International Journal of Pharmaceutics-X
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2024
·
IF 5.2
Liangxing Tu,Ping Han,Yongbing Sun,Yi Jin,Kaili Hu,Meng Cheng,Yisen Shao,Jianfang Feng,Fangying Yuan
Many researchers have studied the oral absorption mechanisms yet, however, considering stabilizers often participate in the absorption process of nanocrystals, these known mechanisms may be incorrect. Hence in this study, we aimed to explore the correct absorption mechanism of nanocrystals by performing related studies on stabilizer-free nanocrystals. We firstly prepared stabilizer-free silymarin nanocrystals by high-pressure homogenization, and then performed absorption-related studies, such as solubility, dissolution rate, pharmacokinetic study, cellular uptake and intracellular transport. Results showed the stabilizer-free silymarin nanocrystals had an average particle size of (450.2 ± 4.46) nm, with PDI of 0.280 ± 0.021 and Zeta potential of −26.9 ± 2.4 mV. The conversion of silymarin crude drug to stabilizer-free silymarin nanocrystals increased the compound's solubility by 1.41 times, with a dissolution rate of 92.2 % in water within 30 min compared to 38.5 % for crude drugs. Pharmacokinetic studies showed the oral bioavailability of stabilizer-free silymarin nanocrystals was found to be 1.48 times greater than that of the crude drugs. The cell experimentation results demonstrated that the stabilizer-silymarin nanocrystals can improve uptake but have poor transmembrane transport properties. Most researchers believe that nanocrystals can enhance transmembrane transport of drugs via an endocytosis-mediated pathway. In fact, nanocrystals are indeed endocytosed more by the cells, but this transport pathway is poor because the cells lack the intracellular transport pathway to transport nanocrystals from the AP side to the BP side. Therefore, we believe that the intracellular transport of nanocrystals can be enhanced by modifications and other carriers if needed to improve nanocrystals' ability to promote oral absorption.
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DRUG DELIVERY
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2023
·
IF 6
Lan Tang,Kaijuan Huang,Wenhui Jiang,Lulu Fu,Ran Zhang,Liting Shen,Zhimin Ou,Ye Huang,Zhenhai Zhang
D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a commonly used nonionic surfactant used as a pharmaceutical carrier in different drug delivery systems. TPGS can reverse P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) and also has anticancer activities. It suggests that when designing antitumor drug preparation, it’s necessary to take into account the antitumor activity of TPGS. Our in vivo studies showed that TPGS exerted the strongest cytotoxicity in MCF-7-ADR cells when compared with seven other tumor cell lines. The further study revealed TPGS caused apoptosis and blocked MCF-7 cell growth in G2/M phase. Mechanistic insights suggested that TPGS increased intracellular calcium ion concentrations, leading to apoptosis via the mitochondrial pathway. Furthermore, two in vivo experiments were performed. One was TPGS, and DOX solution was administered by tail vein injection on MCF-7-ADR tumor bearing nude mice. The other was temperature sensitive TPGS gel (TPGS-TG) was administered by intratumoral injection on MCF-7-ADR tumor bearing nude mice combined with paclitaxel albumin nanoparticles (Abraxane®) administered by tail vein injection. The findings confirmed that TPGS could play its role in anti-tumor to reduce the toxicity of chemotherapeutic drugs and improve the efficiency of drug-resistant tumors, thereby enhancing the development of safe oncology therapeutics.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
·
IF 6.1
Yu Wang,Yao Yu,Yi-Ping Hou,Xue-Wei Mao,Zong-Liang Liu,Jian Cui,Bi Wang,Shu Xu,Yi-Yun Qian,Yan-Qin Jiang,Min Wei,Ping-Ping Song
Botrytis cinerea causes gray mold in many fruit and vegetable crops. We previously found that Seselin (SL) displayed antifungal activity against B. cinerea (EC50 = 6.1 μg·mL–1), and this study investigated the effects of Ca2+ and the Ca2+/CN signaling pathway on its antifungal activity against B. cinerea. The results indicated that exogenous Ca2+, Cyclosporine A, and Verapamil reduced the sensitivity of SL against B. cinerea; SL significantly reduced the intracellular Ca2+ concentration in the hyphae; the sensitivity of strains ΔbcCCH1 and ΔbcMID1 to SL were significantly increased; and the expressions of CCH1, MID1, CNA, PMC1, and PMR1 genes of the Ca2+/CN signaling pathway were significantly downregulated by SL treatment. Hence, SL is a potential compound for developing fungicides against B. cinerea. SL dramatically reduces intracellular Ca2+ concentration and disturbs Ca2+ homeostasis, leading to cell death. The Ca2+/CN signaling pathway plays an important role in the antifungal activity of SL against B. cinerea.
