Search Results (25)

Ionizing radiation (IR) poses a dual challenge in medicine; while essential for cancer therapy, it inflicts collateral damage to normal tissues, particularly the gastrointestinal (GI) tract. High-dose IR triggers acute radiation syndrome (ARS), characterized by crypt stem cell depletion, mucosal barrier disruption, inflammation, and potential progression to fibrosis and secondary malignancy. Emerging evidence identifies the epithelial kinase doublecortin-like kinase 1 (DCLK1)—highly expressed in GI tuft cells and cancer stem-like cells—as a master regulator of post-IR responses. DCLK1 integrates DNA repair (via p53/ATM), and survival signaling (via NF-κB, TGF-β, and MAPK) to promote epithelial regeneration, yet these same mechanisms contribute to therapy resistance and oncogenesis. DCLK1 further modulates the immune microenvironment by skewing macrophages toward an immunosuppressive M2 phenotype, enhancing tissue remodeling, angiogenesis, and immune evasion. Preclinical studies demonstrate that DCLK1 inhibition sensitizes tumors to radiotherapy while preserving mucosal repair. Therapeutic strategies targeting DCLK1, alongside radioprotective agents, immunomodulators, and senolytics, may enhance regeneration, limit fibrosis, and eradicate therapy-resistant cancer stem cells. This review highlights DCLK1’s dual role in regeneration and tumorigenesis and evaluates its potential as a therapeutic target and biomarker in IR-induced GI damage. Full article

Background: High-dose γ-ray exposure (≥7 Gy) in nuclear emergencies induces life-threatening acute radiation syndrome, characterized by rapid hematopoietic collapse (leukocytes <0.5 × 10⁹/L) and gastrointestinal barrier failure. While clinical biomarkers like leukocyte depletion guide current therapies targeting myelosuppression, the concomitant metabolic disturbances and gut microbiota dysbiosis—critical determinants of delayed mortality—remain insufficiently profiled across the 28-day injury-recovery continuum. Methods: This study investigates the effects of ⁶⁰Co γ-ray irradiation on metabolic characteristics and gut microbiota in Sprague Dawley rats using untargeted metabolomics and 16S rRNA sequencing. Meanwhile, body weight and complete blood counts were measured. Results: Body weight exhibited significant fluctuations, with the most pronounced deviation observed at 14 days. Blood counts revealed a rapid decline in white blood cells, red blood cells, and platelets post-irradiation, reaching nadirs at 7–14 days, followed by gradual recovery to near-normal levels by 28 days. Untargeted metabolomics identified 32 upregulated and 33 downregulated plasma metabolites at 14 days post-irradiation, while fecal metabolites showed 47 upregulated and 18 downregulated species at 3 days. Key metabolic pathways impacted included Glycerophospholipid metabolism, alpha-linolenic acid metabolism, and biosynthesis of unsaturated fatty acids. Gut microbiota analysis demonstrated no significant change in α-diversity but significant β-diversity shifts (p < 0.05), indicating a marked alteration in the compositional structure of the intestinal microbial community following radiation exposure. Principal coordinate analysis confirmed distinct clustering between control and irradiated groups, with increased abundance of Bacteroidota and decreased Firmicutes in irradiated rats. These findings highlight dynamic metabolic and microbial disruptions post-irradiation, with recovery patterns suggesting a 28-day restoration cycle. Spearman’s rank correlation analysis explored associations between the top 20 fecal metabolites and 50 abundant bacterial taxa. Norank_f_Muribaculaceae, Prevotellaceae_UCG-001, and Bacteroides showed significant correlations with various radiation-altered metabolites, highlighting metabolite–microbiota relationships post-radiation. Conclusions: This study provides insights into potential biomarkers for radiation-induced physiological damage and underscores the interplay between systemic metabolism and gut microbiota in radiation response. Full article

