CHROMATOGRAPHIA
·
2022
·Vol. 86
·期 2
·185-197
·
IF 2.213
Lin Xinghua,Hao Gugu,Xu Guobin,Sun Fuzhou,Xin Libo,Wu Shuming,Wang Zhongqing,You Jinsong,Huang Fangfang,Song Xuezhi
An unknown peak with a relative retention time (RRT) of 1.47 was noticed in HPLC chromatograms for related substances of mirabegron extended-release tablets. The level of this unknown peak under the accelerated stability condition for 6 months was as high as 0.19%, which had a trend to exceed the identification threshold of 0.2% from ICH Q3B. The purpose of this study was to identify the RRT 1.47 impurity, and we studied its degradation mechanism to control its content to a lower level. The structure of the RRT 1.47 impurity was identified as a mirabegron dimer bridged by methylene via LC–MS and NMR. Investigation on compatibility of drug-excipients indicated that this impurity formed by Mannich reaction between mirabegron and residual formaldehyde in excipients polyethylene glycol (PEG), polyoxyethylene (PEO). Moreover, the determination of formaldehyde content in excipients further proved this speculation. There was a linear relationship between the amount of formaldehyde and the content of generated dimer impurity within a certain range. The reaction between mirabegron and formaldehyde at different temperatures demonstrated that the higher the temperature, the faster the reaction rate and the higher level of this impurity were generated. To understand the kinetics of the reaction, we calculated the rate of dimerization and also the activation energy of the process based on the stability data. During the development of pharmaceutical formulation on mirabegron or similar structure, appropriate excipients should be selected or the formaldehyde content in excipients could be controlled to avoid such reactions to improve the quality of the product.
研究领域:
药物化学
·
制药工程
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2018
·Vol. 22
·期 5
·2774-2790
·
IF 4.302
Qiongli Su,Ting Tao,Lei Tang,Jun Deng,Kwame Oteng Darko,Sichun Zhou,Mei Peng,Shanping He,Qing Zeng,Alex F. Chen,Xiaoping Yang
Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels that are correlated with the sensitivity of anticancer chemotherapeutic drugs. THP is one of the major drugs used in non-muscle-invasive bladder cancer instillation chemotherapy. However, low response ratio of THP (19.7%) treatment to human genitourinary tumours using collagen gel matrix has been observed. This study aims to investigate the effect of down-regulation of PKM2 on THP efficiency. Via inhibitor or siRNA, the effects of reduced PKM2 on the efficiency of THP were determined in 2 human and 1 murine bladder cancer cell lines, using MTT, cologenic and fluorescence approaches. Molecular mechanisms of PKM2 on THP sensitization were explored by probing p-AMPK and p-STAT3 levels via WB. Syngeneic orthotopic bladder tumour model was applied to evaluate this efficiency in vivo, analysed by Kaplan-Meier survival curves, body and bladder weights plus immunohistochemistric tumour biomarkers. PKM2 was overexpressed in bladder cancer cells and tissues, and down-regulation of PKM2 enhanced the sensitivity of THP in vitro. Activation of AMPK is essential for THP to exert anti-bladder cancer activities. On the other hand, down-regulating PKM2 activates AMPK and inhibits STAT3, correlated with THP sensitivity. Compared with THP alone (400 μmol L −1 , 50 μL), the combination with metformin (60 mmol L −1 , 50 μL) stopped growth of bladder cancer completely in vivo (combination group VS normal group P = .078). Down-regulating the expression of PKM2 enhances the anticancer efficiency of THP. This study provides a new insight for improving the chemotherapeutic effect of THP.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Meng-Jie Tang,Yu-Tong Ye,Zhen-Zhen Li,Mi-Zhuan Li,Pan-Pan Chen,Qi-Le Zuo,Mian Li,Zhong-Xiu Chen
The effects of metformin on invertase activity and its inhibition on sucrose digestion were studied. The rapid unfolding kinetics of invertases, followed a two-state model with an inactive intermediate formation. The dynamic interaction between metformin and invertase caused the secondary structure of the enzyme to become less β-sheet, more α-helix, and random coiling oriented, which weakened the binding force between enzyme and its substrate. Metformin acted as a chaotrope and disrupted the hydrogen bonds of water, which facilitated the unfolding of invertase. However, some sugar alcohols, which promoted the H-bond formation of water, could repair the secondary structure of metformin-denatured invertase and therefore regulate the enzyme activity. This research enriches our understanding of the mechanism of enzyme unfolding induced by guanidine compounds. Moreover, because metformin and sugar substitutes are of concern to diabetes, this research also provides useful information for understanding the activity of the digestive enzyme that coexists with metformin and sugar alcohols.
