1.Effect of Collagen on Burn Healing in Rats
Yulin CHEN ; Wei WANG ; Jialing SUN ; Shengie GE ; Wanhe LIN
Academic Journal of Second Military Medical University 1982;0(02):-
In this study collagen was applied locally for the treatment of burn wound in the rat. Twenty rats weighing 18-22g were made into 7% [1 degree burn model and divided into two groups: collagen group and control group. After burn, collagen (0.4ml, once daily) was smeared on the rat wound in the treatment group, whereas saline (0.4ml, once daily) in the control group. It was found that collagen can significantly accelerate burn wound healing by comparing the wound healing time and histological changes.
2.Formulation of a rational dosage regimen of ceftiofur hydrochloride oily suspension by pharmacokineticpharmacodynamic (PK-PD) model for treatment of swine Streptococcus suis infection
Wanhe LUO ; Dehai WANG ; Hua QIN ; Dongmei CHEN ; Yuanhu PAN ; Wei QU ; Lingli HUANG ; Shuyu XIE
Journal of Veterinary Science 2021;22(6):e41-
Background:
Our previously prepared ceftiofur (CEF) hydrochloride oily suspension shows potential wide applications for controlling swine Streptococcus suis infections, while the irrational dose has not been formulated.
Objectives:
The rational dose regimens of CEF oily suspension against S. suis were systematically studied using a pharmacokinetic-pharmacodynamic model method.
Methods:
The healthy and infected pigs were intramuscularly administered CEF hydrochloride oily suspension at a single dose of 5 mg/kg, and then the plasma and pulmonary epithelial lining fluid (PELF) were collected at different times. The minimum inhibitory concentration (MIC), minimal bactericidal concentration, mutant prevention concentration (MPC), post-antibiotic effect (PAE), and time-killing curves were determined. Subsequently, the area under the curve by the MIC (AUC 0–24h /MIC) values of desfuroylceftiofur (DFC) in the PELF was obtained by integrating in vivo pharmacokinetic data of the infected pigs and ex vivo pharmacodynamic data using the sigmoid E max (Hill) equation. The dose was calculated based on the AUC 0–24h /MIC values for bacteriostatic action, bactericidal action, and bacterial elimination.
Results:
The peak concentration, the area under the concentration-time curve, and the time to peak for PELF's DFC were 24.76 ± 0.92 µg/mL, 811.99 ± 54.70 μg·h/mL, and 8.00 h in healthy pigs, and 33.04 ± 0.99 µg/mL, 735.85 ± 26.20 μg·h/mL, and 8.00 h in infected pigs, respectively. The MIC of PELF's DFC against S. suis strain was 0.25 µg/mL. There was strong concentration-dependent activity as determined by MPC, PAE, and the time-killing curves. The AUC 0–24h /MIC values of PELF's DFC for bacteriostatic activity, bactericidal activity, and virtual eradication of bacteria were 6.54 h, 9.69 h, and 11.49 h, respectively. Thus, a dosage regimen of 1.94 mg/kg every 72 h could be sufficient to reach bactericidal activity.
Conclusions
A rational dosage regimen was recommended, and it could assist in increasing the treatment effectiveness of CEF hydrochloride oily suspension against S. suis infections.
3.A robust luminescent assay for screening alkyladenine DNA glycosylase inhibitors to overcome DNA repair and temozolomide drug resistance
Ying-Qi SONG ; Guo-Dong LI ; Dou NIU ; Feng CHEN ; Shaozhen JING ; Vincent Kam Wai Wong ; Wanhe WANG ; Chung-Hang LEUNG
Journal of Pharmaceutical Analysis 2023;13(5):514-522
Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50%of patients do not respond to TMZ,which is associated with repair and/or tolerance of TMZ-induced DNA lesions.Studies have demonstrated that alkyladenine DNA glycosylase(AAG),an enzyme that triggers the base excision repair(BER)pathway by excising TMZ-induced N3-methyladenine(3meA)and N7-methylguanine le-sions,is overexpressed in glioblastoma tissues compared to normal tissues.Therefore,it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glio-blastomas.Herein,we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods.As a proof-of-concept,this assay was used to screen 1440 food and drug administration-approved drugs against AAG,resulting in the repurposing of sunitinib as a potential AAG inhibitor.Sunitinib restored glioblastoma(GBM)cancer cell sensitivity to TMZ,inhibited GBM cell proliferation and stem cell char-acteristics,and induced GBM cell cycle arrest.Overall,this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.
4.A pyrene-based ratiometric fluorescent probe with a large Stokes shift for selective detection of hydrogen peroxide in living cells
Qingxin CHEN ; Ke CHENG ; Wanhe WANG ; Liu YANG ; Yusheng XIE ; Ling FENG ; Jie ZHANG ; Huatang ZHANG ; Hongyan SUN
Journal of Pharmaceutical Analysis 2020;10(5):490-497
Hydrogen peroxide (H2O2) plays a significant role in regulating a variety of biological processes. Dys-regulation of H2O2 can lead to various diseases. Although numerous fluorescent imaging probes for H2O2 have been reported, the development of H2O2 ratiometric fluorescent probe with large Stokes shift re-mains rather limited. Such probes have shown distinct advantages, such as minimized interference from environment and improved signal-to noise ratio. In this work, we reported a new pyrene-based com-pound Py-VPB as H2O2 fluorescent probe in vitro. The probe demonstrated ratiometric detection behavior, large Stokes shift and large emission shift. In addition, the probe showed high sensitivity and selectivity towards H2O2 in vitro. Based on these excellent properties, we successfully applied Py-VPB to the visualization of exogenous and endogenous H2O2 in living cells. Cell imaging study also showed that our probe was localized in the mitochondria. We envision that the probe can provide a useful tool for unmasking the biological roles of mitochondrial H2O2 in living systems.
5.Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer.
Sha-Sha CHENG ; Yuan-Qing QU ; Jia WU ; Guan-Jun YANG ; Hao LIU ; Wanhe WANG ; Qi HUANG ; Feng CHEN ; Guodong LI ; Chun-Yuen WONG ; Vincent Kam Wai WONG ; Dik-Lung MA ; Chung-Hang LEUNG
Acta Pharmaceutica Sinica B 2022;12(3):1390-1405
Cyclin-dependent kinase 9 (CDK9) activity is correlated with worse outcomes of triple-negative breast cancer (TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction (PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CˆN ligand and tested their activity against the CDK9-cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.