Acute radiation syndrome (ARS) occurs when hematopoietic or gastrointestinal cells are damaged by radiation exposure causing DNA damage to the bone marrow and gastrointestinal epithelial stem cell populations. In these highly proliferative cell types, DNA damage inhibits stem cell repopulation. In humans and animals, this inability to regenerate stem cells is lethal. Within this manuscript, several compounds, Amifostine, Captopril, Ciprofloxacin, PrC-210, 5-AED (5-androstene-3β,17β-diol), and 5-AET (5-androstene-3β,7β,17B-triol), are assessed for their ability to protect against ARS in an in vitro and/or in vivo setting. ARS was accomplished by irradiating mouse bone marrow cells or rat intestinal epithelial (IEC-6) cells in vitro with 4–8 Gy and in vivo by exposing Mus musculus to 7.3 Gy of whole-body irradiation. The primary endpoints of this study include cellular viability, DNA damage via γ-H2AX, colony formation, and overall survival at 30-days post-irradiation. In addition to evaluating the radioprotective performance of each compound, this study establishes a distinct set of in vitro assays to predict the overall efficacy of potential radioprotectors in an in vivo model of ARS. Furthermore, these results highlight the need for FDA-approved medical intervention to protect against ARS. Full article

Cancer is the second leading cause of death worldwide. Around half of all cancer patients undergo some type of radiation therapy throughout the course of their treatment. Photon radiation remains (RT) the most widely utilized modality of radiotherapy despite recent advancements in proton radiation therapy (PBT). PBT makes use of the particle’s biological property known as the Bragg peak to better spare healthy tissue from radiation damage, with data to support that this treatment modality is less toxic than photon RT. Hence, proton radiation dosimetry looks better compared to photon dosimetry; however, due to proton-specific uncertainties, unexpected acute, subacute, and long-term toxicities can be encountered. Reported neurotoxicity resulting from proton radiation treatments include radiation necrosis, moyamoya syndrome, neurosensory toxicities, brain edema, neuromuscular toxicities, and neurocognitive toxicities. Pulmonary toxicities include pneumonitis and fibrosis, pleural effusions, and bronchial toxicities. Pericarditis, pericardial effusions, and atrial fibrillations are among the cardiac toxicities related to proton therapy. Gastrointestinal and hematological toxicities are also found in the literature. Genitourinary toxicities include urinary and reproductive-related toxicities. Osteological, oral, endocrine, and skin toxicities have also been reported. The side effects will be comparable to the ones following photon RT, nonetheless at an expected lower incidence. The toxicities collected mainly from case reports and clinical trials are described based on the organs affected and functions altered. Full article

Iron redistribution in the intestine after total body irradiation is an established phenomenon. However, in the literature, there are no reports about the use of X-ray fluorescence microscopy or equivalent techniques to generate semi-quantitative 2D maps of iron in sectioned intestine samples from irradiated mice. In this work, we used X-ray fluorescence microscopy (XFM) to map the elemental content of iron as well as phosphorus, sulfur, calcium, copper and zinc in tissue sections of the small intestine from eight-week-old BALB/c male mice that developed gastrointestinal acute radiation syndrome (GI-ARS) in response to exposure to 8 Gray of gamma rays. Seven days after irradiation, we found that the majority of the iron is localized as hot spots in the intercellular regions of the area surrounding crypts and stretching between the outer perimeter of the intestine and the surface cell layer of villi. In addition, this study represents our current efforts to develop elemental cell classifiers that could be used for the automated generation of regions of interest for analyses of X-ray fluorescence maps. Once developed, such a tool will be instrumental for studies of effects of radiation and other toxicants on the elemental content in cells and tissues. While XFM studies cannot be conducted on living organisms, it is possible to envision future scenarios where XFM imaging of single cells sloughed from the human (or rodent) intestine could be used to follow up on the progression of GI-ARS. Full article