研究领域:
生物化学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2016
·Vol. 40
·期 10
·8225-8228
·
IF 3.277
Ming Zeng,Tao Wang,Dong-Mei Cui,Chen Zhang
An efficient ruthenium-catalyzed synthesis of tri-substituted 1,3,5-triazines from alcohols and biguanides under mild conditions has been developed. The reaction occurred in moderate to good yields and tolerated benzyl alcohol containing functionalities such as halogens. Monosubstituted to tetrasubstituted biguanidines also afforded the desired products.
研究领域:
有机化学
·
催化反应
✓ 已验证
产品关联
DOI
高影响因子
Antibiotics-Basel
·
2022
·Vol. 11
·期 2
·162
·
IF 5.222
Xia Xiao,Quanmin Huan,Yanhu Huang,Yuan Liu,Ruichao Li,Xilan Xu,Zhiqiang Wang
Tigecycline (TIG) is one of the last effective options against multidrug resistance bacteria. Recently, the RND (resistance–nodulation–division) efflux pump gene cluster,tmexCD1-toprJ1, and the tetracycline-efflux pumptet(A) mutation were reported to mediate high level resistance to TIG in clinically important pathogens, weakening the efficacy of TIG. In this study, we report the potent synergistic effect of the antidiabetic drug metformin in combination with TIG againsttet(A) mutant andtmexCD1-toprJ1positiveK. pneumoniae. The fractional inhibitory concentration index (FICI) of TIG and metformin were less than 0.05 for all the tested isolates. The time–kill curve assay showed that the combination of TIG and metformin exhibited much better antimicrobial effect than TIG alone. The synergistic effect was also confirmed in vivo using a well-studiedGalleria mellonellalarvae model. Mechanistic studies demonstrated that metformin disrupted the important component of proton motive force, the electric potential (Δψ) and the function of efflux pump, thereby increasing the intracellular concentration of TIG. This finding revealed that metformin might be a possible adjuvant of TIG for combating with superbugs carrying thetet(A) mutant andtmexCD1-toprJ1genes.Keywords:tigcycline;metformin;tmexCD1-toprJ1;tet(A);synergy
研究领域:
微生物学
·
药理学
·
传染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Cancer
·
2022
·
IF 4.478
Kezhong Tang,Qing Chen,Yanmo Liu,Lantian Wang,Wenjie Lu
Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Sorafenib is the first small-molecule multi-kinase inhibitors approved by FDA for treatment of advanced HCC. Metformin has been demonstrated to have benefit for preventing cancer progression. In human recurrent HCCs, NF-E2-related factor 2 (Nrf2) was overexpressed and associated with poor survival. Nrf2 related signaling pathway plays central role to mediate cellular resistance to sorafenib through protecting HCC cells from ferroptosis. The effect of Combination treatment for HCC cells and the intrinsic mechanism have not been reported. In this study, metformin augmented the anti-tumor effect of sorafenib for HCC through ferroptosis induction by inhibiting Nrf2 related pathway. Based on the results of Nrf2 knockdown and p62 knockdown study, the combination of sorafenib and metformin suppressed proliferation of HCC cells through p62-Keap1-Nrf2/HO1 signaling way. Size of xenografts treated with the combination of sorafenib and metformin was smaller than other groups in vivo . Moreover, the combination treatment greatly induced ferroptosis in HCC cells through inhibiting Nrf2 expression. Based on our findings, the combination treatment suppressed proliferation of HCC cells through ferroptosis induction, by p62-Keap1-Nrf2/HO1 signaling way.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Fan Gao,Lingyun Zhu,Fan Zhang,Meng Li,Hairong Lian,Sen Feng,Xinfeng Cheng,Xianling Xiang
Metformin (MET) and its metabolite guanylurea (GUA) are prevalent in aquatic environments, raising concerns about their potential risks to aquatic organisms. However, the toxicity of these compounds through different exposure routes has not been reported. This study evaluated the effects of MET and GUA on the growth of the green algae Tetradesmus obliquus and on life table parameters of the freshwater rotifer Brachionus calyciflorus through various exposure routes, including waterborne, foodborne, and combined waterborne + foodborne. Our results indicated that both MET and GUA, at concentrations of 1 mg/L and 100 mg/L, inhibited algae growth, with GUA causing greater stress than MET. Additionally, compared to waterborne exposure, foodborne and combined waterborne + foodborne exposures of MET and GUA at these concentrations significantly decreased the net reproductive rate (R 0 ), intrinsic rate of population increase (r m ), and life expectancy (e 0 ) of B. calyciflorus . Notably, the impact of exposure routes on the life table parameters of B. calyciflorus was generally greater than the impact of exposure concentrations. Therefore, previous studies focusing solely on waterborne exposure may have underestimated the toxicity of MET and GUA.
