BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Xiaoyan Sun,Chunli Zhang,Bo Fan,Qingyu Liu,Xiaofeng Shi,Shuxia Wang,Ting Chen,Xueting Cai,Chunping Hu,Handong Sun,Pematenzin Puno,Peng Cao
Chronic myeloid leukemia (CML) is a type of malignancy characterized by harboring the oncogene Bcr-Abl , which encodes the constitutively activated tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors targeting BCR-ABL have revolutionized CML therapy, native and acquired drug resistance commonly remains a great challenge. Thioredoxin 1 (Trx1) and glutamate-cysteine ligase (GCL), which are two major antioxidants that maintain cellular redox homeostasis, are potential targets for cancer therapy and overcoming drug resistance. However, how their inhibition is implicated in CML is still unclear. Here, our results revealed that Trx1 was overexpressed in patients with CML compared with healthy donors. Trx1 expression was greater in imatinib-resistant CML cells than in imatinib-sensitive cells. Pharmacological inhibitors of Trx1 attenuated cell growth and reduced colony formation in both imatinib-sensitive and imatinib-resistant CML cells. Trx1 knockdown suppressed cell growth and suppressed tumor progression in xenograft models. Furthermore, decreased Trx1 expression enhanced the cytotoxicity of the GCL inhibitor buthionine sulfoximine (BSO). We surmise that the combined inhibition of Trx1 and GLC promotes the induction of hydrogen peroxide and depletes GPX4 expression in CML cells, resulting in ferroptosis in cancerous cells. Finally, the combined inhibition of Trx1 and GCL had a synergistic effect on CML cells in murine xenograft models. These findings offer crucial information regarding the combined roles of Trx1 and GCL in triggering ferroptosis in CML and suggest efficacious therapeutic uses for these systems in this disease.
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
ACS Food Science & Technology
·
2023
·
IF 2.3
Yi Wu,Yongtai Wu,Zhenhui Zhang,Jiaxian Cai,Minhua Zong,Lin Li,Xia Zhang,Hong Wu,Bing Li
Advanced glycation end products (AGEs) are widely found in processed foods; their free fractions could significantly affect cellular glucose and lipid metabolism, but this mechanism remains poorly understood. We selected Nε-(carboxymethyl)lysine (CML) as a representative free AGE to study the biochemical processes involved in glucose metabolism, lipid synthesis, and catabolism in human LO2 cells. A combination of biochemical, metabolic flux, and comparative experiments revealed that the mechanism of CML intervention in glucose metabolism mainly involves promoting the dephosphorylation of glucose 6-phosphate and inhibiting the conversion of cis-aconitate to isocitrate in the Krebs cycle. Regarding lipid metabolism, CML combined with high-glucose stimulation synergistically promoted de novo lipogenesis, and CML also promoted fatty acid β-oxidation. These results provide constructive insights into the mechanisms and targets of the imbalance in cellular glucose and lipid metabolism induced by dietary AGEs.
研究领域:
生物化学
·
细胞代谢
·
营养学
✓ 已验证
产品关联
DOI
高影响因子
FOOD CONTROL
·
2025
·
IF 6.3
Yingshuang Lu,Yu Jiang,Mengyu Sun,Lu Dong,Xiaolong Xing,Yan Zhang,Shuo Wang
This study explores the formation of advanced glycation end products (AGEs) in chicken breast during roasting, focusing on the analytical characterization and simulation of dynamic models for the content of carboxymethyllysine (CML) and carboxyethyllysine (CEL), two key AGEs. To systematically investigate the formation patterns of AGEs, the chicken breasts were subjected to five roasting temperatures ranging from 180 °C to 230 °C. At each temperature, samples were roasted to achieve five distinct core temperatures, from 60 °C to 100 °C. Dynamic models for CML and CEL content were constructed using multiple linear regression and partial least squares methods, with the best-fit models identified based on their R 2 and RMSE values, with R 2 values of 0.886 for CEL, 0.954 for CML, and RMSE values indicating minimal prediction error. Our research provides a robust framework for predicting AGEs formation during roasting with validation, offering valuable insights for optimizing cooking processes to balance product quality and safety.
