Scientific Reports
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2025
·Vol. 15
·期 1
·1-14
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IF 3.9
Sun Jinzhou,Chen Qianqian,Zhuang Chumeng,Li Xiaohong,Yu Li,Jin Weifeng
Develop a novel coupled PK-PD model and apply it to quantitatively evaluate the synergistic effects of Hydroxysafflor Yellow A (HSYA) combined with Calycosin (CA) in the treatment of ischemic stroke. A total of 6 rats were modelled for middle cerebral artery occlusion (MCAO). Plasma was collected from the submandibular venous plexus of rats after the administration of HSYA and CA, and was detected and analyzed by LC-MS method. The plasma expression levels of Caspase-9, IL-1β and SOD in rats were also determined by ELISA kit. Meanwhile, a coupled PK-PD model was proposed, incorporating interaction terms between drugs and coupling of pharmacodynamic effects, to quantitatively reveal their interactions. Moreover, a numerical solution technique based on optimization methods was proposed, enabling the model to be effectively applied to experimental data. Based on the coupled PK model, HSYA and CA significantly increased each other’s metabolic rates. The model also showed that CA had a larger apparent volume of distribution and clearance in rats, while HSYA had a shorter mean retention time and elimination half-life. The coupled PK-PD model indicated a synergistic effect between HSYA and CA on all three pharmacodynamic markers, with HSYA contributing more significantly. Despite individual variability among the six rats, the parameter interpretations remained consistent. The proposed coupled PK-PD model and its numerical solution algorithm successfully revealed the synergistic effects of HSYA and CA in the treatment of ischemic stroke. This model lays the foundation for future models with more complex interactions and effects.
研究领域:
药理学
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生物医学工程
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神经科学
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高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2017
·Vol. 181
·期 1
·62-70
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IF 2.399
Zhang Hui,Chang Zhenyu,Mehmood Khalid,Abbas Rao Zahid,Nabi Fazul,Rehman Mujeeb Ur,Wu Xiaoxing,Tian Xinxin,Yuan Xiaodan,Li Zhaoyang,Zhou Donghai
Nano-sized copper particles are widely used in various chemical, physical, and biological fields. However, earlier studies have shown that nano copper particles (40–100 μg/mL) can induce cell toxicity and apoptosis. Therefore, this study was conducted to investigate the role of nano copper in mitochondrion-mediated apoptosis in PK-15 cells. The cells were treated with different doses of nano copper (20, 40, 60, and 80 μg/mL) to determine the effects of apoptosis using acridine orange/ethidium bromide (AO/EB) fluorescence staining and a flow cytometry assay. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in the PK-15 cells were examined using commercially available kits. Moreover, the mRNA levels of the Bax, Bid, Caspase-3, and CYCS genes were assessed by real-time PCR. The results revealed that nano copper exposure induced apoptosis and changed the mitochondrial membrane potential. In addition, nano copper significantly altered the levels of the Bax, Bid, Caspase-3, and CYCS genes at a concentration of 40 μg/mL. To summarize, nano copper significantly ( P < 0.05) decreased the level of SOD and increased the level of MDA in PK-15 cells. Altogether, these results suggest that nano copper can play an important role in inducing the apoptotic pathway in PK-15 cells, which may be the mechanism by which nano copper induces nephrotoxicity.
