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Nanocurcumin attenuates brain injury in rats with desert dry‑heat‑induced exertional heat stroke by suppressing TLR4/MyD88/NF‑κB signaling

  • Authors:
    • Lisong Su
    • Jinquan Qu
    • Jiajia Li
    • Wenhui Shi
    • Laiyang Song
    • Feixing Liang
    • Jiangwei Liu
  • View Affiliations / Copyright

    Affiliations: Desert Medicine Laboratory, General Hospital of Xinjiang Military Command, Ürümqi, Xinjiang Uygur Autonomous Region 830000, P.R. China
    Copyright: © Su et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 243
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    Published online on: July 2, 2026
       https://doi.org/10.3892/mmr.2026.13953
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Abstract

Exertional heat stroke (EHS) is a life‑threatening condition characterized by hyperthermia, systemic inflammation and central nervous system injury, particularly in desert dry‑heat environments. Excessive activation of inflammatory signaling pathways, notably the Toll‑like receptor (TLR)4/myeloid differentiation factor 88 (MyD88)/NF‑κB axis, critically contributes to brain damage and neuroendocrine dysfunction in EHS. Curcumin exhibits anti‑inflammatory and neuroprotective effects; however, poor bioavailability limits its clinical application. Notably, nanocrystal formulations may improve the therapeutic efficacy of curcumin. In the present study, network pharmacology and molecular docking were employed to identify the potential therapeutic targets of curcumin in EHS. A rat model of desert dry‑heat‑induced EHS was established and nanocurcumin was administered intravenously following heat exposure. Histopathological examination, ELISA analyses of neuroendocrine hormones and inflammatory cytokines, serum biochemical assays and western blotting were subsequently performed. These evaluations assessed brain injury, hypothalamic‑pituitary‑adrenal and hypothalamic‑pituitary‑thyroid axes functions, systemic inflammation, peripheral organ injury indicators and activation of the TLR4/MyD88/NF‑κB signaling pathway. Network analysis revealed 138 overlapping target genes between curcumin and EHS, identifying AKT1, TNF, EGFR, BCL2, STAT3, SRC and NFKB1 as key hub genes. Kyoto Encyclopedia of Genes and Genomes pathway analysis highlighted enrichment of the ‘Toll‑like receptor signaling pathway’ and ‘NF‑κB signaling pathway’. Molecular docking indicated favorable binding affinities of curcumin to essential inflammatory proteins, including TLR4, MyD88 and NFKB1. In vivo experiments demonstrated that nanocurcumin reduced neuronal injury in the cerebral cortex and hypothalamus of rats. Furthermore, nanocurcumin significantly decreased serum concentrations of corticotropin‑releasing hormone, corticosterone, thyrotropin‑releasing hormone and thyroid‑stimulating hormone, and restored adrenocorticotropic hormone, total triiodothyronine and free triiodothyronine levels. Nanocurcumin also lowered serum TNF‑α, IL‑6 and IL‑1β levels, and improved biochemical markers of liver, kidney and tissue injury (alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatine kinase and lactate dehydrogenase). Within the 4‑h observation period, medium and high doses of nanocurcumin did not worsen biochemical markers compared with those in the EHS or saline groups. Additionally, nanocurcumin administration dose‑dependently inhibited TLR4, MyD88 and NF‑κB protein expression in brain tissues. In conclusion, nanocurcumin may alleviate brain injury, neuroendocrine dysfunction and systemic inflammation associated with desert dry‑heat‑induced EHS, and may improve biochemical indicators of peripheral organ damage; these effects likely involve suppression of the TLR4/MyD88/NF‑κB signaling pathway. These findings support the use of nanocurcumin as a promising adjunctive therapy for managing EHS.
View Figures

Figure 1

Identification and network
pharmacological analysis of potential curcumin targets for EHS
treatment. (A) Venn diagram illustrating overlapping targets
between curcumin and EHS-related genes. (B) PPI network constructed
from the overlapping targets. (C) Modular analysis highlighting
core subnetworks within the PPI network. The inner core cluster
(red nodes) indicates a densely connected primary target module,
while the outer circle (orange-yellow nodes) represents closely
associated peripheral modules. (D) Interaction network of hub
genes. The top seven hub genes (EGFR, SRC, BCL2, STAT3, AKT1, TNF
and NFKB1), identified using the CytoHubba plugin, and their direct
interactions are shown. (E) Core functional module (cluster 1)
identified by MCODE analysis. (F) Module related to extracellular
matrix remodeling and inflammation (cluster 3) identified by MCODE
analysis. EHS, exertional heat stroke; PPI, protein-protein
interaction.

