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1.
J Nanobiotechnology ; 22(1): 303, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822376

RESUMO

Radiation-induced intestinal injury is the most common side effect during radiotherapy of abdominal or pelvic solid tumors, significantly impacting patients' quality of life and even resulting in poor prognosis. Until now, oral application of conventional formulations for intestinal radioprotection remains challenging with no preferred method available to mitigate radiation toxicity in small intestine. Our previous study revealed that nanomaterials derived from spore coat of probiotics exhibit superior anti-inflammatory effect and even prevent the progression of cancer. The aim of this work is to determine the radioprotective effect of spore coat (denoted as spore ghosts, SGs) from three clinically approved probiotics (B.coagulans, B.subtilis and B.licheniformis). All the three SGs exhibit outstanding reactive oxygen species (ROS) scavenging ability and excellent anti-inflammatory effect. Moreover, these SGs can reverse the balance of intestinal flora by inhibiting harmful bacteria and increasing the abundance of Lactobacillus. Consequently, administration of SGs significantly reduce radiation-induced intestinal injury by alleviating diarrhea, preventing X-ray induced apoptosis of small intestinal epithelial cells and promoting restoration of barrier integrity in a prophylactic study. Notably, SGs markedly improve weight gain and survival of mice received total abdominal X-ray radiation. This work may provide promising radioprotectants for efficiently attenuating radiation-induced gastrointestinal syndrome and promote the development of new intestinal predilection.


Assuntos
Probióticos , Protetores contra Radiação , Esporos Bacterianos , Animais , Probióticos/farmacologia , Camundongos , Administração Oral , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêutico , Protetores contra Radiação/química , Esporos Bacterianos/efeitos da radiação , Lesões por Radiação/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Intestino Delgado/microbiologia , Intestino Delgado/efeitos da radiação , Intestino Delgado/patologia , Humanos , Apoptose/efeitos dos fármacos , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/efeitos da radiação , Intestinos/microbiologia , Intestinos/patologia , Lesões Experimentais por Radiação/patologia
2.
Sci Rep ; 14(1): 13315, 2024 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858439

RESUMO

Exposure to high, marginally lethal doses or higher of ionizing radiation, either intentional or accidental, results in injury to various organs. Currently, there is only a limited number of safe and effective radiation countermeasures approved by US Food and Drug Administration for such injuries. These approved agents are effective for only the hematopoietic component of the acute radiation syndrome and must be administered only after the exposure event: currently, there is no FDA-approved agent that can be used prophylactically. The nutraceutical, gamma-tocotrienol (GT3) has been found to be a promising radioprotector of such exposure-related injuries, especially those of a hematopoietic nature, when tested in either rodents or nonhuman primates. We investigated the nature of injuries and the possible protective effects of GT3 within select organ systems/tissues caused by both non-lethal level (4.0 Gy), as well as potentially lethal level (5.8 Gy) of ionizing radiation, delivered as total-body or partial-body exposure. Results indicated that the most severe, dose-dependent injuries occurred within those organ systems with strong self-renewing capacities (e.g., the lymphohematopoietic and gastrointestinal systems), while in other tissues (e.g., liver, kidney, lung) endowed with less self-renewal, the pathologies noted tended to be less pronounced and less dependent on the level of exposure dose or on the applied exposure regimen. The prophylactic use of the test nutraceutical, GT3, appeared to limit the extent of irradiation-associated pathology within blood forming tissues and, to some extent, within the small intestine of the gastrointestinal tract. No distinct, global pattern of bodily protection was noted with the agent's use, although a hint of a possible radioprotective benefit was suggested not only by a lessening of apparent injury within select organ systems, but also by way of noting the lack of early onset of moribundity within select GT3-treated animals.


Assuntos
Suplementos Nutricionais , Protetores contra Radiação , Animais , Protetores contra Radiação/farmacologia , Vitamina E/farmacologia , Vitamina E/análogos & derivados , Síndrome Aguda da Radiação/prevenção & controle , Síndrome Aguda da Radiação/tratamento farmacológico , Síndrome Aguda da Radiação/patologia , Cromanos/farmacologia , Masculino , Lesões Experimentais por Radiação/prevenção & controle , Lesões Experimentais por Radiação/patologia , Macaca mulatta , Fígado/efeitos dos fármacos , Fígado/efeitos da radiação , Fígado/patologia
3.
Biochem Biophys Res Commun ; 724: 150226, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-38865815

RESUMO

In patients with high-level radiation exposure, gastrointestinal injury is the main cause of death. Despite the severity of damage to the gastrointestinal tract, no specific therapeutic option is available. Tauroursodeoxycholic acid (TUDCA) is a conjugated form of ursodeoxycholic acid that suppresses endoplasmic reticulum (ER) stress and regulates various cell-signaling pathways. We investigated the effect of TUDCA premedication in alleviating intestinal damage and enhancing the survival of C57BL/6 mice administered a lethal dose (15Gy) of focal abdominal irradiation. TUDCA was administered to mice 1 h before radiation exposure, and reduced apoptosis of the jejunal crypts 12 h after irradiation. At later timepoint (3.5 days), irradiated mice manifested intestinal morphological changes that were detected via histological examination. TUDCA decreased the inflammatory cytokine levels and attenuated the decrease in serum citrulline levels after radiation exposure. Although radiation induced ER stress, TUDCA pretreatment decreased ER stress in the irradiated intestinal cells. The effect of TUDCA indicates the possibility of radiation therapy for cancer in tumor cells. TUDCA did not affect cell proliferation and apoptosis in the intestinal epithelium. TUDCA decreased the invasive ability of the CT26 metastatic colon cancer cell line. Reduced invasion after TUDCA treatment was associated with decreased matrix metalloproteinase (MMP)-7 and MMP-13 expression, which play important roles in invasion and metastasis. This study shows a potential role of TUDCA in protecting against radiation-induced intestinal damage and inhibiting tumor cell migration without any radiation and radiation therapy effect.


Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Camundongos Endogâmicos C57BL , Protetores contra Radiação , Ácido Tauroquenodesoxicólico , Animais , Ácido Tauroquenodesoxicólico/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos da radiação , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Protetores contra Radiação/farmacologia , Camundongos , Masculino , Intestinos/efeitos da radiação , Intestinos/efeitos dos fármacos , Intestinos/patologia , Modelos Animais de Doenças , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos da radiação , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Lesões Experimentais por Radiação/prevenção & controle , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação
4.
J Neuroinflammation ; 21(1): 162, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38915029

RESUMO

Radiation retinopathy (RR) is a major side effect of ocular tumor treatment by plaque brachytherapy or proton beam therapy. RR manifests as delayed and progressive microvasculopathy, ischemia and macular edema, ultimately leading to vision loss, neovascular glaucoma, and, in extreme cases, secondary enucleation. Intravitreal anti-VEGF agents, steroids and laser photocoagulation have limited effects on RR. The role of retinal inflammation and its contribution to the microvascular damage occurring in RR remain incompletely understood. To explore cellular and vascular events after irradiation, we analyzed their time course at 1 week, 1 month and 6 months after rat eyes received 45 Gy X-beam photons. Müller glial cells, astrocytes and microglia were rapidly activated, and these markers of retinal inflammation persisted for 6 months after irradiation. This was accompanied by early cell death in the outer retina, which persisted at later time points, leading to retinal thinning. A delayed loss of small retinal capillaries and retinal hypoxia were observed after 6 months, indicating inner blood‒retinal barrier (BRB) alteration but without cell death in the inner retina. Moreover, activated microglial cells invaded the entire retina and surrounded retinal vessels, suggesting the role of inflammation in vascular alteration and in retinal cell death. Radiation also triggered early and persistent invasion of the retinal pigment epithelium by microglia and macrophages, contributing to outer BRB disruption. This study highlights the role of progressive and long-lasting inflammatory mechanisms in RR development and demonstrates the relevance of this rat model to investigate human pathology.


Assuntos
Modelos Animais de Doenças , Retina , Animais , Ratos , Retina/patologia , Retina/efeitos da radiação , Doenças Retinianas/etiologia , Doenças Retinianas/patologia , Inflamação/patologia , Inflamação/etiologia , Lesões Experimentais por Radiação/patologia , Lesões por Radiação/patologia , Lesões por Radiação/etiologia , Masculino , Microglia/efeitos da radiação , Microglia/patologia
5.
Exp Eye Res ; 244: 109946, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38815794

RESUMO

Photobiomodulation (PBM) therapy uses light of different wavelengths to treat various retinal degeneration diseases, but the potential damage to the retina caused by long-term light irradiation is still unclear. This study were designed to detect the difference between long- and short-wavelength light (650-nm red light and 450-nm blue light, 2.55 mW/cm2, reference intensity in PBM)-induced injury. In addition, a comparative study was conducted to investigate the differences in retinal light damage induced by different irradiation protocols (short periods of repeated irradiation and a long period of constant irradiation). Furthermore, the protective role of PARP-1 inhibition on the molecular mechanism of blue light-induced injury was confirmed by a gene knockdown technique or a specific inhibitor through in vitro and in vivo experiments. The results showed that the susceptibility to retinal damage caused by irradiation with long- and short-wavelength light is different. Shorter wavelength lights, such as blue light, induce more severe retinal damage, while the retina exhibits better resistance to longer wavelength lights, such as red light. In addition, repeated irradiation for short periods induces less retinal damage than constant exposure over a long period. PARP-1 plays a critical role in the molecular mechanism of blue light-induced damage in photoreceptors and retina, and inhibiting PARP-1 can significantly protect the retina against blue light damage. This study lays an experimental foundation for assessing the safety of phototherapy products and for developing target drugs to protect the retina from light damage.


Assuntos
Luz , Poli(ADP-Ribose) Polimerase-1 , Retina , Degeneração Retiniana , Animais , Poli(ADP-Ribose) Polimerase-1/metabolismo , Camundongos , Luz/efeitos adversos , Retina/efeitos da radiação , Retina/patologia , Degeneração Retiniana/etiologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Degeneração Retiniana/prevenção & controle , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/metabolismo , Modelos Animais de Doenças , Western Blotting , Masculino , Terapia com Luz de Baixa Intensidade , Luz Azul
6.
Ann Plast Surg ; 93(1): 100-106, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38785378