研究领域:
细胞生物学
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毒理学
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分子生物学
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Antibiotics-Basel
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2022
·Vol. 11
·期 11
·1660
·
IF 5.222
Yan Wang,Lanyu Liu,Qiping Wu,Qiufen Yin,Feifan Xie
Background: The pharmacokinetic/pharmacodynamic (PK/PD) index of carbapenems that best correlates with in vivo antimicrobial activity is percent time of dosing interval in which free drug concentration remains above MIC (%fT > MIC), while the magnitudes of the PK/PD index of carbapenems remains undefined in critically ill sepsis patients.Methods: A sepsis rat model was first developed by comparing the survival outcomes after intraperitoneal injection of different inoculum size (1–10 × 107CFU) ofPseudomonas aeruginosaATCC9027 (MIC = 0.125 mg/L) in neutropenic rats. The PK characteristics of the model drug meropenem in the developed sepsis rat model was then evaluated, and PK modeling and simulation was applied to design meropenem dosing regimens attaining various PD targets (40%fT > MIC, 100%fT > MIC, and 100%fT > 4 × MIC). The microbiological response and survival outcomes for different meropenem treatment regimens were investigated in the rat sepsis model (n= 12 for each group).Results: The optimal inoculum for the rat sepsis model was 1 × 107CFU ofPseudomonas aeruginosaATCC9027. A one-compartment model with first-order absorption best described the PK of meropenem in sepsis rats. Pronounced survival prolongation and lower hazard risk were observed in the treatment groups of 50 or 75 mg/kg/q2.4h (100%fT > MIC) and 75 mg/kg/q2h (100%fT > 4 × MIC) compared to the 75 mg/kg/q6h (40%fT > MIC) group, while meropenem groups with PD targets of 100%fT > MIC and 100%fT > 4 × MIC showed comparable survival curves. Microbiological response for different PD targets is inconclusive due to irregular bacterial counts in blood samples.Conclusions: The PD target of 40%fT > MIC is suboptimal for sepsis rats, and the aggressive 100%fT > 4 × MIC target does not provide a survival benefit against the target of 100%fT > MIC.Keywords:pharmacokinetics;PK/PD;survival;meropenem;sepsis rat model
研究领域:
药理学
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感染病学
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PubMed
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2025
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IF 4.7
Bohan Liang,Jiaojiao Ma,Lingmei Wang,Junxia Zhang,Yan Shang,Yanjie Li,Huazhen Zhu,Yunhua Teng,Shiqi Dong,Huirong Fan
Background and purpose This study investigated whether the “RT-PK” phenomenon, referring to radiation therapy's effects on the pharmacokinetics of chemotherapeutic agents, occurs with cabozantinib, a multikinase inhibitor, after radiotherapy and investigated the underlying mechanisms. Method A quantitative liquid chromatography-tandem mass spectrometry method was developed for cabozantinib. Sprague–Dawley (SD) rats were irradiated with X-rays, and changes in cabozantinib distribution and concentration in the blood and excreta were monitored. The RT-PK phenomenon was confirmed, and further studies examined liver injury and alterations in primary metabolic enzymes in rats and HepG2 cells using hematoxylin and eosin staining, flow cytometry, Western blot, quantitative reverse transcription polymerase chain reaction, and serum biochemical analysis. The mRNA expression of IL6/STAT3 and PXR was also determined. Results X-ray exposure increased the area under the drug–time curve (AUC 0-t ) of cabozantinib by 3.6-fold, and excretion of the drug in the feces was 73 % lower in irradiated rats. Hematoxylin and eosin staining showed hepatocyte and interstitial edema, and serum Alanine transaminase and aspartate transaminase contents were decreased. Radiation induced redox imbalance, increased reactive oxygen species and apoptotic markers, and reduced superoxide dismutase and GSH/GSSG contents. As indicated by western blotting and RT-qPCR, the activation of the IL-6/STAT3 pathway reduced PXR expression, leading to decreased levels of CYP450 3A4, the key enzyme that metabolizes cabozantinib. Conclusions Radiation increased reactive oxygen species, activated the IL-6/STAT3 pathway, and inhibited PXR, thereby reducing CYP450 3A4 expression. These changes led to altered cabozantinib metabolism and the “RT-PK” phenomenon.
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JOURNAL OF APPLIED MICROBIOLOGY
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2024
·Vol. 135
·期 12
·
IF 3.2
Li Jian-Guo,Zhang Chuan-Jian,Liang Liu-Yan,Lu Ting-Yin,Zhong Long-Gen,Zhong Wei-Cheng,Niu Chao-Yan,Sun Jian,Liao Xiao-Ping,Zhou Yu-Feng
AimsMethicillin-resistant Staphylococcus aureus (MRSA) is an important zoonotic pathogen with multidrug-resistant phenotypes increasingly prevalent in both human and veterinary clinics. This study evaluated the potential of auranofin (AF) as an antibiotic adjuvant to enhance the anti-MRSA activity of florfenicol (FFC) and established a pharmacokinetic/pharmacodynamic (PK/PD) model to compare the efficacy of FFC alone or in combination with AF against MRSA.Methods and resultsWe observed an increased susceptibility and significant synergistic effects of MRSA to FFC in the presence of AF. The combination treatment of FFC and AF significantly inhibited MRSA biofilm formation and decreased the metabolic activity of mature biofilms. Importantly, AF fully restored the efficacy of FFC in both Galleria mellonella larvae and murine models. PK/PD studies demonstrated that the AUC24h/MIC targets required to achieve the bacteriostatic and bactericidal effects were significantly lower with the combination therapy compared to florfenicol monotherapy.ConclusionsThese results reveal the potential of AF as a novel adjuvant to improve the efficacy of FFC in treating MRSA invasive infections and provide valuable PK/PD insights for designing effective combination therapies.