Figure 2

Gene function and pathway enrichment
analyses of the potential therapeutic targets of curcumin in
exertional heat stroke. (A) Bubble plot depicting GO enrichment of
overlapping targets, displaying the top 10 significantly enriched
terms across BP, CC and MF categories. Bubble size represents gene
count and color intensity indicates enrichment significance. (B)
Bar plot of GO enrichment results for overlapping targets. (C) KEGG
pathway enrichment bubble plot, showing the top 30 significantly
enriched pathways. Bubble size corresponds to gene count and color
intensity indicates enrichment significance. (D) Bar plot
illustrating KEGG pathway enrichment for overlapping targets. BP,
biological processes; CC, cellular component; GO, Gene Ontology;
KEGG, Kyoto Encyclopedia of Genes and Genomes; MF, molecular
function.

Figure 3

Molecular docking interactions
between curcumin and key hub targets. Representative molecular
docking images illustrating the binding interactions of curcumin
with nine key target proteins: (A) AKT1, (B) SRC, (C) NFKB1, (D)
BCL2, (E) EGFR, (F) STAT3, (G) TNF, (H) MyD88 and (I) TLR4. MyD88,
myeloid differentiation factor 88; TLR4, Toll-like receptor 4.

Figure 4

Effect of nanocurcumin on serum
neuroendocrine hormone levels in rats with EHS. Serum
concentrations of (A) TRH, (B) TSH, (C) FT3, (D) T3, (E) FT4, (F)
T4, (G) CRH, (H) ACTH and (I) CORT across different experimental
groups. Data are presented as the mean ± SD. Statistical analyses
were conducted using one-way ANOVA with Tukey's post hoc test.
*P<0.05, **P<0.01, ****P<0.0001; ns, not significant.
ACTH, adrenocorticotropic hormone; CON, control; CORT,
corticosterone; CRH, corticotropin-releasing hormone; EHS,
exertional heat stroke; FT3, free triiodothyronine; FT4, free
thyroxine; H-NCur, high-dose nanocurcumin; L-NCur, low-dose
nanocurcumin; M-NCur, medium-dose nanocurcumin; NS, normal saline;
T3, total triiodothyronine; T4, total thyroxine; TRH,
thyrotropin-releasing hormone; TSH, thyroid-stimulating
hormone.

Figure 5

Effect of nanocurcumin on the levels
of systemic inflammatory cytokines, and serum biochemical markers
related to peripheral organ and tissue injury in rats with EHS.
Serum concentrations of (A) TNF-α, (B) IL-6 and (C) IL-1β in
different experimental groups. Serum concentrations of (D) ALT, (E)
AST, (F) Cr, (G) BUN, (H) CK and (I) LDH in different experimental
groups. Data are presented as he mean ± SD. Statistical analyses
were performed using one-way ANOVA followed by Tukey's post hoc
test. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001; ns,
not significant. ALT, alanine aminotransferase; AST, aspartate
aminotransferase; BUN, blood urea nitrogen; CK, creatine kinase;
Cr, creatinine; CON, control; EHS, exertional heat stroke; H-NCur,
high-dose nanocurcumin; L-NCur, low-dose nanocurcumin; LDH, lactate
dehydrogenase; M-NCur, medium-dose nanocurcumin; NS, normal
saline.

Figure 6

Histopathological analysis of brain
tissues using H&E and Nissl staining. H&E staining at (A)
×200 and (B) ×400 magnification. Nissl staining at (C) ×200 and (D)
×400 magnification. Red arrows indicate neuronal shrinkage in both
H&E and Nissl staining images. CON, control; EHS, exertional
heat stroke; H&E, hematoxylin and eosin; H-NCur, high-dose
nanocurcumin; L-NCur, low-dose nanocurcumin; M-NCur, medium-dose
nanocurcumin; NS, normal saline.