The risks of severe ionizing radiation exposure are increasing due to the involvement of nuclear powers in combat operations, the increasing use of nuclear power, and the existence of terrorist threats. Exposure to a whole-body radiation dose above about 0.7 Gy results in H-ARS (hematopoietic acute radiation syndrome), which is characterized by damage to the hematopoietic system; higher doses result in further damage to the gastrointestinal and nervous systems. Only a few medical countermeasures for ARS are currently available and approved for use, although others are in development. Cell therapies (cells or products produced by cells) are complex therapeutics that show promise for the treatment of radiation injury and have been shown to reduce mortality and morbidity in animal models. Since clinical trials for ARS cannot be ethically conducted, animal testing is extremely important. Here, we describe cell therapies that have been tested in animal models. Both cells and cell products appear to promote survival and lessen tissue damage after whole-body irradiation, although the mechanisms are not clear. Because radiation exposure often occurs in conjunction with other traumatic injuries, animal models of combined injury involving radiation and future countermeasure testing for these complex medical problems are also discussed. Full article

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril’s effects on the GI following TBI (⁶⁰Co 1.79 or 1.80 Gy, 0.42–0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI. Full article

Radioactivity is a process in which the nuclei of unstable atoms spontaneously decay, producing other nuclei and releasing energy in the form of ionizing radiation in the form of alpha (α) and beta (β) particles as well as the emission of gamma (γ) electromagnetic waves. People may be exposed to radiation in various forms, as casualties of nuclear accidents, workers in power plants, or while working and using different radiation sources in medicine and health care. Acute radiation syndrome (ARS) occurs in subjects exposed to a very high dose of radiation in a very short period of time. Each form of radiation has a unique pathophysiological effect. Unfortunately, higher organisms—human beings—in the course of evolution have not acquired receptors for the direct “capture” of radiation energy, which is transferred at the level of DNA, cells, tissues, and organs. Radiation in biological systems depends on the amount of absorbed energy and its spatial distribution, particularly depending on the linear energy transfer (LET). Photon radiation with low LET leads to homogeneous energy deposition in the entire tissue volume. On the other hand, radiation with a high LET produces a fast Bragg peak, which generates a low input dose, whereby the penetration depth into the tissue increases with the radiation energy. The consequences are mutations, apoptosis, the development of cancer, and cell death. The most sensitive cells are those that divide intensively—bone marrow cells, digestive tract cells, reproductive cells, and skin cells. The health care system and the public should raise awareness of the consequences of ionizing radiation. Therefore, our aim is to identify the consequences of ARS taking into account radiation damage to the respiratory system, nervous system, hematopoietic system, gastrointestinal tract, and skin. Full article

Introduction: Mortality from acute radiation syndrome is frequently caused by hematopoietic or gastrointestinal radiotoxicity, the latter of which currently has no effective treatment. Transforming growth factor-beta 3 (TGF-β3) may decrease the severity of radiation-induced gastrointestinal damage in mice. In addition, treatment with TGF-β3 may alleviate radiation-induced fibrosis. Objectives: The current study aimed to investigate the effect of TGF-β3 treatment on acute and late radiotoxicity in whole body irradiated mice. Methods: C57BL/6J mice were total body irradiated with 8.5 Gy X-rays with or without shielding of one hind leg to alleviate hematopoietic radiotoxicity. The effects of intravenous TGF-β3 treatment were investigated. Body weight and pain expression were monitored. Intestine, lung, and liver tissues were preserved and analyzed. Alpha smooth muscle actin (α-SMA) expression in MRC-5 cells after 3.5 Gy X-irradiation combined with TGF-β3 treatment was analyzed using flow cytometry. Results: All total body irradiated animals died within ten days after irradiation. Ninety-three percent of femur-shielded mice survived until sampling or termination. No effect of TGF-β3 treatment was observed in either group. No increase in collagen content was detected in the lungs or liver from irradiated mice regardless of TGF-β3 treatment. In vitro, α-SMA expression increased synergistically after irradiation and TGF-β3 treatment. Conclusions: Shielding of the femur during total body irradiation decreased acute gastrointestinal radiation toxicity and increased survival. TGF-β3 treatment did not impact symptoms or survival. TGF-β3 treatment and irradiation increased α-SMA expression in MRC-5 cells synergistically. Full article