研究领域:
微生物学
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药理学
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感染性疾病
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JOURNAL OF BIOLOGICAL CHEMISTRY
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2024
·
IF 4
Chengmeng Jin,Wei Hu,Yuqi Wang,Hao Wu,Siying Zeng,Minfeng Ying,Xun Hu
Most cancer cells exhibit high glycolysis rates under conditions of abundant oxygen. Maintaining a stable glycolytic rate is critical for cancer cell growth as it ensures sufficient conversion of glucose carbons to energy, biosynthesis, and redox balance. Here we deciphered the interaction between PKM2 and the thermodynamic properties of the glycolytic pathway. Knocking down or knocking out PKM2 induced a thermodynamic equilibration in the glycolytic pathway, characterized by the reciprocal changes of the Gibbs free energy (ΔG) of the reactions catalyzed by PFK1 and PK, leading to a less exergonic PFK1-catalyzed reaction and a more exergonic PK-catalyzed reaction. The changes of the ΔGs of the two reactions causes the accumulation of intermediates, including the substrate PEP (the substrate of PK), in the segment between PFK1 and PK. The increased concentration of PEP in turn increased PK activity in the glycolytic pathway. Thus, the interaction between PKM2 and the thermodynamic properties of the glycolytic pathway maintains the reciprocal relationship between PK concentration and its substrate PEP concentration, by which, PK activity in the glycolytic pathway can be stabilized and effectively counteracts the effect of PKM2 KD or KO on glycolytic rate. In line with our previous reports, this study further validates the roles of the thermodynamics of the glycolytic pathway in stabilizing glycolysis in cancer cells. Deciphering the interaction between glycolytic enzymes and the thermodynamics of the glycolytic pathway will promote a better understanding of the flux control of glycolysis in cancer cells.
研究领域:
癌症生物学
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代谢途径
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热力学
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PubMed
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VIROLOGY
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2026
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IF 2.6
Qi Liao,Yi-Ge Luo,Jing-Long Ye,Zhi-Yuan Shi,Xu-Meng Feng,Hai-Tao Lu,Hang-Yu Zhou,Junyu Wu,Zhong-Yu Liu
Multiple studies have reported that different clades or strains of Zika virus (ZIKV) replicated with varied efficiency in cell culture. However, the molecular basis of these differences remains unclear. In this study, it was first shown that the d ownstream of the 5′- c yclization s equence p seudo k not (DCS-PK) is required for efficient viral RNA (vRNA) replication of ZIKV, similar to its function in dengue virus life-cycle by using a newly developed ZIKV replicon. Interestingly, a combination of phylogenetic analysis, RNA chemical probing, and structure prediction revealed that substitutions were accumulated in the DCS-PK sequence and its structural integrity was improved during the evolutionary history of ZIKV. By using replicons of representative strains, it was demonstrated that the more stable DCS-PK from the Asian ZIKV strains was more potent in promoting vRNA replication in comparison with the less stable version found only in the early-diverged African strains. The significance of this difference was further supported by the characterization of virus mutants generated by reverse genetics approaches. MR766 mutants harboring a stabilized DCS-PK exhibited a moderate advantage over the corresponding wild type controls in replication fitness, which was detected by direct competition and reporter virus assays. Moreover, introducing a metastable DCS-PK into the Asian FSS13025 strain attenuated viral replication in multiple in vitro models, including human neural stem cells. In summary, our work pointed to a structural adaptation of DCS-PK to enhance ZIKV replication fitness, highlighting an important role of cis -acting RNA elements in natural selection and virus evolution.