RESUMO

BACKGROUND: Exposure to high doses of total body irradiation (TBI) may lead to the development of acute radiation syndrome (ARS). This study was conducted to establish an experimental rat model of TBI to assess the impact of different doses of TBI on survival and the kinetics of changes within the hematopoietic system in ARS. MATERIALS AND METHODS: In this study, 132 Lewis rats irradiated with a 5Gy or 7Gy dose served as experimental models to induce ARS and to evaluate the hematopoietic response of the bone marrow (BM) compartment. Animals were divided into 22 experimental groups (n = 6/group): groups 1-11 irradiated with 5Gy dose and groups 12-22 irradiated with 7Gy dose. The effects of TBI on the hematopoietic response were assessed at 2, 4, 6, 8 hours and 5, 10, 20, 30, 40, 60 and 90 days following TBI. Signs of ARS were evaluated by analyzing blood samples through complete blood count in addition to the clinical assessment. RESULTS: Groups irradiated with 5Gy TBI showed 100% survival, whereas after 7Gy dose, 1.6% mortality rate was observed. Assessment of the complete blood count revealed that lymphocytes were the first to be affected, regardless of the dose used, whereas an "abortive rise" of granulocytes was noted for both TBI doses. None of the animals exhibited signs of severe anemia or thrombocytopenia. All animals irradiated with 5Gy dose regained initial values for all blood cell subpopulations by the end of observation period. Body weight loss was reported to be dose-dependent and was more pronounced in the 7Gy groups. However, at the study end point at 90 days, all animals regained or exceeded the initial weight values. CONCLUSIONS: We have successfully established a rat experimental model of TBI. This study revealed a comparable hematopoietic response to the sublethal or potentially lethal doses of ionizing radiation. The experimental rat model of TBI may be used to assess different therapeutic approaches including BM-based cell therapies for long-term reconstitution of the hematopoietic and BM compartments allowing for comprehensive analysis of both the hematological and clinical symptoms associated with ARS.


Assuntos
Síndrome Aguda da Radiação , Ratos Endogâmicos Lew , Irradiação Corporal Total , Animais , Ratos , Relação Dose-Resposta à Radiação , Modelos Animais de Doenças , Masculino , Hematopoese/efeitos da radiação , Lesões Experimentais por Radiação , Medula Óssea/efeitos da radiação
7.
Int Immunopharmacol ; 136: 112278, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38815353

RESUMO

Intestinal stem cells (ISCs) are pivotal for the maintenance and regeneration of the intestinal epithelium. Berberine (BBR) exhibits diverse biological activities, but it remains unclear whether BBR can modulate ISCs' function. Therefore, we investigated the effects of BBR on ISCs in healthy and radiation-injured mice and explored the potential underlying mechanisms involved. The results showed that BBR significantly increased the length of the small intestines, the height of the villi, and the depth and density of the crypts, promoted the proliferation of cryptal epithelial cells and increased the number of OLFM4+ ISCs and goblet cells. Crypts from the BBR-treated mice were more capable of growing into enteroids than those from untreated mice. BBR alleviated WAI-induced intestinal injury. BBR suppressed the apoptosis of crypt epithelial cells, increased the quantity of goblet cells, and increased the quantity of OLFM4+ ISCs and tdTomato+ progenies of ISCs after 8 Gy WAI-induced injury. Mechanistically, BBR treatment caused a significant increase in the quantity of p-S6, p-STAT3 and p-ERK1/2 positive cryptal epithelial cells under physiological conditions and after WAI-induced injury. In conclusion, BBR is capable of enhancing the function of ISCs either physiologically or after radiation-induced injury, indicating that BBR has potential value in the treatment of radiation-induced intestinal injury.


Assuntos
Berberina , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Células-Tronco , Animais , Berberina/farmacologia , Berberina/uso terapêutico , Células-Tronco/efeitos dos fármacos , Camundongos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos da radiação , Mucosa Intestinal/patologia , Masculino , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/patologia , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/efeitos da radiação , Células Caliciformes/patologia , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/patologia , Fator de Transcrição STAT3/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/efeitos da radiação , Intestino Delgado/patologia , Intestino Delgado/lesões , Intestinos/efeitos dos fármacos , Intestinos/efeitos da radiação
8.
Am J Physiol Gastrointest Liver Physiol ; 326(6): G631-G642, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38593468

RESUMO

Lysophosphatidic acid (LPA) is a bioactive lipid molecule that regulates a wide array of cellular functions, including proliferation, differentiation, and survival, via activation of cognate receptors. The LPA5 receptor is highly expressed in the intestinal epithelium, but its function in restoring intestinal epithelial integrity following injury has not been examined. Here, we use a radiation-induced injury model to study the role of LPA5 in regulating intestinal epithelial regeneration. Control mice (Lpar5f/f) and mice with an inducible, epithelial cell-specific deletion of Lpar5 in the small intestine (Lpar5IECKO) were subjected to 10 Gy total body X-ray irradiation and analyzed during recovery. Repair of the intestinal mucosa was delayed in Lpar5IECKO mice with reduced epithelial proliferation and increased crypt cell apoptosis. These effects were accompanied by reduced numbers of OLFM4+ intestinal stem cells (ISCs). The effects of LPA5 on ISCs were corroborated by studies using organoids derived from Lgr5-lineage tracking reporter mice with deletion of Lpar5 in Lgr5+-stem cells (Lgr5Cont or Lgr5ΔLpar5). Irradiation of organoids resulted in fewer numbers of Lgr5ΔLpar5 organoids retaining Lgr5+-derived progenitor cells compared with Lgr5Cont organoids. Finally, we observed that impaired regeneration in Lpar5IECKO mice was associated with reduced numbers of Paneth cells and decreased expression of Yes-associated protein (YAP), a critical factor for intestinal epithelial repair. Our study highlights a novel role for LPA5 in regeneration of the intestinal epithelium following irradiation and its effect on the maintenance of Paneth cells that support the stem cell niche.NEW & NOTEWORTHY We used mice lacking expression of the lysophosphatidic acid receptor 5 (LPA5) in intestinal epithelial cells and intestinal organoids to show that the LPA5 receptor protects intestinal stem cells and progenitors from radiation-induced injury. We show that LPA5 induces YAP signaling and regulates Paneth cells.


