Pharmaceutics
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2022
·Vol. 14
·期 9
·1937
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IF 6.525
Chenghua Song,Ruichao Wen,Jiaxuan Zhou,Xiaoyan Zeng,Zi Kou,Jia Zhang,Tao Wang,Pengkang Chang,Yi Lv,Rongqian Wu
The increasing resistance of human pathogens promotes the development of novel antimicrobial agents. Due to the physical bactericidal mechanism of membrane disruption, antimicrobial peptides are considered as potential therapeutic candidates without inducing microbial resistance. Scorpion venom-derived peptide,Androctonus amoreuxiAntimicrobial Peptide 1 (AamAP1), has been proved to have broad-spectrum antimicrobial properties. However, AamAP1 can induce hemolysis and shows strong toxicity against mammalian cells. Herein, the antimicrobial activity and mechanism of a novel synthetic antimicrobial peptide, GK-19, derived from AamAP1 and its derivatives, was evaluated. Five bacteria and three fungi were used to evaluate the antimicrobial effects of GK-19 in vitro. Scalded mice models combined with skin and soft tissue infections (SSTIs) were used to evaluate its applicability. The results indicated that GK-19 could not only inhibit Gram-positive and Gram-negative bacterial growth, but also kill fungi by disrupting the microbial cell membrane. Meanwhile, GK-19 showed negligible toxicity to mammalian cells, low hemolytic activity and high stability in plasma. Furthermore, in scalded mice models combined with SSTIs induced by either Methicillin-ResistantStaphylococcus aureus(MRSA) orCandida albicans, GK-19 showed significant antimicrobial and healing effects. Overall, it was demonstrated that GK-19 might be a promising drug candidate in the battle against drug-resistant bacterial and fungal infections.Keywords:antimicrobial peptides;GK-19;skin and soft tissue infections;MRSA;Candida albicans
研究领域:
微生物学
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药理学
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传染病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Haowei Liang,Ruiqin Zhang,Li Zhou,Xiaolong Wu,Jingan Chen,Xinyue Li,Jieqiong Chen,Letian Shan,Hui Wang
Ethnopharmacological relevance Corn stigma (CS), derived from the stigma and style of gramineous plant Zea mays . The medicinal use of CS can be traced back to Dian Nan Materia Medica . Lingnan Medicinal Plants Compendium records its effectiveness in ameliorating diabetes. Diabetes is a metabolic disorder characterized by hyperglycemia and the consequent chronic complications of kidney, heart, brain and other organs, which pose a significant threat to human health. CS has shown great potential in relieving hyperglycemia associated with diabetes. However, the mechanism of CS in treating diabetes remains unclear. Aim of the study To explore the pathogenesis of diabetes and the mechanism of CS improving hyperglycemia in diabetes. Materials and methods We measured apigenin and luteolin contents in CS by UPLC/MS/MS method. Selecting Wistar rats as normal group, and GK rats as model group. For rats, we detected glucose and lipid metabolism indicators, including GHb, AST, ALT, U-Glu, UA, U-TP, U-ALB, and ACR after treatment. For zebrafish, we utilized alloxan and sucrose to establish the diabetes model. Measuring zebrafish blood glucose is employed to evaluate the hypoglycemic capability of CS. In order to explore the mechanism of CS in treating diabetes, we sequenced the transcriptome of zebrafish, compared differentially expressed genes of normal, diabetic, and CS-treated group, and validated multiple enrichment pathways by PCR. Results CS can improve blood glucose levels in both GK rats and diabetic zebrafish. For rats, CS partially restored glucose and lipid metabolism indicators. Transcriptome data from zebrafish showed a close correlation with steroid biosynthesis. The RNA-Sequencing was consistent with PCR results, indicating that CS downregulated gene ( fdft1, lss, cyp51 ) expression concerned with steroid biosynthesis pathway in the diabetes model. Conclusion CS effectively improved blood glucose levels, regulated glucose and lipid metabolism by suppressing gene expression in steroid biosynthesis pathway, and ameliorated hyperglycemia. Our research provides valuable insights for CS in the treatment of diabetes, and proposes a new strategy for selecting clinical medications for diabetes.