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JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2026
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IF 3.4
Chun-Lu Liu,Lu-Lu Yang,Song Fan,Yan Jiang,Hui-Jun Li
An integrated strategy was established for PK-marker selection of Celosiae Semen saponins. • A total of 107 TSCS-related substances were characterized in rats. • Deglycosylation was identified as the predominant biotransformation pathway. • A dual-indicator scoring model integrating deliverability and efficacy was developed. • Celosin I was selected as the optimal PK-marker and celosin H as a complementary marker. The total saponins from Celosiae Semen (TSCS) show hepatoprotective and lipid-lowering effects against metabolic dysfunction-associated steatotic liver disease (MASLD). However, their in vivo metabolic fate and holistic pharmacokinetic (PK) features remain largely uncharacterized. In this study, an integrated PK-marker screening strategy was established by combining in vivo metabolic profiling, area under the curve (AUC)-weighted composite PK analysis, and a dual-indicator scoring model that weights both systemic exposure and in vitro lipid-lowering activity. A total of 25 saponins were characterized in TSCS by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS), and 107 TSCS-related substances (8 prototypes and 99 metabolites) were tentatively characterized in rats, with sequential deglucosylation tentatively characterized as the predominant metabolic pathway. Among the characterized saponins, five representative saponins (celosin J, H, I, K, and L) were selected for bioactivity evaluation and found to concentration-dependently reduced lipid accumulation in palmitic acid (PA)-induced HepG2 cells. Subsequently, a validated liquid chromatography coupled with triple quadrupole tandem mass spectrometry (LC-QQQ-MS/MS) method was developed for simultaneous plasma quantification of these five bioactive saponins, revealing marked exposure differences among them (AUC₀–∞: 40.95–359.05 μg·min/mL). An AUC‑weighted integration model was established to derive composite PK indices (T₁/₂ 428 min, Cₘₐₓ 1.24 μg/mL, AUC₀–∞ 215.45 μg·min/mL) that adequately reflect the holistic systemic behavior of TSCS. On the basis of systemic exposure and in vitro activity, the dual-indicator scoring model identified celosin I as the optimal PK-marker (score 0.910) and celosin H as a complementary marker (score 0.616). In a fructose-induced zebrafish MASLD model, both compounds dose-dependently reduced body length, body weight, hepatic lipid deposition, and hepatic total cholesterol (TC), triglyceride (TG), and free cholesterol (FC) levels and upregulated the expression of peroxisome proliferator-activated receptor α ( PPARα) , carnitine palmitoyltransferase 1α ( CPT-1α) , and acyl-CoA oxidase 1 ( ACOX1) , preliminarily supporting the in vivo relevance of the selected markers. This integrated strategy mitigates the limitations of single-indicator screening approaches and provides a scientific basis for the quality control and standardization of TSCS. Download: Download high-res image (255KB) Download: Download full-size image
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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
·
2024
·Vol. 68
·期 3
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IF 4.1
Xiaonan Zhang,Yan Wang,Sanwang Li,Feifan Xie,Hanxi Yi
Bacterial infections, including those caused by Pseudomonas aeruginosa, often lead to sepsis, necessitating effective antibiotic treatment like carbapenems. The key pharmacokinetic/pharmacodynamic (PK/PD) index correlated to carbapenem efficacy is the fraction time of unbound plasma concentration above the minimum inhibitory concentration (MIC) of the pathogen (%fT > MIC). While multiple targets exist, determining the most effective one for critically ill patients remains a matter of debate. This study evaluated meropenem’s bactericidal potency and its ability to combat drug resistance in Pseudomonas aeruginosa under three representative PK/PD targets: 40% fT > MIC, 100% fT > MIC, and 100% fT > 4× MIC. The hollow fiber infection model (HFIM) was constructed, validated, and subsequently inoculated with a substantial Pseudomonas aeruginosa load (1 × 108 CFU/mL). Different meropenem regimens were administered to achieve the specified PK/PD targets. At specified intervals, samples were collected from the HFIM system and subjected to centrifugation. The resulting supernatant was utilized to determine drug concentrations, while the precipitates were used to track changes in both total and drug-resistant bacterial populations over time by the spread plate method. The HFIM accurately reproduced meropenem’s pharmacokinetics in critically ill patients. All three PK/PD target groups exhibited a rapid bactericidal response within 6 h of the initial treatment. However, the 40% fT > MIC and 100% fT > MIC groups subsequently showed bacterial resurgence and resistance, whereas the 100% fT > 4× MIC group displayed sustained bactericidal activity with no evidence of drug resistance. The HFIM system revealed that maintaining 100% fT > 4× MIC offers a desirable microbiological response for critically ill patients, demonstrating strong bactericidal capacity and effective prevention of drug resistance.
研究领域:
药理学
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感染病学
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临床医学
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高影响因子
Toxics
·
2026
·Vol. 14
·期 5
·430
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IF 4.9
Haobo Qu,Xiaoyu Zhao,Yifan Wang,Sichao Mao,Xingxiang Chen,Kehe Huang,Xinyi Xu
Cadmium (Cd) is a persistent environmental pollutant that poses a significant health risk to humans and animals, with acute exposure known to induce kidney injury. Fucoidan (Fc), a natural bioactive polysaccharide derived from brown algae, exhibits diverse biological activities; however, its potential to protect against Cd-induced kidney damage and the underlying mechanisms remain unclear. In this study, we investigated the effects of Fc on Cd-induced renal injury in vitro and further explored the role of transcription factor EB (TFEB) in regulating autophagy in its protective mechanism. Our results demonstrate that in Cd-exposed porcine kidney cells (PK-15), Fc suppressed the expression of renal inflammatory factors (TNF-α, IL-1β) and kidney injury markers (NGAL, NTN-1, KIM-1), reduced reactive oxygen species (ROS) production, and downregulated apoptosis-related proteins (cleaved caspase-3 and cleaved caspase-9). Mechanistically, Fc upregulated TFEB protein expression, enhanced the levels of lysosomal function-related proteins (Cathepsin B, CTSB; Cathepsin D, CTSD), and reversed Cd-induced autophagic flux blockade. Importantly, TFEB silencing abolished the protective effects of Fc. Collectively, these findings suggest that Fc exerts renoprotective effects against Cd-induced injury by restoring autophagic flux, a process that involves TFEB.
