International Journal of Peptide Research and Therapeutics
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2018
·Vol. 25
·期 4
·1361-1367
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IF 1.132
Li Songtao,Zhao Hongling,Wang Ruxing,Wang Jianping,Mao Xiaoxia,Hao Ting,Chang Xiaomin,Zhao Enhong,Yin Zhifeng,Deng Shuhua,Yang Yaqi,Wang Huina
It is demonstrated that gonadotropin-releasing hormone (GnRH) analogs can directly inhibit the proliferation of reproductive tissue cancer cells, but the poor pharmacokinetic properties still restrict their application in treating hormone-dependent diseases. Modifications in position 6 and 10 of natural GnRH can improve the metabolic stability. In order to study the effect of incorporation Cys 6 substitution with C-terminal Pro 9 -NHEt modification and dimerization of linear peptides on metabolic stability and antiproliferative activity of GnRH analogs, two new GnRH analogs [ l -Cys 6 , desGly 10 , Pro 9 -NHEt]-GnRH ( 1 ) and [ d -Cys 6 , desGly 10 , Pro 9 -NHEt]-GnRH ( 2 ), and their corresponding dimer derivatives ([ l -Cys 6 , desGly 10 , Pro 9 -NHEt]-GnRH) 2 ( 3 ) and ([ d -Cys 6 , desGly 10 , Pro 9 -NHEt]-GnRH) 2 ( 4 ) were synthesized. Incubation of these analogs with human serum was carried out to evaluate their metabolic stability, and direct growth inhibitory effect of the two dimer derivatives 3 and 4 on MCF-7 human breast cancer cell line was examined by MTT assay. The metabolic stability of dimer derivatives 3 and 4 was remarkably improved in comparison with natural GnRH. The d -Cys 6 substituted dimer derivative 4 exhibited higher inhibitory effect (29.6–39.7% growth reduction) on cell growth than its corresponding counterpart 3 (21.8–26.2% growth reduction) at concentration range of 50, 100 and 200 μΜ. The cell growth inhibition of leuprolide was 16.4–27.2% at the tested concentrations. The dimer derivative 4 was the most stable and active GnRH analog in this study and has the potential for future preclinical investigations as promising antitumor drug candidate.
研究领域:
药理学
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肿瘤学
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内分泌学
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DOI
高影响因子
NEUROSCIENCE
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2017
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IF 3.277
Tanzeel Huma,Xintian Hu,Yuanye Ma,Andrew Willden,Joshua Rizak,Muhammad Shahab,Zhengbo Wang
Embryonic stem cells (ESCs) have enormous potential as novel cell-based therapies, but their effectiveness depends on stem cell differentiation and specific signaling regulators, which remain poorly understood. In this study, a kisspeptin peptide (KP-10) was used at different dosages to determine whether rhesus macaque-derived tau GFP-Lyon ES cells underwent kisspeptin-specific neuronal differentiation. It was found that KP-10 exhibited an anti-proliferative effect on the cells and led to morphological changes and cellular differentiation consistent with neuronal stem cell (NSC) development. The cells differentiated into Gonadotrophin Releasing Hormone (GnRH) neuronal-like cell types in response to the KP-10 treatment. There has been a previously observed connection between kisspeptin signaling, GnRH neurons and their dysfunction found in congenital disorders like idiopathic hypogonadotropic hypogonadism (IHH). Although therapeutics are a still a far-off goal, the formation and development of GnRH-positive neuronal-like cells following the application of KP-10 to Lyon NSC cells opens the door for future NSC-based therapies to treat specific reproductive disorders.
研究领域:
神经科学
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生殖生物学
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干细胞研究
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Haoran Xu,Zhuoyi Ye,Xin Gao,Yue Dai,Yang Luo,Zhihao Han,Yueqing Gu
Breast cancer, globally the most common cancer in women, presents significant challenges in treatment. Breast-conserving surgery (BCS), a less traumatic and painful alternative to radical mastectomy, not only preserves the breast’s appearance but also supports postsurgical functional recovery. However, accurately identifying tumors, precisely delineating margins, and thoroughly removing metastases remain complex surgical challenges, exacerbated by the limitations of current imaging techniques, including poor tumor uptake and low signal contrast. Addressing these challenges, our study developed a series of GnRHR-targeted probes (YQGN-n) for fluorescence imaging and surgical navigation of breast cancer through a drug repositioning strategy. Notably, YQGN-7, with its high cellular affinity (Kd of 217.8 nM), demonstrates exceptional selectivity and specificity for breast cancer tumors, surpassing traditional imaging agents like ICG in tumor uptake and pharmacokinetic properties. Furthermore, YQGN-7’s effectiveness in surgical navigation, both for primary breast tumors and metastases, highlights its potential as a revolutionary tool in BCS.
