# Nutrigenomic influence of a curcumin-supplemented high glycemic diet on hippocampal microvasculature in male C57BL/6J mice

**Authors:** Emilio Balbuena, Jennifer M. Rutkowsky, Saivageethi Nuthikattu, Amparo C. Villablanca, Dragan Milenkovic

PMC · DOI: 10.3389/fnut.2025.1736964 · 2026-02-03

## TL;DR

This study explores how adding curcumin to a high glycemic diet affects brain microvasculature in mice, revealing potential neuroprotective effects.

## Contribution

The study identifies specific gene expression changes in hippocampal microvessels due to curcumin supplementation in a high glycemic diet.

## Key findings

- Curcumin modulated 1887 genes in hippocampal microvessels compared to a high glycemic diet alone.
- Modulated genes were linked to pathways like neurodegeneration and blood-brain barrier permeability.
- 307 genes overlapped and were negatively correlated with high glycemic diet effects compared to a low glycemic diet.

## Abstract

Curcumin, a dietary polyphenol primarily derived from turmeric, has potent antioxidant and anti-inflammatory capabilities against diet-related chronic diseases. A high glycemic diet (HGD) has been shown to contribute to cognitive decline and dysfunction of murine brain microvasculature. The goal of our study was to elucidate the multi-genomic effects of curcumin on hippocampal microvessels in mice during consumption of a high glycemic diet.

Male C57BL/6J mice were fed a low glycemic diet (LGD, 12% sucrose/weight), a high glycemic diet (HGD, 34% sucrose), or a HGD with 0.2% curcumin (HGD + Curc) for 12 weeks. Global transcriptomic profiles, including protein coding and non-coding genes, of laser-captured endothelial microvessels of the hippocampus were analyzed via microarrays. Bioinformatic tools were utilized to uncover networks and functional pathways of differentially expressed genes modulated by curcumin as well as interactivity between transcription factors and major curcumin metabolites via in silico docking analysis.

The HGD + Curc treatment influenced the differential expression of 1887 genes compared to HGD alone, which included messenger RNAs, microRNAs, long noncoding RNAs, and small nucleolar RNAs. Of these modulated genes, 307 overlapped and were negatively correlated with the fold change expression of the HGD versus LGD comparison. These protein coding and non-coding gene targets regulated by HGD+Curc were involved in pathways related to neurodegeneration, oxidative phosphorylation, blood-brain barrier permeability, cell signaling, and cellular metabolism.

The results from this study show that curcumin induces complex nutrigenomic modifications that could elucidate its neuroprotective effect against hippocampal microvascular dysfunction induced by a high glycemic diet.

## Linked entities

- **Chemicals:** curcumin (PubChem CID 969516)

