Dose-Response最新文献

Objective: In this study, we investigated the protective effect of Metformin on fibrosis of trabecular meshwork cells induced by TGFβ2.

Methods: Transformed and primary human trabecular meshwork cells (HTMCs) were treated with TGFβ2 or Metformin alone or combination, western blotting and immunofluorescence staining assays to detect autophagy activity and fibrotic proteins expression levels. TGFβ2 or Metformin alone or combination were injected into the anterior chamber of mouse eye. Mouse intraocular pressure (IOP) was measured every week, mouse eye sections were conducted immunofluorescence staining to analyze Col1 and Col3 expression. pSmad3 level and localization to evaluate TGFβ/Smad3 pathway activity. Chloroquine phosphate was used to block autophagy-lysosome pathway.

Results: Metformin activates autophagy of HTMCs in a dose dependent manner and efficiently ameliorates TMCs fibrosis induced by TGFβ2 in vitro and in mouse model, and decreased elevated IOP caused by TGFβ2. Metformin promotes fibrotic proteins degradation through the autophagy-lysosome pathway.

Conclusion: Our study found Metformin could alleviates fibrosis of HTMCs induced by TGFβ2 and decreased elevated IOP in mouse model.

Objectives: FLASH radiotherapy is garnering attention for its capacity to diminish skin toxicity without compromising tumoricidal efficacy, presenting a stark contrast to conventional (CONV) radiotherapy. Despite its promise, the underlying molecular mechanisms of FLASH irradiation (FLASH-IR) on skin are not yet fully elucidated.

Methods: This study investigated the transcriptomic responses of human foreskin fibroblast cells (HFF-1) via the FLASH-IR or CONV irradiation (CONV-IR), employing the next-generation RNA sequencing (RNA-seq) to capture the gene expression profiles. Our comparative analysis aimed to dissect the cellular and molecular pathways influenced by these two irradiation methods.

Results: We identified a spectrum of differentially expressed genes (DEGs), signaling pathways, and transcriptional networks that were either shared or divergent between FLASH-IR and CONV-IR. Particularly, transcription factor NR4A1 showed significant upregulation in response to FLASH-IR, while chromatin stability factor ELF3 was markedly downregulated following CONV-IR. The top 10 up-regulated DEGs were subjected to qPCR validation, confirming their differential expression in response to FLASH-IR and CONV-IR.

Conclusion: Collectively, our findings delineate unique regulatory landscapes of FLASH-IR and CONV-IR on skin cells, corroborating established effects and shedding new light on the molecular interplay within the context of ultra-high dose radiation.

Purpose: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial cytoprotective protein that shields cells from electrophilic and oxidative stress. Mice lacking Nrf2 exhibit heightened susceptibility to myelosuppression due to impaired hematopoietic reconstitution. In this study, we examined the altered sensitivity to ionizing radiation (IR) and 7,12-dimethylbenz(a)anthracene (DMBA) in Nrf2^-/- mice separately.

Materials and methods: Irradiate Nrf2^-/- or wild-type mice with a dose of 4 Gy to observe changes in body weight, survival rate, and blood routine at 12 months. DMBA was used to treat Nrf2^-/- and wild-type mice, and the body weight and survival rate of the mice were measured. The changes of heme oxygenase-1(HO1) and NAD(P)H: quinone oxidoreductase 1(NQO1) in mice treated with IR or DMBA were detected by RT-qPCR and western blotting.

Results: Our results indicate that Nrf2 deficiency leads to more severe blood and immune system injury in mice exposed to IR or DMBA. Additionally, long-term monitoring revealed that Nrf2 deletion resulted in more severe myelosuppression, leukemia-like symptoms, and higher cancer rates. At the mRNA and protein levels, there was no significant increase in HO1 and NQO1 levels in the Nrf2^-/- mice treated with IR or DMBA. These adverse effects might be attributed to the inhibited protein levels of HO1 and NQO1 and significant DNA damage in hematopoietic stem and progenitor cells (HSPCs).

Conclusions: We demonstrate that the genetic deficiency of Nrf2 in mice leads to reduced antioxidant capacity and suppression of hematopoietic and immune system function, resulting in increased sensitivity to IR or DMBA.

Purpose: This work was the first study to show the impact of γ- radiation on adropin levels in the serum and liver tissue of male albino rats.

Methods: Liver tissue and blood samples of rats were collected at 1, 3, 7 and 14 days after whole-body exposure to 7.5 Gy of γ-radiation.

Results: Irradiated groups revealed a marked decrease in adropin associated with a significant increase in STAT3 in the serum and gene expression. Furthermore, lipid profile (cholesterol, T.G, HDL, LDL, VLDL), liver function (AST, ALT, albumin and total protein), complete blood count (RBCs, WBCs, PLT, Hb, Hct%, MCH, MCV, WBCs differential), glucose and insulin were exhibited more noticeable alterations at all time periods of the experiment. In addition, data exhibited an obvious elevation in some inflammatory markers (IL-6) and TOS accompanied by a decline in the TAC.

Conclusion and future scope of work: γ- radiation has adverse effects on adropin that related inversely with STAT3, leading to further damage to liver cells as well as disturbances in lipid and glucose metabolism. Therefore, adropin could be used in people exposed to radiation such radiotherapy to control the serious effects of radiation. Further study is needed to confirm these results.

