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Molecular Mechanisms Responsible for Radiation-Induced Toxicity of Normal Tissue
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Molecular Mechanisms Responsible for Radiation-Induced Toxicity of Normal Tissue

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Toxicogenomics".

Deadline for manuscript submissions: 25 December 2025 | Viewed by 20665

Special Issue Editor

Dr. Rupak Pathak

E-Mail Website
Guest Editor
Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Interests: radioresponsive genes; inflammation; genetic markers of radiation damage; immunotherapy; radioprotectors

Special Issue Information

Dear Colleagues,

Healthy tissue injury during or after cancer radiotherapy enhances morbidity, mortality, and health care expenditures. According to the American Cancer Society report, a little over 1.9 million new cancer cases are expected to be diagnosed in the United States in 2022. Approximately 50% to 60% of these cancer patients will either receive targeted fractionated radiation to eradicate a local tumor or total body irradiation as a conditioning process before bone marrow transplantation. Unfortunately, a strong positive correlation exists between tumor regression due to radiotherapy and healthy tissue toxicity. Radiation damage may also occur from nuclear accidents or warfare. Radiation damage, especially in highly radiosensitive tissues, such as those in the hematopoietic and gastrointestinal systems, may occur within hours to days (early), within weeks (acute), or after months or years (delayed). However, the pathogenesis of the postirradiation healthy tissue toxicity is highly complex in nature. Thus, it is important to define and better understand the genetic basis of and genes involved in healthy tissue radiation damage to allow the development of novel mitigating methods, which would not interfere with cancer therapy. Therefore, we cordially invite authors to contribute original or review articles bringing forth novel insights into this understudied area of research.

Dr. Rupak Pathak
Guest Editor

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Keywords

  • radioresponsive genes
  • inflammation
  • genetic markers of radiation damage
  • immunotherapy
  • radioprotectors
  • DNA damage and repair

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Published Papers (7 papers)