研究领域:
民族药理学
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代谢生物学
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分子医学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Zhijian Lu,Junqing Zhao,Wei Xiao,Zhujun Wang,Qi Ren,Xiaofang Huang,Hui Ouyang,Yulin Feng
Ethnopharmacological relevance N-[2-(1-β-D-Glucopyranosyl-1H-indol-3-yl)acetyl]-L-aspartic acid (GK-A), N-[2-(1-β-D-Glucopyranosyl-1H-indol-3-yl)acetyl]-L-glutamic acid (GK-2) and Eucomic acid are the main active components of Ginkgo Semen , which have strong antitussive effects. However, the pharmacokinetics, tissue distribution, metabolism, and in vitro liver microsome stability of these components in rats remain unstudied. Aim of the study Comprehensive evaluation of the pharmacokinetics, tissue distribution, in vitro liver microsomal stability, and in vivo metabolic behavior of GK-A, GK-2, and Eucomic acid in Ginkgo Semen extract (GSE). Materials and methods A very rapid and highly sensitive LC-MS/MS approach was established to study the pharmacokinetics of orally administered GSE (80 mg/kg) and quantify GK-A, GK-2, and Eucomic acid in various tissues. DESI-MSI was utilized to clearly visualize the spatial distribution of GK-A, GK-2, and Eucomic acid in lung tissue, while UPLC-Q-TOF-MS analyzed the metabolic profiles of GK-A, GK-2, and Eucomic acid in rat plasma and excreta. Results GK-A, GK-2, and Eucomic acid reached T max within 2 h, with MRT 0-t under 4 h following oral GSE administration. GK-A and GK-2 were present in all tissues except the brain, while Eucomic acid was also detected in brain tissue. All three compounds showed high concentrations in the small intestine, kidneys, stomach, and liver. They were metabolized slowly and poorly in liver microsomes from cynomolgus monkeys, rats, dogs, and humans. In total, 14 GK-A metabolites, 8 GK-2 metabolites, and 8 Eucomic acid metabolites were identified in plasma, urine, and feces. Conclusions GK-A, GK-2 and Eucomic acid were all rapidly absorbed by plasma and widely distributed in tissues after oral administration of GSE. There was no accumulation of GK-A, GK-2 and Eucomic acid in the tissues, and the content in the small intestine, kidney, stomach and liver was higher. And Eucomic acid was able to cross the blood-brain barrier, and CYP450 enzyme in the liver was not the main metabolizing enzyme of the extract. GK-A, GK-2 and Eucomic acid were excreted in the feces and urine of the rats, and at the same time, were converted into other metabolites by the rats to be eliminated from the body. The results of this study lay a foundation for the further development and application of GSE.
研究领域:
药理学
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分析化学
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天然产物研究
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民族药理学
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药物代谢
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生物分析化学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2025
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IF 4.8
Lihua Yang,Hang Zhai,Tingting Tian,Botong Liu,Xianpu Ni,Huanzhang Xia*
Background: Aminoglycosides (AGs) are one of the initial classes of antibiotics that have been used clinically and possess broad spectrum of activity. Nevertheless, their clinical utilization is restricted by safety issues associated with nephrotoxicity and ototoxicity.Methods: Glycosyltransferase (GT) KanM2 was introduced into M. echinospora to produce the gentamicin derivatives, in which a kanosamine sugar ring was introduced to replace the garosamine. The premature termination codon (PTC) readthrough activity of genkamicins (GKs) was compared using dual luciferase reporter assay. The toxicity of GK was assessed in vitro in HEK-293 and NCI-H1299 cells and determined based on cell viability calculated after 48 h of treatment with different concentrations of the compounds. The NCI-H1299 cells harbouring the R213X nonsense mutation were treated with different concentrations of the derivatives to compare their expression of p53 proteins. The expression of p53 and its downstream targets p21 and BAX was detected using Western blotting and qRT-PCR in NCI-H1299 cells containing the R213X nonsense mutation treated with different concentrations of GK-Ae and G418. Finally, immunofluorescence and flow cytometry were used to determine the subcellular localization of full-length p53 protein induced by GK-Ae treatment and its effect on apoptosis in cancer cells.Results: Eight gentamicin derivatives were obtained in this study. GK-Ae displayed similar PTC readthrough activity and reduced toxicity compared to natural aminoglycoside G418. Moreover, GK-Ae increased the levels of both p53 and its downstream targets p21 and BAX, and promoted apoptosis of cancer cells.Conclusion: These results demonstrate the potential of combinatorial biosynthesis to increase the diversity of structures of AGs and provide directions for the development of new AGs with low toxicity and high PTC readthrough activity.