研究领域:
食品科学
·
生物化学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
·
2024
·
IF 3.3
Kaihua Liu,Zhijie Liu,Junjian Miao,Yiqun Huang,Keqiang Lai
BACKGROUND N ε-carboxymethyllysine (CML), N ε-carboxyethyllysine (CEL) and α -aminoadipic acid (AAA) are important foodborne hazards and their intake can cause a variety of diseases in humans. It is extremely important to investigate the formation mechanism of CML, CEL and AAA, as well as their association with each other when aiming to control their production. RESULTS A multi-response kinetic model was developed within the glucose-lysine Maillard reaction model system. The concentrations of glucose, lysine, glyoxal (GO), methylglyoxal (MGO), CML, CEL and AAA were quantified at different temperature (100–160 °C) and at different intervals (0–60 min). The experimental data were fitted to the proposed model to calculate kinetic parameters for the corresponding steps. The results indicated that the production of CML was primarily relied on the direct oxidative cleavage of the Amadori product, rather than the reaction between GO and Lys, whereas CEL and AAA were generated through the reaction of MGO with Lys. Significantly, the reaction between α -dicarbonyl compounds and Lys preferentially generated CML and CEL, resulting in the lower concentrations of AAA compared to CML and CEL. CONCLUSION The multi-response kinetic model developed in the present study can be applied well to the Maillard reaction. The relationship between the formation mechanisms of CML, CEL and AAA is also explained. © 2024 Society of Chemical Industry.
研究领域:
食品科学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2023
·
IF 4.8
Jianchao Zhang,Caibing Ma,Yongjun Yu,Chaowei Liu,Lijing Fang,Hai Rao
Proteolysis-targeting chimera (PROTAC) that specifically targets harmful proteins for destruction by hijacking the ubiquitin-proteasome system (UPS) is emerging as a potent anti-cancer strategy. How to efficiently modulate the target degradation remains a challenging issue. In this study, we employ a single amino acid-based PROTAC, which uses the shortest degradation signal sequence as the ligand of the N-end rule E3 ubiquitin ligases to degrade the fusion protein BCR-ABL, an oncogenic kinase that drives the progression of chronic myeloid leukemia (CML). We find that the reduction level of BCR-ABL can be easily adjusted by substituting different amino acids. Furthermore, a single PEG linker is found to achieve the best proteolytic effect. Our efforts have resulted in effective degradation of BCR-ABL protein by the N-end rule pathway and efficient growth inhibition of K562 cells expressing BCR-ABL in vitro , and blunted tumor growth in a K562 xenograft tumor model in vivo . The PROTAC presented has unique advantages including lower effective concentration, smaller molecular size and modular degradation rate. Demonstrating the efficacy of the N-end rule-based PROTACs in vitro and in vivo , our study further expands the limited degradation pathways currently available for PROTACs in vivo and is easily adapted for broader applications in targeted protein degradation.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2019
·Vol. 9
·期 27
·15162-15170
·
IF 3.049
Yuting Wang,Huiyu Hu,David Julian McClements,Shaoping Nie,Mingyue Shen,Chang Li,Yousheng Huang,Jie Chen,Maomao Zeng,Mingyong Xie
Lysine-derived advanced glycation end-products (AGEs), including Nε-carboxymethyllysine (CML), Nε-carboxyethyllysine (CEL) and pyrraline, are prevalent in processed foods. The impact of lipids on AGE formation is still contentious and most of our current knowledge is based only on CML. Little is known about how lipids impact the formation of CEL and pyrraline, or their involvement in formation pathways. This study investigated the effect of lipids (fatty acids and triglycerides) on the formation of CML, CEL and pyrraline simultaneously in model systems subjected to frying temperature. The results showed the presence of the lipids promoted the formation of CML, CEL and pyrraline. The promotion effects on CML and CEL were not dependent on the unsaturation degree and addition level (50, 100 or 150 μmol) of lipid, while pyrraline formation depended on lipid type (fatty acids vs. triglycerides) and level. The concentration of CML and CEL was statistically correlated with the concentration of glyoxal (GO) and methylglyoxal (MGO), respectively. The pyrraline concentration was statistically correlated with fructoselysine concentration. These results suggested that lipids promote the formation of lysine-derived AGEs by impacting the generation of Amadori products and α-dicarbonyl compounds. This information may be useful for optimizing the formulation and processing conditions to create tastier and healthier foods.