Assuntos
Proliferação de Células , Mucosa Intestinal , Receptores de Ácidos Lisofosfatídicos , Regeneração , Transdução de Sinais , Proteínas de Sinalização YAP , Animais , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos da radiação , Camundongos , Regeneração/efeitos da radiação , Proteínas de Sinalização YAP/metabolismo , Proliferação de Células/efeitos da radiação , Células-Tronco/efeitos da radiação , Células-Tronco/metabolismo , Organoides/metabolismo , Organoides/efeitos da radiação , Camundongos Knockout , Apoptose/efeitos da radiação , Lisofosfolipídeos/metabolismo , Intestino Delgado/efeitos da radiação , Intestino Delgado/metabolismo , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia
9.
Int Immunopharmacol ; 133: 111987, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38652961

RESUMO

Radiation-induced kidney injury is a common side effect of radiotherapy, as the pelvic region is in close proximity to the kidneys, posing a risk of inducing radiation-induced kidney injury when treating any pelvic malignancies with radiotherapy. This type of injury typically manifests as chronic kidney disease a few months after radiotherapy, with the potential to progress to end-stage renal disease. Radiation-induced damage involves various components of the kidney, including glomeruli, tubules, interstitium, and extracellular matrix. Therefore, investigating its molecular mechanisms is crucial. In this study, we extensively searched literature databases, selecting recent transcriptomic studies related to acute kidney injury (AKI) published in the past decade. We downloaded the raw RNA sequencing datasets GSE30718 and GSE66494 related to AKI from the GEO database and identified that intestinal-type lectin ITLN1 plays a significant role in regulating radiation-induced kidney injury in rats. Differential gene analysis was performed using chip data from the GEO database, and further bioinformatics analysis identified 13 genes that may be involved in regulating kidney injury, with ITLN1 being the most relevant to kidney damage, thus selected as the target gene for this study. Subsequently, a rat model of radiation-induced kidney injury was established for experimental validation, assessing kidney tissue morphology and injury extent through staining observation and immunohistochemical staining. The protective effect of ITLN1 on kidney function was evaluated by measuring changes in rat body weight and blood pressure, serum kidney injury markers, and kidney structure. The experimental results indicate that overexpression of ITLN1 can improve kidney function in rats with radiation-induced kidney injury by activating the Akt/GSK-3ß/Nrf2 signaling pathway, suppressing oxidative stress, cell apoptosis, inflammation, cellular senescence, and fibrosis. This study highlights the significant role of ITLN1 in regulating kidney injury, providing a novel target for future treatments of radiation-induced kidney injury.


Assuntos
Rim , Animais , Ratos , Rim/patologia , Rim/metabolismo , Rim/efeitos da radiação , Masculino , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/etiologia , Humanos , Lesões por Radiação/genética , Ratos Sprague-Dawley , Transdução de Sinais , Lesões Experimentais por Radiação/metabolismo
10.
Int J Radiat Biol ; 100(5): 767-776, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38442208

RESUMO

PURPOSE: Toxicities from head and neck (H&N) radiotherapy (RT) may affect patient quality of life and can be dose-limiting. Proteins from the transforming growth factor beta (TGF-ß) family are key players in the fibrotic response. While TGF-ß1 is known to be pro-fibrotic, TGF-ß3 has mainly been considered anti-fibrotic. Moreover, TGF-ß3 has been shown to act protective against acute toxicities after radio- and chemotherapy. In the present study, we investigated the effect of TGF-ß3 treatment during fractionated H&N RT in a mouse model. MATERIALS AND METHODS: 30 C57BL/6J mice were assigned to three treatment groups. The RT + TGF-ß3 group received local fractionated H&N RT with 66 Gy over five days, combined with TGF-ß3-injections at 24-hour intervals. Animals in the RT reference group received identical RT without TGF-ß3 treatment. The non-irradiated control group was sham-irradiated according to the same RT schedule. In the follow-up period, body weight and symptoms of oral mucositis and lip dermatitis were monitored. Saliva was sampled at five time points. The experiment was terminated 105 d after the first RT fraction. Submandibular and sublingual glands were preserved, sectioned, and stained with Masson's trichrome to visualize collagen. RESULTS: A subset of mice in the RT + TGF-ß3 group displayed increased severity of oral mucositis and increased weight loss, resulting in a significant increase in mortality. Collagen content was significantly increased in the submandibular and sublingual glands for the surviving RT + TGF-ß3 mice, compared with non-irradiated controls. In the RT reference group, collagen content was significantly increased in the submandibular gland only. Both RT groups displayed lower saliva production after treatment compared to controls. TGF-ß3 treatment did not impact saliva production. CONCLUSIONS: When repeatedly administered during fractionated RT at the current dose, TGF-ß3 treatment increased acute H&N radiation toxicities and increased mortality. Furthermore, TGF-ß3 treatment may increase the severity of radiation-induced salivary gland fibrosis.


