Dose-Response最新文献

Background: In light of the growing problem of antibiotic resistance, it is imperative to investigate new sources, and plants offer a promising supply of bioactive chemicals. Because of its numerous uses in industry, health, and nutrition as well as its antibacterial qualities, Cannabis sativa (C.sativa) has garnered a lot of study interest. This study sought to determine whether ethanolic extracts from C.sativa leaves have antibacterial properties against six human pathogenic microorganisms.

Methodology: The antibacterial activity of C.sativa ethanolic extract was tested against six bacteria according to design of experiments made by Agar diffusion method accompanied by response surface method (RSM) of Minitab 17 software. The different combinations set were, concentration: 5.0, 7.5, and 10.0, pH: 5.0, 6.5, 8.0 and temperature: 35°C, 37.5°C, 40°C. By using RSM, maximum antibacterial activity has been checked for ethanolic extract of C.sativa against six bacteria by choosing three independent variables, temperature, pH, and concentration. In in-Silico studies, homology, threading approach, structure prediction, ligands designing and docking studies was performed against the antimicrobial target sequences for Beta-Lactamase, GABA Receptor, Lipoteichoic Acid, N-Acetylglucosamine (NAG), Peptidoglycan and Topoisomerase-IV through FASTA format from UniProt for structure prediction.

Results: The results indicated that the three concentrations were effective against tested bacteria. Moreover, effect of pH caused a significant variation in zone of inhibition. The graphs presented in this study indicate the highest zone of inhibition for plant extract; have been achieved at concentration of 10.0, pH 5.1 and temperature 37.5°C. It shows that by keeping the pH low, antibacterial activity will increase. Through the multiple regression analysis on the experimental data, the fitted regression model for the response variable and the test variable x₁, x₂, x₃ are correlated by the second order polymeric equation.

Conclusion: It has been concluded that C.sativa can be considered as an effective drug in curing diseases caused by bacteria. Using the optimized values of temperature and pH analyzed in this experiment.

Objectives: Platinum-based chemotherapy remains a mainstay for bladder cancer treatment, yet resistance often arises through activation of the Fanconi anemia (FA) DNA repair pathway. The monoubiquitination of the FANCI-FANCD2 (ID2) complex by FANCL and UBE2T is a critical step in repairing cisplatin-induced interstrand crosslinks (ICLs). Identifying small molecules that block this process may improve the therapeutic efficacy of cisplatin.

Methods: We investigated the effects of piperine, a natural alkaloid from black pepper, on FA pathway activation in bladder cancer cells. A combination of immunoblotting, immunofluorescence, co-immunoprecipitation, qPCR-blocking assays, dot blot analyses, in vitro ubiquitination/discharge assays, biolayer interferometry (BLI), and differential scanning fluorimetry (DSF) were employed to characterize the molecular mechanism. Xenograft models were used to evaluate in vivo efficacy.

Results: Piperine pretreatment markedly suppressed cisplatin-induced monoubiquitination of FANCI and FANCD2 and reduced FANCD2 foci formation in T24, 5637, and RT4 cells. Co-immunoprecipitation confirmed diminished recruitment of downstream nucleases and repair factors (FANCP, FANCQ, PCNA). qPCR-blocking assays showed delayed ICL repair, while dot blot analyses revealed that intrastrand cisplatin adduct removal was unaffected, indicating selective inhibition of ICL repair. Piperine did not alter mRNA or protein expression of FANCL, UBE2T, USP1, or UAF1, nor did it enhance deubiquitinase activity. Instead, in vitro assays demonstrated that piperine blocked FANCL-mediated ubiquitin transfer from UBE2T∼Ub to the ID2 complex, without impairing E2 charging or FANCL-UBE2T binding. BLI confirmed unaltered binding affinity, whereas DSF revealed a significant ΔTm shift for UBE2T, consistent with allosteric modulation. In xenografts, combined cisplatin and piperine treatment significantly reduced tumor growth and attenuated FANCI/FANCD2 monoubiquitination.

Conclusion: Our findings uncover piperine as a natural compound that allosterically inhibits UBE2T activity within the FA pathway, thereby impairing ID2 monoubiquitination and enhancing cisplatin sensitivity in bladder cancer. This study highlights the therapeutic potential of piperine and provides a rationale for targeting the FA repair axis to overcome platinum resistance.

Objectives: HER2 overexpression is almost invariably associated with advanced breast cancer disease and poor prognosis, hence its extensive review. This study therefore aims to discover and analyze potential HER2 inhibitors through computational methods to advance drug discovery and optimization.