Objective: To evaluate the influencing factors of Vancomycin trough concentration in blood, construct an individualized Vancomycin administration model for rational use of Vancomycin. Methods: The clinical data of Vancomycin trough concentration in blood from June 2020 to December 2022 in our hospital were analyzed retrospectively. The effects of age, sex, Vancomycin administration and cumulative dose, albumin, total bilirubin, alanine aminotransferase, Creatinine (CR), urea (Bun), Creatinine clearance rate (Ccr), and time of blood sample collection on Vancomycin trough concentration were analyzed. A linear regression equation for the influencing factors of Vancomycin trough concentration in blood was constructed. Results: Sixty-six patients (82.5%) were treated with Vancomycin by intravenous drip. Significant differences existed in the influence of patients' age, Vancomycin administration, CR, Bun and Ccr on Vancomycin trough concentration (P < 0.05). Vancomycin trough concentration in blood showed negative correlated with Ccr (P < 0.05). The regression model of Vancomycin trough concentration in blood was y = 40.911 - 10.971 × method of administration - 1.715 × collection time + 1.018 × cumulative dose - 0.178 × Ccr, the model could predict 41.30% Vancomycin trough concentration in blood. Conclusion: The influencing factors of Vancomycin trough concentration in blood were complex. The constructed regression model of Vancomycin concentration in plasma may provide a scientific reference for individualized administration of Vancomycin in clinical practice.

Objectives: The intestine exhibits high radiosensitivity and is susceptible to damage during radiotherapy for abdominal or pelvic tumors, especially at radiation doses exceeding 5 Gy, which can lead to severe gastrointestinal complications. This study aims to elucidate the mechanisms of DNA repair and immune responses in radiation-induced intestinal injury, with the goal of enhancing radiotherapy efficacy.

Methods: We employed weighted correlation network analysis (WGCNA) to analyze RNA sequencing data from intestinal tissues collected at various time points following irradiation, as well as from mice with targeted disruption of the NFE2-like bZIP transcription factor 2 (Nrf2) gene and their wild-type counterparts.

Results: Our analysis revealed enhanced DNA repair capacity and attenuated immune response 3.5 days after irradiation. Histone variants and ribosomal proteins were identified as potential contributors to DNA repair processes. We also constructed a competing endogenous RNAs (ceRNA) network including genes from both the DNA repair and immune modules and identified Akr1b8, Gsta3, and Nqo1 as radiation-effect genes regulated by Nrf2.

Conclusions: These findings provide valuable insights into the molecular mechanisms of radiation-induced intestinal injury and suggest potential targets for protecting normal intestinal tissue during radiotherapy. This knowledge may contribute to improved treatment outcomes and enhanced patient well-being.

NCRP Commentary-27 reaffirmed Linear No Threshold (LNT) as the basis for radiation protection and listed six studies with "strong support" for LNT. This paper looks critically at these six studies and shows that they do not support LNT in the dose range of 0-100 mGy. These studies typically admit to no increase in cancer risk at significant dose levels. More importantly this paper shows that these studies assume LNT from the outset, underestimate uncertainty, ignore confounding factors, have biased control groups, and underestimate dose.

Purpose: Application of energy-spectrum computed tomography (CT) to assess specific efficacy of and response to carbon ion radiotherapy (CIRT) of C6 gliomas in rats.

Methods: After establishing C6 glioma rat models, 3 tumor-bearing rats were randomly selected as controls. The remaining were divided into 0 Gy, 1 Gy, and 2 Gy groups for CIRT. Energy-spectrum CT scans were performed, and brain tissues were collected for histopathology and western blot Test. Survival rates in each group were compared.

Results: The results demonstrated that tumors in the 1 Gy and 2 Gy groups decreased at different rates up to 14 days post-CIRT (P < 0.05). Furthermore, compared to pre-CIRT measurements, the energy-spectrum parameters gradually increased in the 0 Gy group, while they decreased in the 2 Gy group. Post-CIRT, the Ki-67 proliferation index and the expression levels of vascu-larassociated proteins in tumor tissues were significantly reduced in the 1 and 2 Gy groups. Additionally, the survival times of tumor-bearing rats were prolonged after CIRT.

Conclusions: CIRT effectively restricts tumor cell growth and proliferation, leading to improved survival rates in rats with C6 gliomas. The use of energy-spectrum CT with immunohistochemistry for quantitative detection can actively support the effectiveness of carbon ion radiotherapy in inhibiting tumor proliferation.

This study constructed a predictive model for occurrence of radiation esophagitis during breast-cancer radiotherapy. 308 breast-cancer patients were analyzed. Lasso regression identified crucial variables that were further integrated into a radiation esophagitis risk score, which was used to segregate patients into high- and low-risk groups. A nomogram model was designed for clinical applicability. Training and validations were performed to assess robustness and generalizability of proposed models, employing C-index, AUCs, calibration curves, and decision curves. SHAP algorithm was used for model interpretation, offering insights into the major contributory factors. Seven significant variables were identified by Lasso regression. C-indexes of nomograms of individual clinical variables and risk score were 0.795 and 0.784, respectively, exhibiting strong predictive ability. In internal validation, AUCs for risk score, nomogram, and logistic models were 0.784, 0.795, and 0.812, respectively. Calibration curves showed a close fit between predicted and observed outcomes across models. Decision curve analysis indicated logistic model's superior clinical utility when the risk threshold was above 0.2. SHAP interpretation emphasized radiation dose, pruritus, molecular type, and hepatic dysfunction as top contributory factors for radiation esophagitis. Models based on interpretable machine learning offer an intuitive tool to assess risk of radiation esophagitis in breast-cancer radiotherapy.