Assuntos
Fibrose , Camundongos Endogâmicos C57BL , Glândulas Salivares , Estomatite , Fator de Crescimento Transformador beta3 , Animais , Fator de Crescimento Transformador beta3/metabolismo , Camundongos , Estomatite/etiologia , Estomatite/patologia , Glândulas Salivares/efeitos da radiação , Glândulas Salivares/patologia , Modelos Animais de Doenças , Masculino , Lesões por Radiação/patologia , Lesões por Radiação/etiologia , Feminino , Lesões Experimentais por Radiação/patologia
11.
Int Immunopharmacol ; 132: 111945, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38555816

RESUMO

BACKGROUND: Emodin, a natural anthraquinone derivative isolated from the roots of Rheum officinale Baill, has many pharmacological effects including anti-inflammatory, antioxidant, antiviral, antibacterial and anti-cancer. However, little is known about the effect of emodin on acute radiation proctitis (ARP). The present study was conducted to determine its effects and elucidate its mechanisms involving AKT/MAPK/NF-κB/VEGF pathways in ARP mice. METHODS: Total 60 C57BL/6 mice were divided randomly into control group, ARP group, AKT inhibitor MK-2206 group, and different doses of emodin groups. ARP mice were induced by 27 Gy of 6 MV X-ray pelvic local irradiation. MK-2206 was given orally for 2 weeks on alternate days. Emodin was administered daily by oral gavage for 2 weeks. Subsequently, all mice were sacrificed on day 15. The rectal tissues were obtained for further tests. The general signs score and the pathological grade were used to evaluate the severity of ARP. The expression of NF-κB, VEGF and AQP1 were determined by immunohistochemistry and western blot. The expression of p-AKT, p-ERK, p-JNK, p-p38, Bcl-2 and Bax were assessed using western blot. RESULTS: The worse general signs and damaged tissue structure of ARP mice were profoundly ameliorated by emodin. The expression of p-AKT, p-ERK, NF-κB, VEGF and AQP1 were significantly increased, resulting in the inflammation-induced angiogenesis in ARP mice. However, the expression of p-JNK and p-p38 were decreased, leading to the reduction of apoptosis in ARP mice. Excitedly, emodin reversed these changes, not only inhibited inflammation-induced angiogenesis, but also promoted apoptosis. Notably, the effects of emodin were similar to that of AKT inhibitor MK-2206, suggesting the involvement of AKT signaling in the effect of emodin. CONCLUSION: These results suggest that emodin attenuates ARP in mice, and the underlying mechanism might involve inhibition of the AKT/ERK/NF-κB/VEGF pathways and the induction of apoptosis mediated by JNK and p38.


Assuntos
Emodina , Camundongos Endogâmicos C57BL , NF-kappa B , Proctite , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular , Animais , Emodina/farmacologia , Emodina/uso terapêutico , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proctite/tratamento farmacológico , Proctite/etiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/patologia , Masculino , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/metabolismo , Reto/patologia , Reto/efeitos dos fármacos
12.
Radiat Res ; 201(5): 406-417, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38319684

RESUMO

The purpose of this investigation was to characterize the natural history of a murine total-abdominal-irradiation exposure model to measure gastrointestinal acute radiation injury. Male CD2F1 mice at 12 to 15 weeks old received total-abdominal irradiation using 4-MV linear accelerator X-rays doses of 0, 11, 13.5, 15, 15.75 and 16.5 Gy (2.75 Gy/min). Daily cage-side (i.e., in the animal housing room) observations of clinical signs and symptoms including body weights on all animals were measured up to 10 days after exposure. Jejunum tissues from cohorts of mice were collected at 1, 3, 7 and 10 days after exposure and radiation injury was assessed by histopathological analyses. Results showed time- and dose-dependent loss of body weight [for example at 7 days: 0.66 (±0.80) % loss for 0 Gy, 6.40 (±0.76) % loss at 11 Gy, 9.43 (±2.06) % loss at 13.5 Gy, 23.53 (± 1.91) % loss at 15 Gy, 29.97 (±1.16) % loss at 15.75 Gy, and 31.79 (±0.76) % loss at 16.5 Gy]. Negligible clinical signs and symptoms, except body weight changes, of radiation injury were observed up to 10 days after irradiation with doses of 11 to 15 Gy. Progressive increases in the severity of clinical signs and symptoms were found after irradiation with doses >15 Gy. Jejunum histology showed a progressive dose-dependent increase in injury. For example, at 7 days postirradiation, the percent of crypts, compared to controls, decreased to 82.3 (±9.5), 69.2 (±12.3), 45.4 (±11.9), 18.0 (±3.4), and 11.5 (± 1.8) with increases in doses from 11 to 16.5 Gy. A mucosal injury scoring system was used that mainly focused on changes in villus morphology damage (i.e., subepithelial spaces near the tips of the villi with capillary congestion, significant epithelial lifting along the length of the villi with a few denuded villus tips). Peak levels of total-abdominal irradiation induced effects on the mucosal injury score were seen 7 days after irradiation for doses ≥15 Gy, with a trend to show a decline after 7 days. A murine multiple-parameter gastrointestinal acute-radiation syndrome severity-scoring system was established based on clinical signs and symptoms that included measures of appearance (i.e., hunched and/or fluffed fur), respiratory rate, general (i.e., decreased mobility) and provoked behavior (i.e., subdued response to stimulation), weight loss, and feces/diarrhea score combined with jejunum mucosal-injury grade score. In summary, the natural-history radio-response for murine partial-body irradiation exposures is important for establishing a well-characterized radiation model system; here we established a multiple-parameter gastrointestinal acute-radiation syndrome severity-scoring system that provides a radiation injury gastrointestinal tissue-based assessment utility.