Radiation therapy for abdominopelvic malignancies often results in damage to the gastrointestinal tract (GIT) and permanent changes in bowel function. An overlooked component of the pathophysiology of radiation-induced bowel injury is the role of the gut microbiome. The goal of this research was to identify the impacts of acute radiation exposure on the GIT and gut microbiome. C57BL/6 mice exposed to whole-body X-rays (0.1–3 Gy) were assessed for histological and microbiome changes 48 h post-radiation exposure. Within the ileum, a dose of 3 Gy significantly decreased crypt depth as well as the number of goblet cells, but increased overall goblet cell size. Overall, radiation altered the microbial distribution within each of the main phyla in a dose- and tissue-dependent manner. Within the Firmicutes phylum, high dose irradiation resulted in significant alterations in bacteria from the class Bacilli within the small bowels, and from the class Clostridia in the large bowels. The 3 Gy radiation also significantly increased the abundance of bacterial families from the Bacteroidetes phylum in the colon and feces. Overall, we identified various alterations in microbiome composition following acute radiation exposure, which could potentially lead to novel biomarkers for tracking patient toxicities or could be used as targets for mitigation strategies against radiation damage. Full article

Ionizing radiation (IR) causes disturbances in the functions of the gastrointestinal tract. Given the therapeutic potential of ouabain, a specific ligand of the Na,K-ATPase, we tested its ability to protect against IR-induced disturbances in the barrier and transport properties of the jejunum and colon of rats. Male Wistar rats were subjected to 6-day intraperitoneal injections of vehicle or ouabain (1 µg/kg/day). On the fourth day of injections, rats were exposed to total-body X-ray irradiation (10 Gy) or a sham irradiation. Isolated tissues were examined 72 h post-irradiation. Electrophysiological characteristics and paracellular permeability for sodium fluorescein were measured in an Ussing chamber. Histological analysis and Western blotting were also performed. In the jejunum tissue, ouabain exposure did not prevent disturbances in transepithelial resistance, paracellular permeability, histological characteristics, as well as changes in the expression of claudin-1, -3, -4, tricellulin, and caspase-3 induced by IR. However, ouabain prevented overexpression of occludin and the pore-forming claudin-2. In the colon tissue, ouabain prevented electrophysiological disturbances and claudin-2 overexpression. These observations may reveal a mechanism by which circulating ouabain maintains tight junction integrity under IR-induced intestinal dysfunction. Full article

The composition of the gut microbiota represents an early indicator of chronic post-radiation outcomes in elderly bone and gastrointestinal homeostasis. Fecal microbiota analyses revealed that the relative abundances of Bacteroides massiliensis, Muribaculum sp., or Prevotella denticola were different between conventional microbiota (CM) and anti-inflammatory restricted microbiota (RM). The murine RM was found conditional on mucosa-associated dysbiosis under both, disturbances of interleukin (IL)-17 signaling and exposure to radiation alone. This review discusses the hypothesis that intestinal microbiota induced alterations in DNA repair and expressed transforming growth factor (TGF)-β in the small intestine, thereby impacting bone microstructure and osteoblast dysfunction in silicon ion (1.5 Gy ²⁸Si ions of 850 MeV/u) irradiated mice. Bacterial microbiota compositions influenced therapeutic approaches, correlated with clinical outcomes in radiotherapy and were associated with alterations of the immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infections during the last global pandemics. In the absence of TGF-β, functional metagenomics, cytokine profiles, bacterial community analyses in human and murine mucosa cells, and inflammatory markers in rat intestines were analyzed. This research finally showed radiation-induced osteolytic damage to correlated with specific features of intestinal bacterial composition, and these relationships were expatiated together with radiation effects on normal tissue cell proliferation. Full article

