Dose-Response最新文献

Background and aim: This study investigated the dose-dependent cardioprotective effects of Pterocarpus indicus extract (P.indicus; LD: 27, MD: 54, HD: 108 mg/kg) against isoproterenol (ISO)-induced myocardial ischemia in rats, focusing on oxidative stress, apoptosis, inflammation, and fibrosis.

Experimental procedure: Rats were pretreated for 14 days and divided into control, ISO, propranolol, and P.indicus (LD, MD, HD) groups. Myocardial injury was assessed via ECG, histopathology, serum biomarkers (CK-MB, LDH, cTnT, IL-6, IL-1β, TNF-α), oxidative markers (SOD, MDA, GSH-Px), and apoptosis-related proteins (Bax, Bcl-2, Caspase-3). Nrf2/HO-1 expression was analyzed by western blot. Phytochemical profiling was performed via UPLC-MS/MS and HPLC. Pharmacokinetics, safety, and therapeutic-regimen efficacy were also evaluated.

Results: P.indicus at MD and HD significantly attenuated ISO-induced ECG abnormalities, histopathological damage, serum injury markers, inflammatory cytokines, and fibrosis (all P < 0.01). Treatment suppressed oxidative stress (restored SOD/GSH-Px, reduced MDA) via Nrf2/HO-1 activation and inhibited apoptosis via Bax/Bcl-2/Caspase-3 modulation. The efficacy of MD (EC₅₀ ∼50 mg/kg) was confirmed by dose-response analysis. Pharmacological inhibition established that both Nrf2 activation and caspase-3 inhibition are necessary for P.indicus's effects. PK studies showed systemic exposure to key compounds (quercetin-3-O-glucoside, ferulic acid, linoleic acid), and a 14-day safety assessment revealed no hepatorenal toxicity. Post-injury therapeutic administration also conferred significant protection.

Conclusion: P. indicus extract confers dose-dependent cardioprotection against ISO-induced myocardial injury through dual modulation of the Nrf2/HO-1 and Bax/Bcl-2/Caspase-3 pathways, with the medium dose (54 mg/kg) identified as optimally effective and well-tolerated.

Background: Radiation-induced lymphopenia (RIL), particularly severe RIL (G3+), significantly impacts cancer outcomes. This retrospective study aimed to determine the role of irradiation dose to the thymus on RIL in breast cancer (BC) patients who received adjuvant radiotherapy (RT).

Methods: BC patients who received adjuvant RT in 2019 and had available complete blood count data were included. RIL was defined according to CTCAE v5.0 criteria. Logistic regression identified thymic dosimetric and clinical parameters linked to G3+ RIL, ROC analysis determined optimal protective thresholds, and Delong test compared model performance.

Results: The data of a total of 93 consecutive patients were retrospectively retrieved, with 37.6% (35/93) experienced G3+ RIL. Logistic regression analysis identified thymic dosimetric factors (mean dose, V5, V10), baseline ALC, RT technique and IMNI were associated with G3+ RIL. ROC analysis showed that a combined model of baseline clinical and thymic dosimetry parameters had the highest AUC (0.869). The optimal cutoffs for avoiding G3+ RIL were baseline ALC $\le$ 1.5 $\times$ 10⁹/L, thymus V5 $\le$ 52.76%, thymus V10 $\le$ 9.08%, MTD $\le$ 6.12 Gy, respectively.

Conclusions: Thymic radiation dose correlated with severe lymphopenia in breast cancer radiotherapy. Prospective trials are needed to validate these dose constraints for clinical use.

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.