Assuntos
Síndrome Aguda da Radiação , Animais , Camundongos , Masculino , Síndrome Aguda da Radiação/patologia , Síndrome Aguda da Radiação/etiologia , Relação Dose-Resposta à Radiação , Jejuno/efeitos da radiação , Jejuno/patologia , Modelos Animais de Doenças , Índice de Gravidade de Doença , Trato Gastrointestinal/efeitos da radiação , Trato Gastrointestinal/patologia , Peso Corporal/efeitos da radiação , Lesões Experimentais por Radiação/patologia
13.
Radiat Res ; 201(5): 460-470, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38376474

RESUMO

With the current volatile geopolitical climate, the threat of nuclear assault is high. Exposure to ionizing radiation from either nuclear incidents or radiological accidents often lead to major harmful consequences to human health. Depending on the absorbed dose, the symptoms of the acute radiation syndrome and delayed effects of acute radiation exposure (DEARE) can appear within hours, weeks to months. The lung is a relatively radiosensitive organ with manifestation of radiation pneumonitis as an acute effect, followed by apparent fibrosis in weeks or even months. A recently developed, first-of-its-kind murine model for partial-body irradiation (PBI) injury, which can be used to test potential countermeasures against multi-organ damage such as gastrointestinal (GI) tract and lungs was used for irradiation, with 2.5% bone marrow spared (BM2.5-PBI) from radiation exposure. Long-term damage to lungs from radiation was evaluated using µ-CT scans, pulmonary function testing, histopathological parameters and molecular biomarkers. Pulmonary fibrosis was detected by ground glass opacity observed in µ-CT scans of male and female C57BL/6J mice 6-7 months after BM2.5-PBI. Lung mechanics assessments pertaining to peripheral airways suggested fibrotic lungs with stiffer parenchymal lung tissue and reduced inspiratory capacity in irradiated animals 6-7 months after BM2.5-PBI. Histopathological evaluation of the irradiated lungs revealed presence of focal and diffuse pleural, and parenchymal inflammatory and fibrotic lesions. Fibrosis was confirmed by elevated levels of collagen when compared to lungs of age-matched naïve mice. These findings were validated by findings of elevated levels of pro-fibrotic biomarkers and reduction in anti-inflammatory proteins. In conclusion, a long-term model for radiation-induced pulmonary fibrosis was established, and countermeasures could be screened in this model for survival and protection/mitigation or recovery from radiation-induced pulmonary damage.


Assuntos
Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Fibrose Pulmonar , Animais , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , Camundongos , Masculino , Feminino , Pulmão/efeitos da radiação , Pulmão/patologia , Pneumonite por Radiação/patologia , Pneumonite por Radiação/etiologia , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/etiologia
14.
Int J Radiat Biol ; 100(5): 689-708, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38306495

RESUMO

PURPOSE: This research endeavor was undertaken to elucidate the impact of an innovative ascorbate formulation on the regeneration process of full-thickness excision wounds in a rat model exposed to whole-body gamma irradiation, replicating conditions akin to combat or radiation emergency scenarios. MATERIALS AND METHODS: We established a comprehensive rat model by optimizing whole body γ-radiation doses (5-9 Gy) and full-thickness excision wound sizes (1-3 cm2) to mimic radiation combined injury (RCI). The developed RCI model was used to explore the healing potential of ascorbate formulation. The study includes various treatment groups (i.e., sham control, radiation alone, wound alone, radiation + wound, and radiation + wound + formulation). The ascorbate formulation was applied twice daily, with a 12-hour gap between each application, starting 1 hour after the initiation of the wound. The healing potential of the formulation in the RCI context was evaluated over 14 days through hematological, molecular, and histological parameters. RESULTS: The combination of a 5 Gy radiation dose and a 1 cm2 wound was identified as the optimal setting to develop the RCI model for subsequent studies. The formulation was used topically immediately following RCI, and then twice daily until complete healing. Treatment with the ascorbate formulation yielded noteworthy outcomes and led to a substantial reduction (p < .05) in the wound area, accelerated epithelialization periods, and an increased wound contraction rate. The formulation's localized healing response improved organ weights, normalized blood parameters, and enhanced hematopoietic and immune systems. A gene expression study revealed the treatment up-regulated TGF-ß and FGF, and down-regulated PDGF-α, TNF-α, IL-1ß, IL-6, MIP-1α, and MCP-1 (p < .05). Histopathological assessments supported the formulation's effectiveness in restoring cellular architecture and promoting tissue regeneration. CONCLUSION: Topical application of the ascorbate formulation in RCI resulted in a significant improvement in delayed wound healing, leading to accelerated wound closure by mitigating the expression of inflammatory responses.


Assuntos
Administração Tópica , Ácido Ascórbico , Pele , Cicatrização , Animais , Ácido Ascórbico/farmacologia , Ácido Ascórbico/administração & dosagem , Ratos , Cicatrização/efeitos dos fármacos , Cicatrização/efeitos da radiação , Pele/efeitos da radiação , Pele/efeitos dos fármacos , Pele/lesões , Pele/patologia , Masculino , Modelos Animais de Doenças , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/patologia , Ratos Sprague-Dawley , Raios gama , Irradiação Corporal Total
15.
Am J Pathol ; 194(6): 975-988, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38423356

RESUMO

Radiation-induced enteritis, a significant concern in abdominal radiation therapy, is associated closely with gut microbiota dysbiosis. The mucus layer plays a pivotal role in preventing the translocation of commensal and pathogenic microbes. Although significant expression of REGγ in intestinal epithelial cells is well established, its role in modulating the mucus layer and gut microbiota remains unknown. The current study revealed notable changes in gut microorganisms and metabolites in irradiated mice lacking REGγ, as compared to wild-type mice. Concomitant with gut microbiota dysbiosis, REGγ deficiency facilitated the infiltration of neutrophils and macrophages, thereby exacerbating intestinal inflammation after irradiation. Furthermore, fluorescence in situ hybridization assays unveiled an augmented proximity of bacteria to intestinal epithelial cells in REGγ knockout mice after irradiation. Mechanistically, deficiency of REGγ led to diminished goblet cell populations and reduced expression of key goblet cell markers, Muc2 and Tff3, observed in both murine models, minigut organoid systems and human intestinal goblet cells, indicating the intrinsic role of REGγ within goblet cells. Interestingly, although administration of broad-spectrum antibiotics did not alter the goblet cell numbers or mucin 2 (MUC2) secretion, it effectively attenuated inflammation levels in the ileum of irradiated REGγ absent mice, bringing them down to the wild-type levels. Collectively, these findings highlight the contribution of REGγ in counteracting radiation-triggered microbial imbalances and cell-autonomous regulation of mucin secretion.