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Research

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13 pages, 2538 KiB  
Article
Integrative Analysis of Radiation-Induced Senescence-Associated Secretory Phenotype Factors in Kidney Cancer Progression
by Shubhankar Suman
Genes 2025, 16(1), 85; https://doi.org/10.3390/genes16010085 - 15 Jan 2025
Viewed by 1100
Abstract
Background: Ionizing radiation (IR) is a well-known inducer of cellular senescence and the senescence-associated secretory phenotype (SASP). SASP factors play dual roles in cancer, either promoting or inhibiting its development. This study investigates IR-induced SASP factors specifically secreted by renal cortical epithelial (RCE) [...] Read more.
Background: Ionizing radiation (IR) is a well-known inducer of cellular senescence and the senescence-associated secretory phenotype (SASP). SASP factors play dual roles in cancer, either promoting or inhibiting its development. This study investigates IR-induced SASP factors specifically secreted by renal cortical epithelial (RCE) cells and their role in promoting renal cell carcinoma (RCC) progression. Methods: Proteomic data from the SASP Atlas were analyzed to identify IR-induced factors unique to RCE cells, with subsequent evaluations performed at both the gene and protein levels. Thirty-seven proteins were identified as exclusively upregulated and secreted by senescent RCE cells. Gene expression analysis of these RCE-specific SASP factors was conducted using the Gene Expression database of Normal and Tumor tissues (GENT2) and The Cancer Genome Atlas (TCGA). To assess their prognostic relevance in RCC, the corresponding proteins were further analyzed using the Human Protein Atlas (HPA), emphasizing the relationship between SASP factor expression and RCC progression. Results: ALDH18A1 and ASPH emerged as key RCE-specific SASP factors with significant upregulation at both the gene and protein levels (Log2 ratio > 1.15, p < 0.05). These proteins are implicated in pro-cancer activities and are strongly associated with poor prognostic outcomes in RCC. Their critical roles in RCC progression underscore their potential as promising therapeutic targets for the prevention and treatment of the disease. Conclusions: This study provides novel insights into the role of IR-induced SASP in renal carcinogenesis, marking the first identification of ALDH18A1 and ASPH as specific secreted proteins associated with tumor progression in RCC. This study suggests that ALDH18A1 and ASPH hold promise as early biomarkers for RCC and as therapeutic targets for disease prevention and treatment. Full article
(This article belongs to the Special Issue Molecular Mechanisms Responsible for Radiation-Induced Toxicity of Normal Tissue)
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10 pages, 214 KiB  
Article
Validating Disease Associations of Drug-Metabolizing Enzymes through Genome-Wide Association Study Data Analysis
by Evan Leskiw, Adeline Whaley, Peter Hopwood, Tailyn Houston, Nehal Murib, Donna Al-Falih and Ryoichi Fujiwara
Genes 2024, 15(10), 1326; https://doi.org/10.3390/genes15101326 - 15 Oct 2024
Cited by 1 | Viewed by 1398
Abstract
Background and Objectives: Phase I and phase II drug-metabolizing enzymes are crucial for the metabolism and elimination of various endogenous and exogenous compounds, such as small-molecule hormones, drugs, and xenobiotic carcinogens. While in vitro and animal studies have suggested a link between genetic [...] Read more.
Background and Objectives: Phase I and phase II drug-metabolizing enzymes are crucial for the metabolism and elimination of various endogenous and exogenous compounds, such as small-molecule hormones, drugs, and xenobiotic carcinogens. While in vitro and animal studies have suggested a link between genetic mutations in these enzymes and an increased risk of cancer, human in vivo studies have provided limited supportive evidence. Methods: Genome-wide association studies (GWASs) are a powerful tool for identifying genes associated with specific diseases by comparing two large groups of individuals. In the present study, we analyzed a GWAS database to identify key diseases genetically associated with drug-metabolizing enzymes, focusing on UDP-glucuronosyltransferases (UGTs). Results: Our analysis confirmed a strong association between the UGT1 gene and hyperbilirubinemia. Additionally, over ten studies reported a link between the UGT1 gene and increased low-density lipoprotein (LDL) cholesterol levels. UGT2B7 was found to be associated with testosterone levels, total cholesterol levels, and vitamin D levels. Conclusions: Despite the in vitro capability of UGT1 and UGT2 family enzymes to metabolize small-molecule carcinogens, the GWAS data did not indicate their genetic association with cancer, except for one study that linked UGT2B4 to ovarian cancer. Further investigations are necessary to fill the gap between in vitro, animal, and human in vivo data. Full article