研究领域:
环境科学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2025
·
IF 5.5
Xiaochen Wang,Dong Zhou,Jun Qin,Yuanyue Zhang,Jiale Li,Mengjie Wan,Yimin Zhu,Guang Yang
Conventional cancer treatments face significant limitations, prompting the exploration of immune combination therapies targeting immune checkpoints as a means to overcome these challenges. The PD-1/PD-L1 signaling pathway plays a crucial role in tumor proliferation and immune evasion. TPP1, a peptide inhibitor targeting PD-L1, effectively blocks this pathway and suppresses tumor growth. Metformin has been shown to inhibit cancer cell proliferation, migration, and invasion while inducing apoptosis and inhibiting the expression of PD-L1. To leverage the synergistic therapeutic effects of TPP-1 and metformin, we designed and constructed a peptide–small molecule drug delivery system using tumor cell membranes. First, nanoscale tumor cell membrane vesicles were prepared via hypotonic ultrafiltration and coupled with the TPP1 peptide through co-incubation to form TPP1–cell membrane complexes. Simultaneously, mesoporous silica nanomaterials were synthesized and loaded with metformin by using the sol–gel method. Finally, the two components were mixed and sonicated to create the final drug delivery system. Both in vitro and in vivo experimental results demonstrated that this tumor cell membrane-based drug delivery system significantly prolonged the half-life of TPP1, maintained its ability to activate T cells and promote IFN-γ secretion, and effectively inhibited tumor growth. Our constructed nanodelivery system could provide a promising therapeutic platform for co-delivery of peptides and small-molecule inhibitors in cancer therapy.
研究领域:
生物医学工程
·
肿瘤学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Fan Gao,Hao Wen,Sen Feng,Meng Li,Lingyun Zhu,Yongzhi Zhang,Yilong Xi,Xianling Xiang
The emerging contaminants metformin (MET) and its degradation product guanylurea (GUA) are released into aquatic environments through wastewater treatment plants (WWTPs). Thus, the environmental risks of wastewater with more treatments may be underestimated due to the lower effect concentration of GUA and the higher detected concentration of GUA in treated wastewater in comparison with MET. In this study, we aimed to investigate the combined toxicity mode of MET and GUA to Brachionus calyciflorus by simulating the degrees of wastewater treatments through adjustments to the ratio of MET and GUA in medium. The results showed that the 24 h-LC 50 of MET, GUA, their mixtures of equal concentrations and the mixtures of equal toxic units to B. calyciflorus were 907.44, 544.53, 1185.82 and 940.52 mg/L, respectively, demonstrating GUA is significantly more toxic than MET. An antagonistic interaction between MET and GUA was found in mixture toxicity assessments. Compared with the control, MET treatments only significantly affected the intrinsic rate of population increase of rotifers (r m ), while all life-table parameters were significantly affected by GUA. In addition, at medium and high concentrations (120 and 600 μmol/L), the net reproductive rate (R 0 ) and r m of rotifers under GUA were significantly lower than those under MET. Notably, increased proportion of GUA relative to MET in binary-mixture treatments resulted in increased survival risk and reduced fecundity of rotifers. Moreover, the responses of population dynamics to exposures of MET and GUA were mainly attributed to the reproduction of rotifer, indicating that an improved wastewater treatment process is necessary to protect aquatic ecosystems . The study highlights the importance of considering the combined toxicity of emerging contaminants and degradation product in environmental risk assessment , especially the unintentional transformations of parent compound in treated wastewater.