Figure 7

Effect of nanocurcumin on
TLR4/MyD88/NF-κB signaling pathway protein expression in the brain
tissues of rats with EHS. (A) Representative western blotting
images showing MyD88, TLR4, NF-κB and β-actin expression. (B)
Semi-quantitative densitometric analysis of MyD88/β-actin,
TLR4/β-actin and NF-κB/β-actin ratios. Data are presented as the
mean ± SD. Statistical analyses were performed using one-way ANOVA
followed by Tukey's post hoc test. *P<0.05, **P<0.01,
***P<0.001, ****P<0.0001. CON, control; EHS, exertional heat
stroke; H&E, hematoxylin and eosin; H-NCur, high-dose
nanocurcumin; L-NCur, low-dose nanocurcumin; M-NCur, medium-dose
nanocurcumin; MyD88, myeloid differentiation factor 88; NS, normal
saline; TLR4, Toll-like receptor 4.
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Copy and paste a formatted citation
Spandidos Publications style
Su L, Qu J, Li J, Shi W, Song L, Liang F and Liu J: Nanocurcumin attenuates brain injury in rats with desert dry‑heat‑induced exertional heat stroke by suppressing TLR4/MyD88/NF‑&kappa;B signaling. Mol Med Rep 34: 243, 2026.
APA
Su, L., Qu, J., Li, J., Shi, W., Song, L., Liang, F., & Liu, J. (2026). Nanocurcumin attenuates brain injury in rats with desert dry‑heat‑induced exertional heat stroke by suppressing TLR4/MyD88/NF‑&kappa;B signaling. Molecular Medicine Reports, 34, 243. https://doi.org/10.3892/mmr.2026.13953
MLA
Su, L., Qu, J., Li, J., Shi, W., Song, L., Liang, F., Liu, J."Nanocurcumin attenuates brain injury in rats with desert dry‑heat‑induced exertional heat stroke by suppressing TLR4/MyD88/NF‑&kappa;B signaling". Molecular Medicine Reports 34.3 (2026): 243.
Chicago
Su, L., Qu, J., Li, J., Shi, W., Song, L., Liang, F., Liu, J."Nanocurcumin attenuates brain injury in rats with desert dry‑heat‑induced exertional heat stroke by suppressing TLR4/MyD88/NF‑&kappa;B signaling". Molecular Medicine Reports 34, no. 3 (2026): 243. https://doi.org/10.3892/mmr.2026.13953
Copy and paste a formatted citation
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Spandidos Publications style
Su L, Qu J, Li J, Shi W, Song L, Liang F and Liu J: Nanocurcumin attenuates brain injury in rats with desert dry‑heat‑induced exertional heat stroke by suppressing TLR4/MyD88/NF‑&kappa;B signaling. Mol Med Rep 34: 243, 2026.
APA
Su, L., Qu, J., Li, J., Shi, W., Song, L., Liang, F., & Liu, J. (2026). Nanocurcumin attenuates brain injury in rats with desert dry‑heat‑induced exertional heat stroke by suppressing TLR4/MyD88/NF‑&kappa;B signaling. Molecular Medicine Reports, 34, 243. https://doi.org/10.3892/mmr.2026.13953
MLA
Su, L., Qu, J., Li, J., Shi, W., Song, L., Liang, F., Liu, J."Nanocurcumin attenuates brain injury in rats with desert dry‑heat‑induced exertional heat stroke by suppressing TLR4/MyD88/NF‑&kappa;B signaling". Molecular Medicine Reports 34.3 (2026): 243.
Chicago
Su, L., Qu, J., Li, J., Shi, W., Song, L., Liang, F., Liu, J."Nanocurcumin attenuates brain injury in rats with desert dry‑heat‑induced exertional heat stroke by suppressing TLR4/MyD88/NF‑&kappa;B signaling". Molecular Medicine Reports 34, no. 3 (2026): 243. https://doi.org/10.3892/mmr.2026.13953
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