Methodology: A ligand-based virtual screening (LBVS) approach was employed to screen compounds from the ChEMBL database. From 8900 initial matches, 39 candidate compounds were selected based on structural similarity and ADME properties. Molecular docking was performed to assess binding affinity with HER2, followed by molecular dynamics (MD) simulations to evaluate complex stability. Additionally, a QSAR (quantitative structure-activity relationship) model was established to elucidate key structural features influencing inhibitory activity.

Results: Five lead compounds were prioritized based on strong docking scores (<-8.4 kcal/mol). Among them, compound 2048788 (-11.0 kcal/mol, predicted pIC₅₀ ≈ 8.6) and compound 3956509 (pIC₅₀ ≈ 8.4) showed superior binding affinity and pharmacokinetic properties compared to FDA-approved drugs (doxorubicin, letrozole, lanatuzumab). MD simulations confirmed complex stability. The initial QSAR model showed low predictive power (R² = 0.18, RMSE = 1.19), but after feature selection, performance improved significantly (RMSE = 0.57). Key positive contributors included hydrogen bond donor count (r = 0.63), lipophilicity (LogP, r = 0.60), and sp³ carbon fraction (r =0.60), while excessive polarity and aromaticity reduced activity. Compounds within the 450-500 Da molecular weight range exhibited the highest activity (pIC₅₀ = 8.0-8.6).

Conclusion: This study integrated virtual screening, docking, MD simulations, and QSAR modeling to identify compound 2048788 as a highly promising HER2 inhibitor. These findings provide a strong foundation for further optimization and the preclinical development of targeted HER2 therapies.

The validity of the linear-no-threshold (LNT) model in radiation regulation remains contested. Although extensive experimental evidence challenges it, epidemiological studies-especially cohort and case-control designs-are still used to justify its application. This article focuses on a key methodological limitation of individual-level epidemiological studies, particularly the reported link between residential radon and lung cancer. Pooled case-control analyses suggest a linear dose-response relationship consistent with the LNT model, while ecological studies show mixed results. Case-control data are often deemed more reliable than ecological studies, but their validity requires reexamination. A central issue is the neglect of radon's role within the broader context of indoor air pollution. Because more than 90% of radon decay products adhere to airborne particles, measured radon levels can effectively serve as a proxy for indoor particulate matter (PM), which is a complex mixture of harmful compounds. Since PM2.5 is a well-established lung carcinogen, the observed radon-lung cancer association may reflect PM2.5 effects rather than radon itself. This confounding is weaker in ecological studies, which use regional averages less directly tied to individual homes. When experimental evidence, evolutionary reasoning, and ecological findings contradict individual-level studies, it is possible that the latter are inherently flawed by design. Continued reliance on epidemiological studies to uphold the LNT model should therefore be critically reconsidered.

The field of dose-response research has evolved dramatically, propelled by advancements in exposomics concept, multi-omics technologies, and a growing appreciation of low-dose effects across disciplines. This editorial article highlights recent key publications in Dose-Response that reflect these trends and outlines the journal's renewed commitment to publishing rigorous, innovative research that bridges traditional toxicology with modern systems biology. Meanwhile, this editorial article also addresses the future directions for Dose-Response. Finally, Dose-Response will remain dedicated to advancing the science of biological responsiveness to low-dose stressors. By embracing exposomics, multi-omics, and mechanistic toxicology, we aim to foster interdisciplinary dialogue and translate research into evidence-based policies. Through collaboration with our authors, reviewers, and readers, from global scientific community, we wish and also confident to reach this exciting new chapter.

Objective: MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression and remain stable in biological fluids, even under harsh conditions. Their stability and responsiveness to environmental stressors make them strong candidates for radiation biodosimetry. This study aimed to (1) establish a robust in vivo pipeline for miRNAome profiling and (2) identify plasma-based miRNA biomarkers of ionizing radiation at low and high doses.

Methods: BALB/c mice were exposed to sham, 100 mGy, or 2 Gy of X-rays. Plasma was collected 6 h post-irradiation. Total RNA was extracted, and next-generation sequencing was used to profile the plasma miRNAome. Differentially expressed miRNAs were identified relative to sham controls, and selected candidates were validated using RT-qPCR.

Results: A total of 630 unique miRNAs were detected. High-dose exposure (2 Gy) significantly upregulated 14 and downregulated 5 miRNAs. Seven miRNAs were significantly induced at 100 mGy, including miR-126a-5p and miR-133a-3p, which were exclusive to low-dose exposure. Five miRNAs were shared between both doses, indicating dose-independent responses. RT-qPCR confirmed expression trends.

