d9996d70-c480-11e5-8491-001a4ae51247	PMC2934698	Because this mutation involves substitution of glycine by serine in the middle of the 10th TMD of hENT3, we hypothesized that the hydroxyl group of Ser blocks the transport activity of hENT3 by altering the packing of the 10th TMD with other helices, thereby altering the transport of the nucleoside within the translocation pore.