Dose-Response最新文献

Objectives: This study delineates the U-Shaped Dose-Dependent Modulation of Ginkgolide B (GB) on macrophage function, highlighting its capacity to enhance bacterial phagocytosis and attenuate systemic inflammation in sepsis.

Methods: RAW264.7 cells were co-cultured with GB, and flow cytometry was used to assess macrophage phagocytosis and polarization. Rats were divided into five groups: Healthy, cecal ligation and puncture (CLP), and three GB treatment groups. Survival was monitored over 7 days, and arterial blood was analyzed to assess acidosis. Histological examination was performed to evaluate organ damage, while ELISA measured inflammatory factors in blood and peritoneal lavage fluid (PLF). Finally, bacterial colony counts in the PLF were analyzed to assess peritoneal macrophage bacterial clearance capacity.

Results: GB co-culture enhanced macrophage bacterial phagocytosis. GB treatment alleviated acidosis and improved survival in septic rats. It also reduced pro-inflammatory cytokines TNF-α and IL-6 while increasing anti-inflammatory IL-10 levels. GB injection decreased bacterial load in the PLF, indicating enhanced macrophage bacterial clearance.

Conclusion: GB enhances macrophage phagocytic activity, improves bacterial clearance, increases the survival rate of septic rats, and reduces systemic inflammation.

Objectives: Exposure of the developing fetus to high doses of ionizing radiation during prenatal development can result in growth restriction of the fetus, or a reduction in offspring growth. The developmental stage of the offspring at the time of irradiation is of interest, in order to characterize any potential periods of sensitivity for radiation-induced growth restriction effects. The goal of the present study was the development of a mouse model of radiation-induced growth restriction, following X-ray irradiation during late gestation.

Methods: Pregnant BALB/cAnNCrl mice were irradiated with different irradiation conditions from gestational day (GD) 14-17. Treatments included an acute dose of 1.82 Gy X-ray irradiation on GD 14, 15 or 16. The effects of dose fractionation were also studied with one group receiving 0.455 Gy x 4 daily fractions from GD 14-17 (cumulative dose of 1.82 Gy). Another group also received a pre-treatment with 61 mGy X-ray irradiation on GD 14, 24 h prior to the 1.82 Gy on GD 15, to test for the possibility of a radiation-induced adaptive response.

Results: Evidence for growth restriction was observed in all irradiation groups, with the greatest degree of growth restriction observed in the 1.82 Gy on GD 14 group. Evidence for growth restriction was based on a reduced gestational weight gain by pregnant dams and significant decrease in fetal weight and length measurements. Evidence for an adaptive response was not observed in the present study, as the combination group had similar outcomes to the group that only received the 1.82 Gy challenge irradiation dose.

Conclusion: The establishment of a mouse model of radiation-induced growth restriction during late gestation will facilitate the ability for future work into determining the precise cellular and physiological effects on offspring, and the development of future countermeasures to protect against such adverse effects.

Objective: To explore the value of 5T magnetic resonance imaging (MRI) T1ρ and T2 mapping sequences in evaluating muscle changes around knee osteoarthritis (KOA).

Methods: 50 KOA patients and 36 healthy volunteers underwent knee MRI and peripheral muscle T1ρ/T2 mapping scans, comparing intergroup differences in each muscle's T1ρ/T2 values and analyzing their correlation with KOA severity.

Results: The T1ρ and T2 values of the vastus medialis, vastus lateralis, biceps femoris, medial head of gastrocnemius, lateral head of gastrocnemius, and popliteus in KOA patients were higher than those in healthy volunteers, as well as the T2 values of the sartorius and semimembranosus. The T1ρ value of the vastus medialis is positively correlated with the whole-organ MRI score (WORMS) for the knee. The T2 values of the vastus medialis, sartorius, semimembranosus, popliteus, medial head of gastrocnemius, lateral head of gastrocnemius, biceps femoris and vastus lateralis are also positively correlated with the WORMS for the knee.