研究领域:
药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MATERIALS & DESIGN
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2022
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IF 9.417
Yuqin Yang,Desheng Cai,Yisong Shu,Zhihua Yuan,Wenmin Pi,Yaozhi Zhang,Jihui Lu,Jingyi Jiao,Xuehao Cheng,Feifei Li,Penglong Wang,Haimin Lei
It is crucial to inhibit tumor growth and distant metastasis for breast cancer (BC) therapy. However, the treatment primarily dependent on surgery, chemotherapy, and radiotherapy is far from satisfactory. It had been demonstrated that the CXCL1/2-S100A8/9 axis played an essential role in BC therapy. Therefore, we constructed a natural product hydrogel for BC therapy by blocking CXCL1 signaling. The GK-GA (phytochemicals of Genkwa Flos -glycyrrhizic acid) hydrogel was designed in a one-step “green” approach. The pharmacodynamics study showed GK-GA exhibited significant anti-tumor and anti-lung metastasis activities, resulting in the inhibition rate of tumor growth (IRG) over 90 % at 6.25 mg·kg −1 , and did not display any obvious toxicity. In addition, the potent antitumor efficiency was also attributed to aggregation/assembly-induced retention (AIR) property. RNA sequencing analysis revealed the gene expression was significantly down-regulated in the GK-GA group, which were BCL2, CASP3, CXCL1, CXCL2, CXCR2, S100A8, S100A9, and confirmed further by western blot (WB). Our findings indicated natural product GK-GA hydrogel inhibited tumor growth and lung metastasis via the BCL2-CASP3 mitochondrial apoptosis pathway as well as the CXCL1/2-S100A8/9 pathway. This study provides inspiration for the fabrication of new excipients-free nano-dispersion in a one-step, no‐carrier‐added, organic solvent-free, “green” approach, particularly for small molecular antitumor agents.
研究领域:
肿瘤学
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药学
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分子生物学
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癌症治疗
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产品关联
DOI
高影响因子
Frontiers in Pharmacology
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2022
·
IF 5.988
Sa Yang,Shijie Cao,Congyu Li,Jichao Zhang,Chang Liu,Feng Qiu,Ning Kang
Non-alcoholic fatty liver disease (NAFLD) is a major public health problem in many countries. Berberine (BBR) is an effective therapeutic agent in alleviating NAFLD. Berberrubine (BRB) is one of the main active metabolites of BBR, which shows significant anti-obesity and antihypoglycemic effects. However, whether BRB is responsible for the in vivo therapeutic effect and the underlying mechanism of BRB on NAFLD have not been elucidated. In this study, the ability of BRB to ameliorate NAFLD, together with its molecular mechanism, was investigated. The results showed that BRB treatments could significantly improve hepatic steatosis and insulin resistance in high-fat diet (HFD)-fed mice and oleic acid (OA)-treated HepG2 cells. Meanwhile, BBR and BRB treatment similarly prevented lipid accumulation by regulating the protein expression of ATGL, GK, PPARα, CPT-1, ACC1, FAS, and CD36. In addition, compared with BBR, BRB could maintain glucose homeostasis via GLUT2, GSK3β, and G6Pase in HFD-fed mice. Furthermore, the components of the gut microbiota in mice were analyzed by 16S rRNA gene sequencing. BBR and BRB treatment could greatly modify the structure and composition of gut microbiota. At the genus level, BBR and BRB treatment decreased Lactobacillus and Romboutsia , while BBR increased beneficial bacteria, such as Akkermansia and Bacteroides , and BRB increased beneficial bacteria, such as Ileibacterium and Mucispirillum . Altogether, both BRB and BBR were active in alleviating NAFLD in vivo and BRB might be used as a functional material to treat NAFLD clinically.
研究领域:
药理学
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代谢学
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胃肠病学
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微生物学
✓ 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）