Page 54 - JCTR-11-1

Journal of Clinical and
Translational Research Hesperidin enhances repair of γ-irradiated wounds

elicits inflammation required for wound regeneration by radiotherapy typically involves multiple fractions of smaller
promoting cell proliferation, adhesion, and differentiation. doses of radiation over an extended period. The present
However, prolonged inflammation delays wound study holds clinical relevance as it employs a regimen
repair, regeneration, and scar development. NF-κB is similar to clinical radiotherapy to study the effect of
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upregulated after wounding and irradiation. Hesperidin fractionated radiation on wound repair and regeneration
blocks excessive transcriptional activation of NF-κB, while exploring the application of hesperidin in this setting.
accelerating the repair and regeneration of irradiated Our study demonstrates that daily hesperidin treatment
wounds observed in this study. 78,124,125 COX-2 is elevated before exposure to fractionated γ-radiation expedites
after wounding, and hesperidin suppresses its expression wound healing in mice, as evidenced by enhanced wound
to augment regenerative responses. 78,120,126 contraction, increased synthesis of collagen, DNA, and NO,
The vascular endothelial growth factor (VEGF), as well as improved fibroblast proliferation and increased
tumor necrosis factor-alpha (TNF-α), and transforming vasculature in the wound bed. The enhancement in wound
growth factor-beta (TGF-β) are essential in promoting the repair and regeneration may be attributed to hesperidin’s
growth of fibroblasts, keratinocytes, and endothelial cells, ability to increase the synthesis of crucial molecules, such as
thereby expediting the wound healing process. Although DNA, collagen, and NO while inhibiting or scavenging free
the levels of these growth factors were not measured, radicals induced by wounding and irradiation. In addition,
it is plausible that hesperidin could have increased the hesperidin’s downregulation of PARP, NF-kB, and COX-2,
expression of VEGF, TNF-α, and TGF-β at a molecular and upregulation of VEGF, TNF-α, TGF-β, MMP-2, MMP-
level, leading to accelerated regenerative responses and 9, Nrf2, and vitagenes likely contributed to the enhanced
faster wound repair in this study. 7,119,120 Wounding and regeneration and repair of irradiated wounds. Our findings
irradiation activate a cascade of oxidative stress, which suggest that strategies to modulate the pathophysiological
may be counteracted by stimulating vitagenes that aid environment of irradiated wounds using hesperidin may hold
in wound repair and regeneration through elevated significant promise for improving radiation-impaired wound
expression of vitagenes. The nuclear factor erythroid healing. Further studies are warranted to better understand
2-related factor 2 (Nrf2) signaling plays a crucial role the molecular mechanisms by which hesperidin initiates and
in countering oxidative stress by stimulating vitagenes, supports tissue repair processes in irradiated wounds.
including heat shock proteins, heme oxygenase-1,
NAD(P)H-quinone oxidoreductase, GSH transferase, Acknowledgments
GSHPx, sirtuin-1, and the thioredoxin system. 127,128 Plant We thank Dr. M. S. Vidyasagar and Dr. GJR. Soloman from
polyphenols have been found to abate oxidative stress by the Department of Radiotherapy and Oncology, Kasturba
stimulating Nrf2 signaling and vitagenes. The increase Medical College, Manipal, India, for providing the
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in GSHPx and GSH concentrations is due to hesperidin’s necessary irradiation facilities and dosimetry assistance.
ability to upregulate Nrf2 and vitagenes, promoting We also thank Prof. Chunchulkar and Mrs. Geetha J.
wound healing by enhancing the antioxidant system. 45,120 Nayak from the Department of Mechanical Engineering,
Similarly, hesperetin, the aglycone form of hesperidin, has Manipal Institute of Technology, Manipal, India, for their
been reported to upregulate Nrf2 and vitagenes. Matrix expertise in calculating wound areas.
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metalloproteinases (MMP), also known as gelatinase, play
a crucial role in angiogenesis, matrix remodeling (MMP-2), Funding
and re-epithelialization of regenerating wounds (MMP-9).
Hesperidin upregulates both MMP-2 and MMP-9 to This study was funded by the ICMR (No.45/1/2005/BMS/
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heal irradiated wounds. Poly-ADP ribose polymerase TRM) and DRDO (No. DLS/81/4822/LSRB-78/EPB/2005),
(PARP) regulates cell proliferation and is hyperactivated Government of India, New Delhi.
during wound healing, as it is involved in inflammation, Conflict of interest
cell proliferation, and migration and is co-activated with
NF-κB. 131,132 Hesperidin treatment attenuated PARP The authors declare no conflicts of interest.
activation and accelerated wound healing in this study. 45
Author contributions
5. Conclusion Conceptualization: Ganesh Chandra Jagetia

Most animal models of radiation-impaired wound healing Investigation: All authors
involve irradiating the whole animal or a localized skin Methodology: Kota V. N. M. Rao
flap with a single large dose of radiation, which limits Writing – original draft: Ganesh Chandra Jagetia
the applicability of these findings to humans, in which Writing – review & editing: Ganesh Chandra Jagetia

Volume 11 Issue 1 (2025) 48 doi: 10.36922/jctr.24.00049