研究领域:
肿瘤学
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医学影像学
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药理学
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产品关联
DOI
PubMed
高影响因子
AQUATIC TOXICOLOGY
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2024
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IF 4.1
Qi Sun,Jun Dong,Zehui Su,Xuanyun Huang,Xiaoning Gao,Kun Hu,Xiaoling Gong
This study evaluates the impact of environmentally relevant, low-concentration deltamethrin exposure to Eriocheir sinensis ovaries. Our findings revealed that even at a concentration of 0.05 µg/L, deltamethrin exposure can induce significant ovarian toxicity through a 5-day exposure, with gradual amplification detected with time, demonstrating the toxicity amplification effect. Hematoxylin and Eosin staining revealed that low-concentration deltamethrin exposure produces pathological damage consistent with acute toxicity—yolk granules were dissolved and oocyte membranes were ruptured. High-throughput RNA-sequencing data indicated that the acute and low-concentration exposure groups involved completely different pathways and molecular functions, suggesting distinct mechanisms for their toxic effects. Following the identification of phospholipase D (PLD) as a potential core factor regulating the toxicity amplification effect of low concentration deltamethrin, we delved into subsequent mechanism studies using quantitative real-time PCR, immunofluorescence and enzyme-linked immunosorbent assay. Through the GnRH signaling pathway, increased PLD indirectly stimulates augmented estradiol secretion, subsequently inducing apoptosis by upregulating Cathepsin D, which can activate the key executioners of apoptosis—caspases (CASP3 and CASP7). In conclusion, low-concentration deltamethrin exposures can induce significant ovarian damage through apoptosis mediated by the upregulation of PLD in the ovaries of Eriocheir sinensis at environmentally relevant concentrations, which lays the preliminary theoretical groundwork for further elucidating the mechanism of toxicity amplification effect of pesticide exposure at low concentrations.
研究领域:
环境毒理学
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分子生物学
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水生生态学
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
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2023
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IF 3.4
Xiaoyan He,Jiwei Liu,Tao Song,Yiying Sun,Xiaoyan Lu,Nuannuan Li,Kaoxiang Sun
A satisfactory drug release profile for gonadotropin-releasing hormone (GnRH) agonist drugs is high initial release followed by small amount of drug release per day. In the present study, three water-soluble additives (NaCl, CaCl2 and glucose) were selected to improve the drug release profile of a model GnRH agonist drug-triptorelin from PLGA microspheres. The pore manufacturing efficiency of the three additives was similar. The effects of three additives on drug release were evaluated. Under the optimal initial porosity, the initial release amount of microspheres containing different additives was comparable, this ensured a good inhibitory effect on testosterone secretion in the early stage. For NaCl or CaCl2 containing microspheres, the drug remaining in the microsphere depleted rapidly after the initial release. The testosterone concentration gradually returned to an uncontrolled level. However, for glucose containing microspheres, it was found that the addition of glucose could not only increase the initial release of the drug but also assist in the subsequent controlled drug release. A good and long-time inhibitory effect on testosterone secretion was observed in this formulation. The underlying cause why the incorporation of glucose delayed the subsequent drug release was investigated. SEM results showed that considerable pores in glucose containing microspheres were healed during the microspheres incubation. After thermal analysis, an obvious glass transition temperature (Tg) depression was observed in this formulation. As Tg decreased, polymer chains are able to rearrange at lower temperatures. This, morphologic change was reflected in the gradual closure of the pores, and is the likely reason that drug release slowed down after the initial release.HIGHLIGHTSThe addition of glucose could not only increase the burst release of the drug but also delay the subsequent drug release.High initial burst and a sustained drug release helped obtain a good inhibitory effect on testosterone secretion.As Tg decreased, polymer chain was prone to rearrange. Morphologic change was reflected in the gradual closure of the pores. This was the reason that drug release slowed down after the initial burst.
研究领域:
药剂学
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药物递送系统
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药理动力学
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DOI
PubMed
高影响因子
Frontiers in Endocrinology
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2024
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IF 3.9
Zhou Fang,Mao Jianhong
Objective: Precocious puberty (PP) is a prevalent endocrine disorder affecting the physical and mental wellbeing of children. Identifying the triggering factors of PP has become a central issue. This study seeks to investigate the metabolomic and transcriptomic alterations in PP.Material and methods: First, 37 school-aged girls diagnosed with PP and 25 age-matched prepubertal control girls were recruited, and the fecal samples were collected for non-targeted metabolomic analysis to screen for differentially expressed metabolites (DEMs). Subsequently, an animal model of PP was constructed by danazol administration to neonatal female rats, and both fecal non-targeted metabolomics and serum next-generation transcriptomic sequencing were performed to screen DEMs and differentially expressed genes (DEGs) in PP. Moreover, the DEM co-existing in clinical and animal models was administrated to PP rats to explore the role of the target metabolite in PP.Results: A total of 24 DEMs in PP clinical samples and 180 DEMs and 425 DEGs in PP animal samples were identified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these DEMs and DEGs were enriched in disease-associated pathways, including fatty acid synthesis, glycerolipid metabolism, pyrimidine metabolism, steroid hormone biosynthesis, progesterone-mediated oocyte maturation, and gonadotropin-releasing hormone (GnRH) signaling pathway, forming a tight DEM–DEG pathway regulatory network. Further DEM validation demonstrated that thymine supplementation delayed the opening of the vagina and development of PP in model rats.Conclusion: This study reveals that the metabolomic and transcriptomic changes, along with enriched pathways, are implicated in PP based on clinical and animal analyses. The findings may provide new strategies and research avenues for PP treatment.
研究领域:
内分泌学
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分子生物学
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儿科
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代谢组学
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转录组学
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产品关联
DOI
PubMed
高影响因子
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