研究领域:
食品科学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
REGULATORY TOXICOLOGY AND PHARMACOLOGY
·
2016
·
IF 2.227
Xin Liu,Liangqing Zheng,Rong Zhang,Gang Liu,Shensheng Xiao,Xiaoting Qiao,Yongning Wu,Zhiyong Gong
Nε-(carboxymethyl)lysine (CML) as a novel potential noxious compound in various food products has aroused extensive concern in recent years. This study aimed to investigate the oral acute and subacute toxicity of CML in mice as per OECD 420 and 407 guidelines. Acute administration of 2000 and 5000 mg/kg CML did not induce any mortality within 14 days, nevertheless some toxicological symptoms and histopathological changes were observed. The estimated LD 50 of CML was >5000 mg/kg. In subacute toxicity test , CML was dosed at 200, 500 and 1000 mg/kg in both genders for 28 days. The body weights reduced which was accompanied with the decrease of food consumptions. Hematology parameters viz. RBC , HGB and MCH showed minor alteration but these were still within normal range. Biochemical analysis of hepatic and renal function markers showed significant elevating in AST , ALT , Cr and BUN etc. Histopathological alterations were observed in lung, liver, kidney and spleen. Subacute toxicity of CML involved oxidative stress caused by reducing antioxidant enzyme (SOD and GSH-Px) activities, and significantly increasing lipid peroxide (MDA) level. In conclusion, CML was unlikely to present an acute hazard, but repeated administration could produce deleterious effects on mice especially inducing liver and kidney damage through oxidative stress.
研究领域:
毒理学
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食品科学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
PLANT CELL AND ENVIRONMENT
·
2023
·Vol. 46
·期 11
·3592-3610
·
IF 7.3
Shunyu Xiang,Jing Wang,Xiaoyan Wang,Xiaozhou Ma,Haoran Peng,Xin Zhu,Jin Huang,Mao Ran,Lisong Ma,Xianchao Sun
Control of plant virus diseases largely depends on the induced plant defence achieved by the external application of synthetic chemical inducers with the ability to modify defence-signalling pathways. However, most of the molecular mechanisms underlying these chemical inducers remain unknown. Here, we developed a chitosan-coated lentinan-loaded hydrogel and discovered how it protects plants from different virus infections. The hydrogel was synthesized by coating chitosan on the surface of the calcium alginate-lentinan (LNT) hydrogel (SL-gel) to form a CSL-gel. CSL-gels exhibit the capacity to prolong the stable release of lentinan and promote Ca 2+ release. Application of CSL-gels on the root of plants induces broad-spectrum resistance against plant viruses (TMV, TRV, PVX and TuMV). RNA-seq analysis identified that Nicotiana benthamiana calmodulin-like protein gene 3 ( NbCML3 ) is upregulated by the sustained release of Ca 2+ from the CSL-gel, and silencing and overexpression of NbCML alter the susceptibility and resistance of tobacco to TMV. Our findings provide evidence that this novel and synthetic CSL-gel strongly inhibits the infection of plant viruses by the sustainable release of LNT and Ca 2+ . This study uncovers a novel mode of action by which CSL-gels trigger NbCML3 expression through the stable and sustained release of Ca 2+ .