Keywords: fucoidan; cadmium; autophagy; TFEB
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ANNALS OF CLINICAL AND LABORATORY SCIENCE
·
2017
·Vol. 47
·期 6
·676-686
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IF 0.727
Mingxiu Guan,Yingna Tong,Xiaobin Liu,Dong Dong,Yunli Zhou
Background M2 type Pyruvate kinase (PKM2) is the key rate-limiting enzyme of glycolysis, and it mainly exists as a dimer in tumor cells.This study aims to establish an enzyme kinetic assay for serum tumor M2 pyruvate kinase (TuM2-PK), and to evaluate its diagnosticvalue in breast cancer. Methods The catalytic kinetics of Pyruvate Kinase (PK) was examined. Its allosteric regulation property and Michaelis constant werethen measured. Next, the levels of TuM2-PK in serum were detected and compared with results from an enzyme-linked immunosorbentassay (ELISA). Finally, the levels of TuM2-PK among breast cancer patients, post-mastectomy patients, patients with benignbreast diseases, and healthy controls were compared. Results A PK kinetic assay was established in this study. The assay reaction time is 108 seconds, and the optimum pH level is 8.0.In the presence of the allosteric activator fructose 1, 6-bisphosphate (FBP), the Km of PK for phosphoenolpyruvate (PEP) is0.15 mmol/L and the Vmax is 330 μmol/min. The levels of TuM2-PK in serum obtained by enzyme kinetics are comparable to theELISA results. Both assays showed that TuM2-PK in breast cancer patients was increased from stage I to IV. Importantly, TuM2-PKlevels were significantly different between early and late-stage breast cancer patients (stage I and stage II vs. stage IIIand IV), as well as between late-stage and non-malignant patients (p<0.05). No statistical difference was found between benign breast disease patients and healthy controls. Conclusions An enzyme kinetic assay of serum TuM2-PK was successfully established and may be useful for breast cancer diagnosis.
研究领域:
肿瘤学
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生物化学
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癌症诊断
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酶学
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JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2023
·
IF 3.4
Jia Sun,Rong Li,Jingya Zhang,Yong Huang,Yuan Lu,Chunhua Liu,Yongjun Li,Ting Liu
Shenxiong glucose injection (SGI) containing a water extract from the roots of Danshen and Ligustrazine hydrochloride, is the main drug used for the prevention and treatment of acute myocardial ischemia (AMI) in China. Based on the characteristics of drug clinical applications, this study aims to uncover the compatibility mechanism of SGI by investigating pharmacokinetic (PK) and pharmacodynamic (PD) differences between Danshen glucose injection (DGI), Ligustrazine glucose injection (LGI) and SGI groups after multiple dosing during the pathological state from the perspective of metabolic enzymes. Compared to the LGI group, the absorption (C max ) and exposure (AUC) of ligustrazine increased significantly, and the protein expression of CYP1A2, CYP2C11 and CYP3A2 in the SGI group decreased significantly. Furthermore, the PK and PD experimental data for Danshen and ligustrazine in AMI rats were fitted to obtain a PK-PD binding model with three components. PK-PD parameter analysis showed that in the SGI group the IC50 values of ligustrazine and danshensu on AST, CK-MB, cTn-I and the IC 50 values of rosmarinic acid on AST and CK-MB were lower than the DGI or LGI group. It is speculated that Danshen inhibited CYP1A2, CYP2C11 and CYP3A2 mediating the metabolism of ligustrazine and decreased the expression of these three isozymes, which further affected the in vivo process of ligustrazine. Moreover, the combination of Danshen and ligustrazine could have better regulating effect on AST, CK-MB and cTn-I. This preliminary study has provided a scientific basis for understanding the compatibility mechanism of SGI from the viewpoint of the regulation of CYP enzymes in the PK-PD model.
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