## Full-text entities

- **Genes:** PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], Gm20675 (predicted gene 20675) [NCBI Gene 105245795], Mmp11 (matrix metallopeptidase 11) [NCBI Gene 17385] {aka MMP-11, SL-3, ST3, Stmy3}, RELA (RELA proto-oncogene, NF-kB subunit) [NCBI Gene 5970] {aka AIF3BL3, CMCU, NFKB3, p65}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Creb1 (cAMP responsive element binding protein 1) [NCBI Gene 12912] {aka 2310001E10Rik, 3526402H21Rik, Creb, Creb-1}, GSK3A (glycogen synthase kinase 3 alpha) [NCBI Gene 2931], Ndufc1 (NADH:ubiquinone oxidoreductase subunit C1) [NCBI Gene 66377] {aka 2310016K22Rik, CI-KFYI, KFYI}, Caln1 (calneuron 1) [NCBI Gene 140904] {aka 9630012C17Rik, Cabp8, MNCb-0849}, Chsy3 (chondroitin sulfate synthase 3) [NCBI Gene 78923] {aka 4833446K15Rik}, Atp5mc3 (ATP synthase membrane subunit c locus 3) [NCBI Gene 228033] {aka 6030447M23, Atp5g3}, Cox5b (cytochrome c oxidase subunit 5B) [NCBI Gene 12859], Atp1a3 (ATPase, Na+/K+ transporting, alpha 3 polypeptide) [NCBI Gene 232975] {aka Atpa-2}, Ndst2 (N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 2) [NCBI Gene 17423] {aka Mndns, NDST-2}, Ndufa13 (NADH:ubiquinone oxidoreductase subunit A13) [NCBI Gene 67184] {aka 2700054G14Rik, CDA016, CGI-39, CI-B16.6, GRIM-19, Grim19}, Brwd3 (bromodomain and WD repeat domain containing 3) [NCBI Gene 382236] {aka Brodl, D030064D06Rik, Gm10452, Gm596}, Maf (MAF bZIP transcription factor) [NCBI Gene 17132] {aka 2810401A20Rik, A230108G15Rik, c-maf}, Epb41l1 (erythrocyte membrane protein band 4.1 like 1) [NCBI Gene 13821] {aka 4.1N, Epb4.1l1, NBL1, mKIAA0338}, Dock3 (dedicator of cyto-kinesis 3) [NCBI Gene 208869] {aka MOCA, PBP, mKIAA0299}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, Shh (sonic hedgehog) [NCBI Gene 20423] {aka 9530036O11Rik, Dsh, HHG-1, Hhg1, Hx, Hxl3}, Epm2aip1 (EPM2A interacting protein 1) [NCBI Gene 77781] {aka A930003G21Rik, mKIAA0766}, Srp54a (signal recognition particle 54A) [NCBI Gene 24067] {aka 54kDa, Srp54}, Hs3st3a1 (heparan sulfate (glucosamine) 3-O-sulfotransferase 3A1) [NCBI Gene 15478] {aka 3Ost3a, Hs3st3a}, Cdk5 (cyclin dependent kinase 5) [NCBI Gene 12568] {aka Crk6}, Tfap2a (transcription factor AP-2, alpha) [NCBI Gene 21418] {aka AP-2, AP2alpha, Ap-2 (a), Ap2, Ap2tf, Tcfap2a}, Grin2a (glutamate receptor, ionotropic, NMDA2A (epsilon 1)) [NCBI Gene 14811] {aka GluN2A, GluRepsilon1, NMDAR2A, NR2A}, Ccnd2 (cyclin D2) [NCBI Gene 12444] {aka 2600016F06Rik, Vin-1, Vin1, cD2}, Rhoa (ras homolog family member A) [NCBI Gene 11848] {aka Arha, Arha1, Arha2}, Nrf1 (nuclear respiratory factor 1) [NCBI Gene 18181] {aka D6Ertd415e}, HK2 (hexokinase 2) [NCBI Gene 3099] {aka HKII, HXK2}, Atp6v0b (ATPase, H+ transporting, lysosomal V0 subunit B) [NCBI Gene 114143] {aka 2310024H13Rik, Atp6f, VMA16}, Abcc10 (ATP-binding cassette, sub-family C member 10) [NCBI Gene 224814] {aka Mrp7, mFLJ00002}, Tgif1 (TGFB-induced factor homeobox 1) [NCBI Gene 21815] {aka Tgif}, Atp6v0e2 (ATPase, H+ transporting, lysosomal V0 subunit E2) [NCBI Gene 76252] {aka 0610006O14Rik, NM9.2}, Apbb1 (amyloid beta precursor protein binding family B member 1) [NCBI Gene 11785] {aka Fe65, Rir}, Vamp1 (vesicle-associated membrane protein 1) [NCBI Gene 22317] {aka Syb-1, Syb1, VAMP-1, lew}, Hsp90ab1 (heat shock protein 90 alpha (cytosolic), class B member 1) [NCBI Gene 15516] {aka 90kDa, Hsp84, Hsp84-1, Hsp90, Hspcb}, Atp1b2 (ATPase, Na+/K+ transporting, beta 2 polypeptide) [NCBI Gene 11932] {aka Amog, Atpb-2}, Insr (insulin receptor) [NCBI Gene 16337] {aka 4932439J01Rik, CD220, D630014A15Rik, IR, IR-A, IR-B}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, Lgi1 (leucine-rich repeat LGI family, member 1) [NCBI Gene 56839], Atp1b1 (ATPase, Na+/K+ transporting, beta 1 polypeptide) [NCBI Gene 11931] {aka Atp4b, Atpb, Atpb-1, NKbeta1}, UNG (uracil DNA glycosylase) [NCBI Gene 7374] {aka DGU, HIGM4, HIGM5, UDG, UNG1, UNG15}, Uqcr11 (ubiquinol-cytochrome c reductase, complex III subunit XI) [NCBI Gene 66594] {aka 0710008D09Rik, Uqcr}, Grin2b (glutamate receptor, ionotropic, NMDA2B (epsilon 2)) [NCBI Gene 14812] {aka GluN2B, GluRepsilon2, NR2B, Nmdar2b}, Cox5a (cytochrome c oxidase subunit 5A) [NCBI Gene 12858] {aka CcOX}, TGFB3 (transforming growth factor beta 3) [NCBI Gene 7043] {aka ARVD, ARVD1, LDS5, RNHF, TGF-beta3}, HDAC3 (histone deacetylase 3) [NCBI Gene 8841] {aka HD3, KDAC3, RPD3, RPD3-2}, F3 (coagulation factor III, tissue factor) [NCBI Gene 2152] {aka CD142, TF, TFA}, Atp1a2 (ATPase, Na+/K+ transporting, alpha 2 polypeptide) [NCBI Gene 98660] {aka Atpa-3, mKIAA0778}, Alg5 (ALG5 dolichyl-phosphate beta-glucosyltransferase) [NCBI Gene 66248] {aka 1500026A19Rik, 2600005J22Rik}, Abcc5 (ATP-binding cassette, sub-family C member 5) [NCBI Gene 27416] {aka 2900011L11Rik, Abcc5a, Abcc5b, Mrp5}, SP1 (Sp1 transcription factor) [NCBI Gene 6667], Gm14325 (predicted gene 14325) [NCBI Gene 329575], MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, PRKG1 (protein kinase cGMP-dependent 1) [NCBI Gene 5592] {aka AAT8, PKG, PKG1, PRKG1B, PRKGR1B, cGK}, Rab6b (RAB6B, member RAS oncogene family) [NCBI Gene 270192] {aka 9630015C03, C330006L04Rik, D9Bwg0185e}, Atp5f1b (ATP synthase F1 subunit beta) [NCBI Gene 11947] {aka Atp5b}
- **Diseases:** dyskinesias (MESH:D004409), musculoskeletal (MESH:D009140), type 2 diabetes (MESH:D003924), dementia (MESH:D003704), HGD (MESH:D008228), LGD (MESH:D009800), neurodevelopmental disorders (MESH:D002658), multiple sclerosis (MESH:D009103), CNS disorders (MESH:D002494), memory loss (MESH:D008569), chronic diseases (MESH:D002908), facial clefts (MESH:C537767), brain cancer (MESH:D001932), endothelial (MESH:D005642), nervous system (MESH:D009422), cognitive decline (MESH:D003072), metastasis (MESH:D009362), ALS (MESH:D000690), hippocampal impairment (MESH:D000092223), microvascular dysfunction (MESH:D017566), atherosclerosis (MESH:D050197), colon cancer (MESH:D015179), diabetic complications (MESH:D048909), death (MESH:D003643), ataxia (MESH:D001259), vascular dementia (MESH:D015140), diabetic cardiomyopathy (MESH:D058065), intellectual disability (MESH:D008607), Rett syndrome (MESH:D015518), hyperglycemic (MESH:D006944), tumorigenic (MESH:D002471), ischemic stroke (MESH:D002544), diabetic retinopathy (MESH:D003930), cardiovascular diseases (MESH:D002318), insulin resistance (MESH:D007333), prion disease (MESH:D017096), Hypoxic (MESH:D002534), neurological disease (MESH:D020271), obesity (MESH:D009765), branchio-oculo-facial syndrome (MESH:D019280), cardiomyopathy (MESH:D009202), fragile X and Rett syndromes (MESH:D005600), neurological dysfunction (MESH:D009461), synaptic degeneration (MESH:D012183), hypoxia (MESH:D000860), Chronic hyperglycemia (MESH:D006943), MetS (MESH:D024821), glioma (MESH:D005910), congenital abnormalities (MESH:D000013), prostate cancer (MESH:D011471), inflammation (MESH:D007249), diseases (MESH:D004194), degenerative diseases (MESH:D019636), mitochondrial dysfunction (MESH:D028361), Alzheimer's and Parkinson's (MESH:D010300), dyslipidemia (MESH:D050171), cancer (MESH:D009369), chromosomal abnormalities (MESH:D002869), Huntington's (MESH:D006816), ischemic (MESH:D002545)
- **Chemicals:** SYBR Green I (MESH:C098022), polyphenol (MESH:D059808), endocannabinoid (MESH:D063388), sucrose (MESH:D013395), lipid (MESH:D008055), bisdemethoxycurcumin (MESH:C034786), ROS (MESH:D017382), folate (MESH:D005492), glucose (MESH:D005947), Curcumin (MESH:D003474), hexahydrocurcumin (MESH:C569902), heparan sulfate (MESH:D006497), LDL-(C (-), Hematoxylin (MESH:D006416), glucuronic acid (MESH:D020723), tetrahydrocurcumin (MESH:C096277), nitro blue tetrazolium chloride (MESH:C094100), phenoxyl radicals (MESH:C042329), carbohydrate (MESH:D002241), dihydrocurcumin (MESH:C476661), corn starch (MESH:D013213), carotenoids (MESH:D002338), curcuminoid (MESH:D036381), water (MESH:D014867), glycogen (MESH:D006003), demethoxycurcumin (MESH:C050229), biotin (MESH:D001710), galactose (MESH:D005690), blood glucose (MESH:D001786), curcumin Glucuronide (MESH:C000591193), cholesterol (MESH:D002784), NO (MESH:D009569), chondroitin sulfate (MESH:D002809), cGMP (MESH:D006152), fat (MESH:D005223), 5-bromo-4-chloro-3-indolyl phosphate (MESH:C035455), oxygen (MESH:D010100), sulfate (MESH:D013431), sugar (MESH:D000073893), xylazine (MESH:D014991), aldosterone (MESH:D000450), TG (MESH:D014280), sialic acid (MESH:D019158)
- **Species:** Curcuma longa (turmeric, species) [taxon 136217], Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090]
- **Cell lines:** /6J — Homo sapiens (Human), Cutaneous melanoma, Cancer cell line (CVCL_W797)

## Figures

11 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12909243/full.md

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Source: https://tomesphere.com/paper/PMC12909243