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ANALYTICAL CHEMISTRY
·
2021
·
IF 6.986
Bin Jiao,Huimin Ye,Xinwei Liu,Jiexun Bu,Junhan Wu,Wenpeng Zhang,Yunfeng Zhang,Zheng Ouyang
The development of miniature mass spectrometry (MS) systems with simple analysis procedures is important for the transition of applying MS analysis outside traditional analytical laboratories. Here, we present Mini 14, a handheld MS instrument with disposable sample cartridges designed based on the ambient ionization concept for intrasurgical tissue analysis and surface analysis. The instrumentation architecture consists of a single-stage vacuum chamber with a discontinuous atmospheric interface and a linear ion trap. A major effort in this study for technical advancement is on making handheld MS systems capable of automatically adapting to complex conditions for in-field analysis. Machine learning is used to establish the model for autocorrecting the mass offsets in the mass scale due to temperature variations and a new strategy is developed to extend the dynamic concentration range for analysis. Mini 14 weighs 12 kg and can operate on battery power for more than 3 h. The mass range exceeds m/z 2000, and the full peak width at half-maximum is Δm/z 0.4 at a scanning speed of 700 Th/s. The direct analysis of human brain tissue for identifying glioma associated with isocitrate dehydrogenase mutations has been achieved and a limit of detection of 5 ng/mL has been obtained for analyzing illicit drugs in blood.
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CHEMICAL & PHARMACEUTICAL BULLETIN
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2021
·Vol. 69
·期 11
·1054-1060
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IF 1.645
Yuqin Zhou,Weitong Hu,Xiangli Zhang,Yi Wang,Wenya Zhuang,Fengzhi Li,Qingyong Li
In the evaluation of the druggability of candidate compounds, it was vital to predict the oral bioavailability of compounds from apparent permeability (Papp) across Caco-2 cell-culture model of intestinal epithelium cultured on commercial transwell plate inserts. The study was to investigate the transport characteristics and permeability of FL118 (10, 11-Methylenedioxy-20(S)-camptothecin) derivatives 7-Q6 (7-(4-Ethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin) and 7-Q20 (7-(4-Trifluoromethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin). Transport characteristics and permeability of the tested compounds to the small intestine were assessed at different concentrations (0.5, 1 µM) via Caco-2 cell monolayers model in vitro. Uptake studies based on Caco-2 cells, including temperatures, concentrations, and the influence of efflux transporters, were combined to confirm the transport characteristics of the tested compounds. Furthermore, cytotoxicity results showed that the concentrations used in the experiments were non-toxic and harmless to cells. In addition, The Papp of 7-Q6 was (3.69 ± 1.07) × 10−6 cm/s with efflux ratio (ER) 0.98, while the Papp of 7-Q20 was (7.78 ± 0.89) × 10−6 cm/s with ER 1.05 for apical-to-basolateral (AP→BL) at 0.5 µM, suggesting that 7-Q20 might possess higher oral bioavailability in vivo. Furthermore, P-glycoprotein (P-gp) was proved to slightly affect the accumulations of 7-Q20, while the absorption of 7-Q6 was irrelevant with P-gp and breast cancer resistant protein (BCRP) based on the cellular uptake assays. Accordingly, 7-Q6 was completely absorbed by passive diffusion, and 7-Q20 was mainly dependent on passive diffusion with being effluxed by P-gp slightly. Meanwhile, both 7-Q6 and 7-Q20 were potential antitumor drugs that might exhibit high oral bioavailability in the body.