Irradiation can be an effective treatment for ovarian cancer, but its use is limited by intestinal toxicity. Thus, strategies to mitigate toxicity are important and can revitalize the current standard of care. We previously established that LR-IL-22 protects the intestine from WAI. We now hypothesize that LR-IFN-β is an effective radiation protector and mitigator and is rapidly cleared from the digestive tract, making it an option for intestinal radioprotection. We report that the gavage of LR-IFN-β during WAI provides improved intestinal barrier integrity and significantly preserves the numbers of Lgr5+GFP+ intestinal stem cells, improving survival. The rapid clearance of the genetically engineered probiotic from the digestive tract renders it a safe and feasible radiation mitigator. Therefore, the above genetically engineered probiotic is both a feasible and effective radiation mitigator that could potentially revolutionize the management of OC patients. Furthermore, the subsequent addition of platinum/taxane-based chemotherapy to the combination of WAI and LR-IFN-β should reduce tumor volume while protecting the intestine and should improve the overall survival in OC patients. Full article

The damaging effect of ionizing radiation (IR) exposure results in the disturbance of the gut natural barrier, followed by the development of severe gastrointestinal injury. However, the dose and application segment are known to determine the effects of IR. In this study, we demonstrated the dose- and segment-specificity of tight junction (TJ) alteration in IR-induced gastrointestinal injury in rats. Male Wistar rats were subjected to a total-body X-ray irradiation at doses of 2 or 10 Gy. Isolated jejunum and colon segments were tested in an Ussing chamber 72 h after exposure. In the jejunum, 10-Gy IR dramatically altered transepithelial resistance, short-circuit current and permeability for sodium fluorescein. These changes were accompanied by severe disturbance of histological structure and total rearrangement of TJ content (increased content of claudin-1, -2, -3 and -4; multidirectional changes in tricellulin and occludin). In the colon of 10-Gy irradiated rats, lesions of barrier and transport functions were less pronounced, with only claudin-2 and -4 altered among TJ proteins. The 2-Gy IR did not change electrophysiological characteristics or permeability in the colon or jejunum, although slight alterations in jejunum histology were noted, emphasized with claudin-3 increase. Considering that TJ proteins are critical for maintaining epithelial barrier integrity, these findings may have implications for countermeasures in gastrointestinal acute radiation injury. Full article

Similar to previous pandemics, COVID-19 has been succeeded by well-documented post-infectious sequelae, including chronic fatigue, cough, shortness of breath, myalgia, and concentration difficulties, which may last 5 to 12 weeks or longer after the acute phase of illness. Both the psychological stress of SARS-CoV-2 infection and being diagnosed with COVID-19 can upregulate cortisol, a stress hormone that disrupts the efferocytosis effectors, macrophages, and natural killer cells, leading to the excessive accumulation of senescent cells and disruption of biological barriers. This has been well-established in cancer patients who often experience unrelenting fatigue as well as gut and blood–brain barrier dysfunction upon treatment with senescence-inducing radiation or chemotherapy. In our previous research from 2020 and 2021, we linked COVID-19 to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via angiotensin II upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. In 2021 and 2022, these hypotheses were validated and SARS-CoV-2-induced cellular senescence as well as microbial translocation were documented in both acute SARS-CoV-2 infection, long COVID, and ME/CFS, connecting intestinal barrier dysfunction to disabling fatigue and specific infectious events. The purpose of this narrative review is to summarize what is currently known about host immune responses to translocated gut microbes and how these responses relate to fatiguing illnesses, including long COVID. To accomplish this goal, we examine the role of intestinal and blood–brain barriers in long COVID and other illnesses typified by chronic fatigue, with a special emphasis on commensal microbes functioning as viral reservoirs. Furthermore, we discuss the role of SARS-CoV-2/Mycoplasma coinfection in dysfunctional efferocytosis, emphasizing some potential novel treatment strategies, including the use of senotherapeutic drugs, HMGB1 inhibitors, Toll-like receptor 4 (TLR4) blockers, and membrane lipid replacement. Full article