研究领域:
环境科学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2020
·
IF 2.971
Xuemei Liu,Deliang Liu,Youyou Shuai,Huilin Li,Hengxia Zhao,Xin Qu,Shufang Chu,Xuewen Zhang
Context HuoxueJiangtang decoction (ZY) is a traditional Chinese medicine for the treatment of diabetes.Objective The protective effect of ZY on renal injury in diabetic nephropathy rats was investigated in this study.Materials and methods Fifty 4-week-old SPF Wistar male rats were selected to construct diabetic nephropathy model rats (DN) group by continuous high-fat feeding for 4 weeks, followed by a tail vein injection of 30 mg/kg streptozotocin for 1 week. The experimental rats were divided into six groups of 10 rats: normal (control), DN, DN + ZY, DN + metformin, DN + metformin + ZY, and DN + metformin + captopril (positive control) groups. Among the groups, 6.25 g/kg ZY, 250 mg/kg metformin, and 17.5 mg/kg captopril were given to the rats by gavage once a day for 16 weeks. Blood glucose, dietary behaviour, biochemical indicators, and gene expression changes were measured in each group.Results Metformin + ZY treatment significantly lowered blood glucose, water intake, urine total protein, urine albumin, urine volume, serum triglyceride, and serum cholesterol levels in the DN group. The pathological changes of kidney tissue showed that the DN + metformin + ZY group had a protective effect on kidney tissue damage. And ZY and metformin + ZY treatments repaired the expression of genes in the DN group.Discussion and conclusion The ZY and metformin combined treatment showed a clear therapeutic effect on kidney damage in DN. This study provides a potential mechanism for the treatment of diabetic nephropathy with ZY combined with metformin.
研究领域:
中医药学
·
糖尿病研究
·
肾脏病学
✓ 已验证
DOI
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2025
·
IF 5.6
Yan Li,Sedrati Manar,Xinxiang Chai,Yanzhen Lou,Guohua Jiang
Microneedle technology has emerged as a potential new means of painless drug delivery for diabetic patients. Maintaining blood glucose levels (BGLs) within the normal range for a long time is important for people with diabetes. However, it is a new challenge to realize long-term therapy due to insufficient drug loading. In this study, a polymeric porous microneedle array with continuous micropores was prepared by combining the microtemplate method and pore-causing agent method. By changing the ratio of a pore-causing agent, the fluid uptake capacity and mechanical strength were adjusted to balance the trade-off between rapid imbibition and the mechanical properties of puncture. A special drug loading chamber was developed to realize a large package (135.69 mg) of metformin-loaded porous microneedle system. Experiments in diabetic rat models in vivo showed that the prepared porous microneedles can effectively puncture the skin and maintain stable BGLs up to 7 h × 5 cycles over five experimental cycles (108 h) without the risk of hypoglycemia. These results suggested that the high-dose polymeric porous microneedle-mediated metformin delivery system had the advantages of rapid response and durable release, and was a potential candidate for sustained-release transdermal drug delivery in patients with diabetes mellitus and even chronic conditions.
研究领域:
生物医学工程
·
药剂学
·
材料科学
·
内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Functional Biomaterials
·
2024
·Vol. 15
·期 12
·388
·
IF 5
Siwei Sun,Xinyi Hou,Ke Li,Chenqi Huang,Yu Rong,Jiao Bi,Xueping Li,Daocheng Wu
Metformin (Met) is one of the most commonly prescribed first-line drugs for diabetes treatment. However, it has several issues, including low bioavailability, therapeutic platform, and side effects at high doses. In order to improve the therapeutic efficiency of Met, this study proposes a strategy of using Met and curcumin (Cur) to prepare Cur-Zn(II)-Met infinite coordination polymer nanoparticles (CM ICP NPs), and combining this with intraperitoneal injections, for the treatment of diabetic mice. Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), nanoparticle analysis, cytotoxicity experiments, and mice experiments were used to investigate structure, properties, and application effects. The results showed that CM ICP NPs exhibit a high drug encapsulation rate (100%), good stability, and an absence of in vivo and in vitro toxicity. The blood glucose level of diabetic mice after treatment was reduced to 6.7 ± 0.65 mmol/L at the seventh week. In terms of therapeutic mechanism, it appears that Met and Cur can synergistically regulate blood glucose in mice from multiple paths. This study provides a promising method for the treatment of diabetes using Met and other drugs.
研究领域:
药理学
·
生物医学工程
·
代谢疾病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）