Conclusion: This study identified distinct and shared circulating miRNA signatures for low- and high-dose radiation exposure. These findings support the potential of miRNAs as minimally invasive, dose-stratified biomarkers for radiation biodosimetry.

Objective: High-throughput gene expression analysis represents a promising approach for evaluating irradiation doses in vitro. This study aimed to identify preferred reference genes for normalizing RT-qPCR data in human peripheral blood following X-ray irradiation.

Methods: We assessed the stability of GAPDH, 18S rRNA, UBC, HPRT, DPM1, ITFG1, MRPS5, and ACTB, which are commonly utilized in radiation biodosimetry studies. Three whole blood samples from healthy donors were divided into three culture time groups (2, 12, and 24 hours) and subjected to X-ray doses of 0, 0.5, 1.2, and 3.5 Gy, resulting in a total of 12 subgroups. NormFinder, geNorm, BestKeeper, and ΔCt were employed to evaluate the stability of the candidate genes. RefFinder was utilized to comprehensively rank the candidates and identify suitable reference genes.

Results: The preferred reference genes identified were UBC, HPRT, and GAPDH for 2-hour culture time; for 12 hours, UBC, HPRT, and 18S rRNA were preferred; and for 24 hours, 18S rRNA, MRPS5, and GAPDH were preferred.

Conclusion: This study presents novel findings of reference genes suitable for normalizing RT-qPCR data following X-ray irradiation in human peripheral blood across three distinct culture periods. It offers valuable insights for the selection of reference genes in radiation biodosimetry research.

This mini-review explores adaptive responses in organisms exposed to high radiation levels, drawing comparisons between Chernobyl's wildlife-specifically its darker-pigmented frogs-and residents of Ramsar, Iran, a region with high natural background radiation. Chernobyl's wildlife adaptations are not surprising, as substantial evidence in humans, demonstrates similar adaptation to high radiation levels. Studies reveal that mechanisms such as increased melanin production in frogs and enhanced DNA repair capabilities in Ramsar residents help mitigate radiation damage. These adaptations provide a framework for understanding resilience to environmental stressors and contribute to broader discussions on evolutionary survival mechanisms in extreme environments. By examining ecological and physiological responses across species, this review sheds light on radiation's role in natural selection and potential applications for environmental and radiobiological research.

Background: Radiation therapy for brain tumors often leads to radiation-induced brain injury, which is closely linked to microglial hyperactivation and neuroinflammation. Lycium barbarum polysaccharide (LBP), the primary active component of Lycium barbarum, may provide neuroprotection by suppressing microglial overactivation and reducing neuroinflammation.

Methods: BV2 microglial cells were pretreated with LBP for 12 hours (h), exposed to 10 Gy X-ray irradiation, and then post-treated with LBP for another 12 h. We assessed microglial polarization and measured levels of nitric oxide (NO), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and key proteins in the IKKβ/IκBα/NF-κB pathway.

Results: LBP treatment shifted microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype and significantly decreased the release of NO, IL-1β, and TNF-α following irradiation.

Conclusion: Our findings demonstrate that LBP mitigates radiation-induced microglial inflammation by inhibiting the IKKβ/IκBα/NF-κB pathway, suggesting its potential as a radioprotective agent against radiotherapy-induced neuroinflammation.

Traumatic brain injury (TBI) is an important condition with high rates of disability and mortality worldwide. Post-traumatic seizure (PTS) frequently occur following TBI, manifesting in both early and late stages. Recurrent PTS without timely intervention may progress to post-traumatic epilepsy (PTE), which defined as the occurrence of two or more unprovoked seizures. Early pharmacological intervention is essential to mitigate the risk of PTE and enhance the prognosis for patients with TBI. Antiepileptic drugs (AEDs) offer a viable strategy for managing PTS. Recent studies indicated that AEDs are more effective in early post-traumatic seizure compared to late post-traumatic seizure, and their efficacy and safety require further evaluation. As research advances in the pathophysiological changes after TBI and the pathogenesis of PTS, current investigations are increasingly focused on neurological damage. Novel compounds targeting various pathways, including antioxidants, anti-neuroinflammatory agents, glutamate modulators and anti-oxidative stress compounds, have demonstrated promising potential in preclinical studies for PTS intervention. This review focuses on the research progress of different AEDs in PTS intervention and discusses the recent developments of emerging PTS intervention strategies based on multiple pathways, providing insights into the clinical application of AEDs and new directions for the development of new drugs for PTS intervention.