Assuntos
Enterite , Microbioma Gastrointestinal , Células Caliciformes , Homeostase , Camundongos Knockout , Animais , Enterite/microbiologia , Enterite/metabolismo , Enterite/patologia , Camundongos , Células Caliciformes/patologia , Células Caliciformes/metabolismo , Humanos , Proteínas Associadas a Pancreatite/metabolismo , Mucina-2/metabolismo , Disbiose/microbiologia , Disbiose/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Fator Trefoil-3/metabolismo , Camundongos Endogâmicos C57BL , Lesões por Radiação/metabolismo , Lesões por Radiação/microbiologia , Lesões por Radiação/patologia , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/microbiologia
16.
Naunyn Schmiedebergs Arch Pharmacol ; 397(7): 5193-5205, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38252300

RESUMO

Perturbations produced by ionizing radiation on intestinal tissue are considered one of highly drastic challenges in radiotherapy. Animals were randomized into five groups. The first group was allocated as control, and the second was subjected to whole body γ-irradiation (10 Gy). The third was administered HA NP (17.6 mg/kg/day; i.p.) and then irradiated. The fourth one received MitoQ (2 mg/kg/day; i.p.) and then irradiated. The last group received MitoQ/HA NP (2 mg/kg/day; i.p.) for 5 days prior to irradiation. Mice were sacrificed a week post-γ-irradiation for evaluation. MitoQ/HA NP ameliorated mitochondrial oxidative stress as indicated by rising (TAC) and glutathione peroxidase and decreasing malondialdehyde, showing its distinguished antioxidant yield. That impacted the attenuation of apoptosis, which was revealed by the restoration of the anti-apoptotic marker and lessening proapoptotic caspase-3. Inflammatory parameters dwindled via treatment with MitoQ/HA NP. Moreover, this new NP exerts its therapeutic action through a distinguished radioprotective pathway (Hmgb1/TLR-4.) Subsequently, these antioxidants and their nanoparticles conferred protection to intestinal tissue as manifested by histopathological examination. These findings would be associated with its eminent antioxidant potential through high mitochondria targeting, enhanced cellular uptake, and ROS scavenging. This research underlines MitoQ/HA NP as a new treatment for the modulation of intestinal damage caused by radiotherapy modalities.


Assuntos
Antioxidantes , Apoptose , Raios gama , Ácido Hialurônico , Compostos Organofosforados , Estresse Oxidativo , Protetores contra Radiação , Ubiquinona , Animais , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Raios gama/efeitos adversos , Camundongos , Compostos Organofosforados/farmacologia , Masculino , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêutico , Antioxidantes/farmacologia , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ácido Hialurônico/farmacologia , Lesões Experimentais por Radiação/prevenção & controle , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/metabolismo , Nanopartículas , Intestinos/efeitos dos fármacos , Intestinos/efeitos da radiação , Intestinos/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação
17.
Stem Cell Res Ther ; 14(1): 325, 2023 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-37953266

RESUMO

BACKGROUND: Stromal vascular fraction (SVF) treatment promoted the regeneration of the intestinal epithelium, limiting lethality in a mouse model of radiation-induced gastrointestinal syndrome (GIS). The SVF has a heterogeneous cell composition; the effects between SVF and the host intestinal immunity are still unknown. The specific role of the different cells contained in the SVF needs to be clarified. Monocytes-macrophages have a crucial role in repair and monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2. METHODS: Mice exposed to abdominal radiation (18 Gy) received a single intravenous injection of SVF (2.5 × 106 cells), obtained by enzymatic digestion of inguinal fat tissue, on the day of irradiation. Intestinal immunity and regeneration were evaluated by flow cytometry, RT-PCR and histological analyses. RESULTS: Using flow cytometry, we showed that SVF treatment modulated intestinal monocyte differentiation at 7 days post-irradiation by very early increasing the CD11b+Ly6C+CCR2+ population in the intestine ileal mucosa and accelerating the phenotype modification to acquire CX3CR1 in order to finally restore the F4/80+CX3CR1+ macrophage population. In CX3CR1-depleted mice, SVF treatment fails to mature the Ly6C-MCHII+CX3CR1+ population, leading to a macrophage population deficit associated with proinflammatory environment maintenance and defective intestinal repair; this impaired SVF efficiency on survival. Consistent with a CD11b+ being involved in SVF-induced intestinal repair, we showed that SVF-depleted CD11b+ treatment impaired F4/80+CX3CR1+macrophage pool restoration and caused loss of anti-inflammatory properties, abrogating stem cell compartment repair and survival. CONCLUSIONS: These data showed that SVF treatment mitigates the GIS-involving immunomodulatory effect. Cooperation between the monocyte in SVF and the host monocyte defining the therapeutic properties of the SVF is necessary to guarantee the effective action of the SVF on the GIS.