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JOURNAL OF NATURAL PRODUCTS
·
2017
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IF 3.281
Jie Gao,Haji A. Aisa
Ten new terpenoids, including five diterpenoids (1–5), three nortriterpenoids (6–8), and two triterpenoids (9, 10), and 15 known terpenoids (11–25) were isolated from an acetone extract of Euphorbia soongarica. Sooneuphoramine (1) is the first example of a euphoractine B-type diterpenoid alkaloid, while sooneuphanones A–C (6–8) are rare nortriterpenoids from the Euphorbia genus. The isolated terpenoids were tested for their cytotoxicity and multidrug resistance (MDR) reversal activity, 10 of which showed moderate cytotoxicity against the KB and KBv200 cell lines, while 11 compounds exhibited P-gp modulating potential. The triterpenoid sooneuphanone D (9) possessed a remarkable MDR reversal activity much higher than the positive control, verapamil.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2023
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IF 5.8
Jie Huang,Xiao Tang,Ziqiong Yang,Jianqiu Chen,Kun Wang,Chengnan Shi,Zihan Liu,Ming Wu,Qian Du
Irinotecan (CPT-11) is used as a first or second-line chemotherapy drug for the treatment and management of colorectal cancers. In vitro studies have shown that 7-ethyl-10-hydroxycamptothecin (SN38), the active metabolite of CPT-11, displays promising anticancer efficacy. However, its poor aqueous solubility and hydrolytic degradation result in its lower oral bioavailability and impracticable clinical application. To overcome these limitations, a novel amphiphilic chitosan derivative, deoxycholic acid decorated N’-nonyl-trimethyl chitosan, was synthesized. Nano-micelles loaded with SN38 were subsequently prepared to enhance the bioavailability and anti-tumor efficacy of the drug through oral administration. The nano-micelles demonstrated improved dilution stability, enhanced greater mucosal adherence, significant P-gp efflux inhibition, and increased drug transport in the intestine by paracellular and transcellular pathways. Consequently, both the in vivo pharmacokinetic profile and therapeutic efficacy of SN38 against cancer were substantially improved via the micellar system . Thus, the developed polymeric micelles can potentially enhance the SN38 oral absorption for cancer therapy, offering prospective avenues for further exploration.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2021
·
IF 5.875
Xiaoyu Lu,Hangyi Wu,Yiping Liang,Zhenhai Zhang,HuiXia Lv
Most anticancer drugs are not orally bioavailable due to their undesirable physicochemical properties and inherent physiological barriers. In this study, a polymeric prodrug strategy was presented to enhance the oral bioavailability of BCS class IV drugs using paclitaxel (PTX) as the model drug. PTX was covalently conjugated with cholic acid-functionalized PEG by a redox-sensitive disulfide bond . Cholic acid-functionalized PEGylated PTX (CPP) achieved remarkably improved PTX solubility (>30,000-fold), as well as favorable stability under the physiological environment and controlled drug release in the tumor. Meanwhile, CPP could self-assemble into nanoparticles with an average size of 56.18 ± 2.06 nm and drug loading up to 17.6% (w/w). Then, permeability study on Caco-2 cell monolayers demonstrated that CPP obtained an approximately 4-fold increase by apical sodium-dependent bile acid transporter (ASBT) mediated transport, compared with Taxol®. Pharmacokinetic studies carried out in rats confirmed that the oral bioavailability of CPP was 10-fold higher than that of Taxol®. Finally, significant improvement in the antitumor efficacy of CPP against breast cancer was confirmed on MDA-MB-231 cells. In summary, this prodrug-based cascade strategy offers new ways for chemotherapeutic drugs whose oral delivery is limited by solubility and permeability, also endows drugs with the capacity of tumor-specific release.
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Frontiers in Pharmacology
·
2021
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IF 5.811
Li Sinai,Liu Hongxu,Li Yue,Qin Xiaomei,Li Mengjie,Shang Juju,Xing Wenlong,Gong Yanbing,Liu Weihong,Zhou Mingxue
Background: Heart failure (HF) is the end stage of ischemic cardiovascular diseases; nonetheless, safe and effective therapeutic agents for HF are still lacking, and their discovery remains challenging. Our previous studies demonstrated that Shen-Yuan-Dan Capsule (SYDC), a hospital preparation of traditional Chinese herbal, effectively protected ischemic injury in cardiovascular diseases. However, its therapeutic effects and possible mechanisms on HF remain unclear.Methods: A zebrafish HF model treated with verapamil was developed to assess the therapeutic effect of SYDC on HF zebrafish. Zebrafish were administered with SYDC and digoxin (positive control) by direct soaking. After drug treatment, zebrafish were randomly assigned to the visual observation and image acquisition using a Zebralab Blood Flow System. The reactive oxygen species (ROS), MDA, and SOD levels were determined by fluorescence signal detection, TBA, and WST-8 methods. RT-PCR determined the mRNA expressions of Caspase-3, Caspase-1, Bcl-2, Bax, IL-1β, NF-κB, and TNF-α.Results: SYDC significantly inhibited the levels of heart dilatation and venous congestion and markedly increased the levels of cardiac output, blood flow dynamics, and heart rates in HF zebrafish (p < 0.05, p < 0.01, and p < 0.001). Moreover, SYDC also significantly decreased the levels of MDA and ROS and increased the level of SOD in HF zebrafish. The RT-PCR results revealed that SYDC decreased the expression of Caspase-1, Caspase-3, Bax, IL-1β, NF-κB, and TNF-α but increased the expression of Bcl-2 in HF zebrafish (p < 0.05, p < 0.01, and p < 0.001).Conclusions: SYDC improved the heart function in verapamil-induced HF zebrafish and alleviated inflammation and apoptosis by inhibiting the ROS-mediated NF-κB pathway.