(This article belongs to the Special Issue Molecular Mechanisms Responsible for Radiation-Induced Toxicity of Normal Tissue)
18 pages, 4697 KiB  
Article
Pre-Administration of PLX-R18 Cells Protects Mice from Radiation-Induced Hematopoietic Failure and Lethality
by Vidya P. Kumar, Shukla Biswas, Gregory P. Holmes-Hampton, Michal Sheleg, Sasha Stone, Betre Legesse, Racheli Ofir and Sanchita P. Ghosh
Genes 2022, 13(10), 1756; https://doi.org/10.3390/genes13101756 - 28 Sep 2022
Cited by 3 | Viewed by 2704
Abstract
Acute Radiation Syndrome (ARS) is a syndrome involving damage to multiple organs caused by exposure to a high dose of ionizing radiation over a short period of time; even low doses of radiation damage the radiosensitive hematopoietic system and causes H-ARS. PLacenta eXpanded [...] Read more.
Acute Radiation Syndrome (ARS) is a syndrome involving damage to multiple organs caused by exposure to a high dose of ionizing radiation over a short period of time; even low doses of radiation damage the radiosensitive hematopoietic system and causes H-ARS. PLacenta eXpanded (PLX)-R18 is a 3D-expanded placenta-derived stromal cell product designated for the treatment of hematological disorders. These cells have been shown in vitro to secrete hematopoietic proteins, to stimulate colony formation, and to induce bone marrow migration. Previous studies in mice showed that PLX-R18 cells responded to radiation-induced hematopoietic failure by transiently secreting hematopoiesis related proteins to enhance reconstitution of the hematopoietic system. We assessed the potential effect of prophylactic PLX-R18 treatment on H-ARS. PLX-R18 cells were administered intramuscularly to C57BL/6 mice, −1 and 3 days after (LD70/30) total body irradiation. PLX R18 treatment significantly increased survival after irradiation (p < 0.0005). In addition, peripheral blood and bone marrow (BM) cellularity were monitored at several time points up to 30 days. PLX-R18 treatment significantly increased the number of colony-forming hematopoietic progenitors in the femoral BM and significantly raised peripheral blood cellularity. PLX-R18 administration attenuated biomarkers of bone marrow aplasia (EPO, FLT3L), sepsis (SAA), and systemic inflammation (sP-selectin and E-selectin) and attenuated radiation-induced inflammatory cytokines/chemokines and growth factors, including G-CSF, MIP-1a, MIP-1b, IL-2, IL-6 and MCP-1, In addition, PLX-R18 also ameliorated radiation-induced upregulation of pAKT. Taken together, prophylactic PLX-R18 administration may serve as a protection measure, mitigating bone marrow failure symptoms and systemic inflammation in the H-ARS model. Full article
(This article belongs to the Special Issue Molecular Mechanisms Responsible for Radiation-Induced Toxicity of Normal Tissue)
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11 pages, 3523 KiB  
Article
Molecular Cytogenetics Reveals Mosaicism in Human Umbilical Vein Endothelial Cells
by Regina L. Binz and Rupak Pathak
Genes 2022, 13(6), 1012; https://doi.org/10.3390/genes13061012 - 3 Jun 2022
Cited by 4 | Viewed by 2915
Abstract
Primary human umbilical vein endothelial cells (HUVECs) are consistently the most reliable in vitro model system for studying the inner lining of blood and lymphatic vessels or the endothelium. Primary human cells originate from freshly isolated tissues without genetic manipulation and generally show [...] Read more.
Primary human umbilical vein endothelial cells (HUVECs) are consistently the most reliable in vitro model system for studying the inner lining of blood and lymphatic vessels or the endothelium. Primary human cells originate from freshly isolated tissues without genetic manipulation and generally show a modal number of 46 chromosomes with no structural alterations, at least during early passages. We investigated the cytogenetic integrity of HUVECs with conventional (G-banding) and molecular cytogenetic methods (spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH)). Our G-band data shows two X-chromosomes, confirming these HUVECs originate from a female donor. Notably, some cells consistently exhibit an unfamiliar banding pattern on one X chromosome toward the distal end of the long arm (Xq). Our FISH analysis confirms that approximately 50% of these HUVECs have a deletion of the Xq terminal region. SKY analysis indicates that the deleted region is apparently not integrated into any other chromosome. Finally, we demonstrated the presence of a similar Xq deletion in the daughter cell line, EA.hy926, which was generated by fusing HUVECs with A549 (a thioguanine-resistant clone of adenocarcinomic human alveolar basal epithelial cells). These findings will advance comprehension of HUVECs biology and will augment future endothelial studies. Full article
(This article belongs to the Special Issue Molecular Mechanisms Responsible for Radiation-Induced Toxicity of Normal Tissue)
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Review