Assuntos
Monócitos , Lesões Experimentais por Radiação , Fração Vascular Estromal , Animais , Camundongos , Tecido Adiposo , Intestinos , Macrófagos , Células Estromais , Lesões Experimentais por Radiação/terapia
18.
Nan Fang Yi Ke Da Xue Xue Bao ; 43(10): 1815-1820, 2023 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-37933660

RESUMO

OBJECTIVE: To observe the therapeutic effect of metformin on pathological pain in mice with radiation dermatitis and explore the underlying mechanism. METHODS: Thirty-two male adult ICR mice were randomized into normal control group, radiation dermatitis model group, metformin treatment (200 mg/kg) group and gabapentin (100 mg/kg) group (n=8).In the latter two groups, metformin treatment was administered after modeling via intraperitoneal injection and gabapentin by gavage on a daily basis for 16 days; the mice in the control group and model group received intraperitoneal injection of normal saline.After the last administration, radiation dermatitis was graded in each group.Mechanical withdraw threshold (MWT) and thermal withdrawal latency (TWL) of the mice were tested one day before and at 1, 4, 8, 12 and 16 days after modeling.Western blotting was used to measure the protein expression levels of p38MAPK, p-p38MAPK, NF-κB p65 and p-NF-κB p65 in the L4-L6 spinal cord, and the concentrations of IL-1ß, IL-6 and TNF-α in the spinal cord tissue were determined with ELISA. RESULTS: Compared with those in the control group, the mice in the other 3 groups showed obvious symptoms of radiation dermatitis after modeling (P<0.05), which were significantly alleviated by treatment with metformin (P<0.05).The mice in the model group exhibited significant decreases in MWT and TWL (P<0.05), which were improved by treatment with metformin and gabapentin (P<0.05).Compared with those in the model group, the levels of p-p38MAPK, p-NF-κB p65, IL-1ß, IL-6 and TNF-α in the spinal cord were significantly decreased in the mice after metformin treatment (P<0.05). CONCLUSION: Metformin can significantly ameliorate pathological pain symptoms in mice with radiation dermatitis possibly by inhibiting the activation of p38MAPK/NF-κB signaling pathway.


Assuntos
Sistema de Sinalização das MAP Quinases , Metformina , NF-kappa B , Radiodermite , Animais , Masculino , Camundongos , Gabapentina/uso terapêutico , Interleucina-6/metabolismo , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Dor , Fator de Necrose Tumoral alfa/metabolismo , Metformina/uso terapêutico , Lesões Experimentais por Radiação/tratamento farmacológico , Radiodermite/tratamento farmacológico
19.
Biomed Pharmacother ; 163: 114808, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37146417

RESUMO

Radiotherapy is a prevalent treatment modality for thoracic tumors; however, it can lead to radiation-induced lung injury (RILI), which currently lacks effective interventions. ACT001, a prodrug of micheliolide, has demonstrated promising clinical application potential, yet its impact on RILI requires further validation. This study aims to investigate the radioprotective effects of ACT001 on RILI and elucidate its underlying mechanism. Sprague-Dawley rats were utilized to induce RILI following 20 Gy X-ray chest irradiation, and lung tissue inflammation and fibrosis were assessed using hematoxylin and eosin (H&E) and Masson staining. Lung injury, inflammation, and oxidative stress markers were evaluated employing commercial kits. Pyroptosis-related differentially expressed genes (DEGs) were analyzed using a microarray dataset from the Gene Expression Omnibus (GEO) database, and their functions and hub genes were identified through protein-protein interaction networks. Pyroptosis-related genes were detected via RT-qPCR, western blotting, immunofluorescence, and immunohistochemistry. The results demonstrated that ACT001 ameliorated RILI, diminished pro-inflammatory cytokine release and fibrosis, and mitigated the activation of the NLRP3 inflammasome while inhibiting pyroptosis in lung tissue. In conclusion, our study reveals that ACT001 can suppress NLRP3 inflammasome-mediated pyroptosis and improve RILI, suggesting its potential as a novel protective agent for RILI.


Assuntos
Lesão Pulmonar , Lesões Experimentais por Radiação , Ratos , Animais , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/patologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/prevenção & controle , Raios X , Inflamação
20.
Expert Opin Drug Discov ; 18(7): 797-814, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37073409

RESUMO

BACKGROUND: Animal models are vital for the development of radiation medical countermeasures for the prophylaxis or treatment of acute radiation syndrome and for the delayed effects of acute radiation exposure. Nonhuman primates (NHPs) play an important role in the regulatory approval of such agents by the United States Food and Drug Administration following the Animal Rule. Reliance on such animal models requires that such models are well characterized. METHODS: Data gathered from both male and female animals under the same conditions and gathered concurrently are limited; therefore, the authors compared and contrasted here the radiosensitivity of both male and female NHPs provided different levels of clinical support over a range of acute, total-body gamma irradiation, as well as the influence of age and body weight. RESULTS: Under matched experimental conditions, the authors observed only marginal, but clearly evident differences between acutely irradiated male and female NHPs relative to the measured response endpoints (rates of survival, blood cell changes, and cytokine fluctuations). These differences appeared to be accentuated by the level of exposure as well as by the nature of clinical support. CONCLUSION: Additional studies with both sexes under various experimental conditions and different radiation qualities run concurrently are needed.


Assuntos
Síndrome Aguda da Radiação , Lesões Experimentais por Radiação , Animais , Estados Unidos , Masculino , Feminino , Tolerância a Radiação , Modelos Animais de Doenças , Síndrome Aguda da Radiação/tratamento farmacológico , Macaca mulatta
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