Conclusion: The 5T MRI T1ρ and T2 mapping techniques can sensitively and quantitatively evaluate the changes in peri-articular muscles with KOA, providing important references for the clinical diagnosis and treatment of KOA.

Objectives: Resistance to platinum-based chemotherapy in bladder cancer is closely associated with activation of the Fanconi anemia (FA) DNA interstrand crosslink repair pathway. Identifying pharmacological inhibitors of FA signaling may improve therapeutic response. We investigated the effects of the natural compound toosendanin (TSN) on FA pathway regulation in this study.

Methods: Bladder cancer cell lines (T24, RT4, J82) were pretreated with TSN and exposed to ultraviolet C (UVC). FANCI/FANCD2 monoubiquitination, FANCD2 nuclear foci, FA core gene expression, and JAK/STAT1 signaling were quantified. A T24 xenograft model was used to validate FA pathway inhibition in vivo. Statistical analyses were performed using one-way ANOVA followed by Tukey's post-hoc test (mean ± SD; n = 3 independent replicates; Shapiro-Wilk test for normality).

Results: TSN reduced UVC-induced 58% FANCI (P = 0.004, n = 3) and 77% FANCD2 monoubiquitination (P = 0.004, n = 3) in bladder cancer cells, and decreased FANCD2 foci-positive nuclei by 27% (P = 0.015, n = 3). Co-immunoprecipitation assays further revealed that TSN disrupted 56% interaction between the FANCI-FANCD2 complex and the key scaffold protein SLX4 (FANCP) (P = 0.002, n = 6). TSN down-regulated FA core genes (FANCA, FANCC, FANCF, FANCM) by 30 to 65% (all P < 0.05, n = 3) as well as decreased STAT1 phosphorylation by 45% (P = 0.013, n = 3) and the binding capacity of STAT1 on these FA genes' promoter by 33% to 47% (all P < 0.05, n = 3). In xenograft tumors, TSN also reduced 70% FANCI (P = 0.007, n = 3) and 45% FANCD2 monoubiquitination (P = 0.011, n = 3) as well as expression of FANCA, FANCC, FANCF, FANCM by 26% to 38% (all P < 0.05, n = 3). TSN selectively sensitized bladder cancer cells to UVC-induced cytotoxicity (IC50 decreased 35%, P = 0.026, n = 3), without affecting the viability of human urothelial cell SV-HUC-1 cells or lung adenocarcinoma A549 cells (both P > 0.05, n = 3).

Conclusion: TSN inhibits FA DNA repair signaling in bladder cancer by suppressing JAK/STAT1-mediated FA core gene transcription, supporting its potential as a combinatorial agent to overcome cisplatin resistance.

Background: Phenotypic age acceleration (PhenoAgeAccel) reflects biological aging, with higher values indicating faster aging. While linked to adverse outcomes in the general population, its relation to mortality in asthma remains unclear.

Methods: We analyzed 3817 adults with physician-diagnosed asthma from NHANES (1999-2010, 2015-2018) with mortality follow-up through 2019. PhenoAgeAccel was calculated from clinical biomarkers, and associations with all-cause and cardiovascular mortality were assessed using weighted Cox models, restricted cubic splines, and subgroup/sensitivity analyses.

Results: During a median follow-up of 13.2 years, higher PhenoAgeAccel was independently associated with greater risks of all-cause mortality (HR = 1.03, 95% CI: 1.03-1.04) and cardiovascular mortality (HR = 1.02, 95% CI: 1.01-1.04). Compared with the lowest quartile, participants in the highest had a 3.42-fold higher all-cause and 2.72-fold higher cardiovascular mortality risk. Associations were nonlinear for all-cause but roughly linear for cardiovascular mortality, and consistent across subgroups and sensitivity tests.

Conclusions: Higher PhenoAgeAccel was independently associated with increased risks of all-cause and cardiovascular mortality among adults with asthma, indicating that biological aging markers may serve as useful tools for risk assessment and individualized care.

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.