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29 pages, 2361 KiB  
Review
Potential Applications of Nanoparticles in Improving the Outcome of Lung Cancer Treatment
by Agnishwar Girigoswami and Koyeli Girigoswami
Genes 2023, 14(7), 1370; https://doi.org/10.3390/genes14071370 - 28 Jun 2023
Cited by 24 | Viewed by 6472
Abstract
Lung cancer is managed using conventional therapies, including chemotherapy, radiation therapy, or a combination of both. Each of these therapies has its own limitations, such as the indiscriminate killing of normal as well as cancer cells, the solubility of the chemotherapeutic drugs, rapid [...] Read more.
Lung cancer is managed using conventional therapies, including chemotherapy, radiation therapy, or a combination of both. Each of these therapies has its own limitations, such as the indiscriminate killing of normal as well as cancer cells, the solubility of the chemotherapeutic drugs, rapid clearance of the drugs from circulation before reaching the tumor site, the resistance of cancer cells to radiation, and over-sensitization of normal cells to radiation. Other treatment modalities include gene therapy, immunological checkpoint inhibitors, drug repurposing, and in situ cryo-immune engineering (ICIE) strategy. Nanotechnology has come to the rescue to overcome many shortfalls of conventional therapies. Some of the nano-formulated chemotherapeutic drugs, as well as nanoparticles and nanostructures with surface modifications, have been used for effective cancer cell killing and radio sensitization, respectively. Nano-enabled drug delivery systems act as cargo to deliver the sensitizer molecules specifically to the tumor cells, thereby enabling the radiation therapy to be more effective. In this review, we have discussed the different conventional chemotherapies and radiation therapies used for inhibiting lung cancer. We have also discussed the improvement in chemotherapy and radiation sensitization using nanoparticles. Full article
(This article belongs to the Special Issue Molecular Mechanisms Responsible for Radiation-Induced Toxicity of Normal Tissue)
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15 pages, 670 KiB  
Review
TLR4—A Pertinent Player in Radiation-Induced Heart Disease?
by Basveshwar Gawali, Vijayalakshmi Sridharan, Kimberly J. Krager, Marjan Boerma and Snehalata A. Pawar
Genes 2023, 14(5), 1002; https://doi.org/10.3390/genes14051002 - 28 Apr 2023
Cited by 6 | Viewed by 2597
Abstract
The heart is one of the organs that is sensitive to developing delayed adverse effects of ionizing radiation (IR) exposure. Radiation-induced heart disease (RIHD) occurs in cancer patients and cancer survivors, as a side effect of radiation therapy of the chest, with manifestation [...] Read more.
The heart is one of the organs that is sensitive to developing delayed adverse effects of ionizing radiation (IR) exposure. Radiation-induced heart disease (RIHD) occurs in cancer patients and cancer survivors, as a side effect of radiation therapy of the chest, with manifestation several years post-radiotherapy. Moreover, the continued threat of nuclear bombs or terrorist attacks puts deployed military service members at risk of exposure to total or partial body irradiation. Individuals who survive acute injury from IR will experience delayed adverse effects that include fibrosis and chronic dysfunction of organ systems such as the heart within months to years after radiation exposure. Toll-like receptor 4 (TLR4) is an innate immune receptor that is implicated in several cardiovascular diseases. Studies in preclinical models have established the role of TLR4 as a driver of inflammation and associated cardiac fibrosis and dysfunction using transgenic models. This review explores the relevance of the TLR4 signaling pathway in radiation-induced inflammation and oxidative stress in acute as well as late effects on the heart tissue and the potential for the development of TLR4 inhibitors as a therapeutic target to treat or alleviate RIHD. Full article
(This article belongs to the Special Issue Molecular Mechanisms Responsible for Radiation-Induced Toxicity of Normal Tissue)
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15 pages, 1492 KiB  
Review
Radiation-Induced Intestinal Normal Tissue Toxicity: Implications for Altered Proteome Profile
by Enoch K. Larrey and Rupak Pathak
Genes 2022, 13(11), 2006; https://doi.org/10.3390/genes13112006 - 2 Nov 2022
Cited by 2 | Viewed by 2239
Abstract
Radiation-induced toxicity to healthy/normal intestinal tissues, especially during radiotherapy, limits the radiation dose necessary to effectively eradicate tumors of the abdomen and pelvis. Although the pathogenesis of intestinal radiation toxicity is highly complex, understanding post-irradiation alterations in protein profiles can provide crucial insights [...] Read more.
Radiation-induced toxicity to healthy/normal intestinal tissues, especially during radiotherapy, limits the radiation dose necessary to effectively eradicate tumors of the abdomen and pelvis. Although the pathogenesis of intestinal radiation toxicity is highly complex, understanding post-irradiation alterations in protein profiles can provide crucial insights that make radiotherapy safer and more efficient and allow for increasing the radiation dose during cancer treatment. Recent preclinical and clinical studies have advanced our current understanding of the molecular changes associated with radiation-induced intestinal damage by assessing changes in protein expression with mass spectrometry-based approaches and 2-dimensional difference gel electrophoresis. Studies by various groups have demonstrated that proteins that are involved in the inflammatory response, the apoptotic pathway, reactive oxygen species scavenging, and cell proliferation can be targeted to develop effective radiation countermeasures. Moreover, altered protein profiles serve as a crucial biomarkers for intestinal radiation damage. In this review, we present alterations in protein signatures following intestinal radiation damage as detected by proteomics approaches in preclinical and clinical models with the aim of providing a better understanding of how to accomplish intestinal protection against radiation damage. Full article
(This article belongs to the Special Issue Molecular Mechanisms Responsible for Radiation-Induced Toxicity of Normal Tissue)
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