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JOURNAL OF SEPARATION SCIENCE
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2020
·Vol. 43
·期 11
·2105-2114
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IF 2.878
Can Wu,Nani Wang,Pingcui Xu,Xuping Wang,Dan Shou,Yan Zhu
Cell membrane chromatography is a powerful tool for screening active components from complex matrices. New cell membrane carriers need to be developed to increase the coverage of cell membranes on the surface of stationary phases, thereby improving cell membrane chromatographic retention. In this work, we prepared polyvinyl alcohol-poly dimethyl diallyl ammonium chloride modified silica gel as a cell membrane carrier. Osteoblast cell was used as cell membrane source, which was widely used to evaluate the osteogenic activity of drugs. The new cell membrane chromatographic stationary phase was used to screen anti-osteoporosis components in Liuwei Dihuang decoction-containing serum. The chemical structures of the new modified materials were characterized by scanning electronic microscopy, Fourier transform infrared spectroscopy, and elemental analysis characterization. Compared with the common cell membrane column, the cell membrane coverage of this modified material was increased by 30%, and thus provided a stronger retention effect in positive drugs. Nineteen metabolites in rat serum samples were retained on the cell membrane chromatography and identified by ultra-high-performance liquid chromatography/time-of-flight mass spectrometry. Among those, four components (morroniside, catalpol, loganin, and acteoside) were selected for in vitro pharmacodynamics validation. They significantly increased the osteoblast proliferation. The new modified material was successfully applied to screen anti-osteoporosis components from Liuwei Dihuang Decoction-containing serum.
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ONCOLOGY REPORTS
·
2020
·Vol. 44
·期 3
·927-938
·
IF 3.417
Songhui Zhou,Ruicheng Wang,Hong Xiao
The resistance of cancer cells to carboplatin restricts their efficacy in the clinical setting, and a solution to reverse the resistance is urgently required for the treatment of ovarian cancer. An increasing number of studies have found associations between obesity and the incidence, and mortality rates of female cancer. However, the association between adipocytes and the resistance of ovarian cancer has rarely been reported. Based on this, the present study first revealed the inductive effect of adipocytes on the resistance of ovarian cancer to carboplatin using in vivo and in vitro experiments. Subsequently, it was identified that the angiopoietin‑like 4 (ANGPTL4) secreted by adipocytes played a vital role in the resistance of ovarian cancer using bioinformatics analysis, cellular and molecular biological experiments, as well as forward and backward validation. The glycosylated ANGPTL4 protein could bind with integrin α5β1 on the surface of ovarian cancer cells; following which, it could activate the c‑myc/NF‑κB pathway and stimulate the expression of the antiapoptotic protein Bcl‑xL, as well as the ABC transporter family members ABCB1, ABCC1 and ABCG2. Thus, inducing the resistance of ovarian cancer to carboplatin. In conclusion, targeting the adipocyte‑derived ANGPTL4 combined with the application of carboplatin contributes to the clinical treatment for ovarian cancer.
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Insects
·
2020
·Vol. 11
·期 5
·280
·
IF 2.22
Zhao Li,Tingwei Cai,Yao Qin,Yunhua Zhang,Ruoheng Jin,Kaikai Mao,Xun Liao,Hu Wan,Jianhong Li
The ATP-binding cassette (ABC) transporter superfamily is one of the largest groups of proteins and plays a non-negligible role in phase III of the detoxification process, which is highly involved in the response of insects to environmental stress (plant secondary metabolites and insecticides). In the present study, inNilaparvata lugens, we identified 32 ABC transporters, which are grouped into eight subfamilies (ABCA–H) based on phylogenetic analysis. The temporal and spatial expression profiles suggested that the nymphal stages (1st–5th) and adult males showed similarity, which was different from eggs and adult females, andNlABCA1,NlABCA2,NlABCB6,NlABCD2,NlABCG4,NlABCG12,NlABCG15, andNlABCH1were highly expressed in the midgut and Malpighian tubules. In addition,ABCG12, which belongs to the ABC transporter G subfamily, was significantly upregulated after exposure to sulfoxaflor, nitenpyram, clothianidin, etofenprox, chlorpyrifos, and isoprocarb. Moreover, verapamil significantly increased the sensitivity ofN. lugensto nitenpyram, clothianidin, etofenprox, chlorpyrifos, and isoprocarb. These results provide a basis for further research on ABC transporters involved in detoxification inN. lugens, and for a more comprehensive understanding of the response ofN. lugensto environmental stress.Keywords:ABC transporters;detoxification;Nilaparvata lugens;insecticides
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