研究领域:
植物病理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF ONCOLOGY
·
2022
·Vol. 60
·期 5
·1-14
·
IF 5.884
Hang Sun,Youjie Li,Xiao Wang,Xue Zhou,Simin Rong,Dongmin Liang,Guangbin Sun,Huizhen Cao,Hongfang Sun,Ranran Wang,Yunfei Yan,Shuyang Xie,Yunxiao Sun
Chronic myeloid leukemia (CML) is a hematological disease, and imatinib (IM) resistance represents a major problem for its clinical treatment. In the present study, the role of tribbles pseudokinase 2 (TRIB2) in IM resistance of CML and the possible mechanism were investigated. It was found that TRIB2 was highly expressed in IM‑resistant patients with CML through the Oncomine database and this conclusion was confirmed using reverse transcription‑quantitative PCR and western blot experiments. Knockdown of TRIB2 was found to increase the drug sensitivity of KG cells to IM using Cell‑Counting Kit‑8 (CCK‑8) assays, and the low‑expression TRIB2 mice were further found to be more sensitive to the IM and have a higher survival rate in leukemia model mice. Moreover, using western blot and luciferase experiments, it was found that TRIB2 could regulate c‑Fos through the ERK signaling pathway, and c‑Fos suppressed the transcriptional activity and the expression of miR‑33a‑5p. Further investigation identified that the binding site for c‑Fos to function on miR‑33a‑5p was the ‑958‑965 region. Finally, CCK‑8 assays and western blot experiments demonstrated that miR‑33a‑5p could inhibit the proliferation of KG cells and reduce IM resistance by suppressing the expression of HMGA2. In conclusion, it was demonstrated that TRIB2 regulates miR‑33a‑5p to reverse IM resistance in CML, which may help identify novel targets and therapeutic strategies for the clinical treatment of IM resistance.
研究领域:
肿瘤学
·
血液学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2019
·
IF 3.571
Dan Xu,Lin Li,Xia Zhang,Hong Yao,Mingquan Yang,Zuoqi Gai,Bing Li,Di Zhao
A large portion of Maillard reaction products (MRPs) cannot be absorbed in the upper gut and therefore may be further decomposed and utilized by colonic microbiota (CM). This work reported the stability of UV-absorbent MRPs, fluorescent MRPs and peptide-bound N(ε)-(carboxymethyl)-lysine (CML) in high molecular weight (HMW, >10 kDa), medium molecular weight (MMW, 1–10 kDa), and low molecular weight (LMW, <1 kDa) gastrointestinal digests of glyoxal-glycated casein in the presence of CM. Fluorescent MRPs showed high stability, whereas UV-absorbent MRPs may be partially decomposed. A higher depletion rate of CML was found in the LMW fraction (38.7%) than in the MMW (21.7%) and HMW (9.6%) fractions. The 16S rRNA sequencing results revealed both beneficial and detrimental changes in CM composition induced by the glycated fractions. Generation of short-chain and branched-chain fatty acids in fermentation solutions with glycated fractions was significantly suppressed compared with that in fermentation solution with unglycated digests. This work revealed the possible interplay between peptide-bound MRPs and CM.
研究领域:
食品科学
·
微生物学
·
营养学
✓ 已验证
DOI
PubMed
高影响因子
Food & Function
·
2024
·
IF 5.1
Yi Wu,Yuqi Yang,Yanhong Zhong,Yongtai Wu,Zhenhui Zhang,Zichen Yan,Bingxin Liu,Wei Wang
This study delves into the dynamics of dietary Advanced Glycation End-products (dAGEs) on host health and gut microbiota. Using 13C-labeled Carboxymethyllysine (CML) bound casein, we identify bound AGEs as the primary entry route, contrasting with free AGEs dominating urinary excretion. Kidneys, not the liver, accumulate dAGEs, emphasizing their pivotal role in health effects. High AGEs (HA) diet prompts rapid gut microbiota changes, with an initial stress-induced mutation phase followed by stabilization. Bacteroides and Parabacteroides emerge as potential dAGEs-utilizing bacteria, influencing microbiota composition. Concurrent metabolic shifts affect lipid and carbohydrate pathways, persisting over time and impacting host metabolic homeostasis. This study illuminates the intricate interplay between dietary AGEs, gut microbiota, and host health, offering insights into the health consequences of short and long-term HA dietary patterns.
研究领域:
营养学
·
微生物学
·
代谢组学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LWT-FOOD SCIENCE AND TECHNOLOGY
·
2022
·
IF 6.056
Xin Xu,Tian Xue,Qingqing Jiang,Daming Fan,Mingfu Wang,Yueliang Zhao
The inhibitory effects of four hydrocolloids, including alginic acid, pectin, carboxymethylcellulose sodium salt, and chitosan on the formation of two typical toxic advanced glycation end products N Ɛ -(carboxymethyl) lysine (CML) and N Ɛ -(carboxyethyl) lysine (CEL) were investigated in chemical models and fish patties. All the four hydrocolloids were found to significantly inhibit CML and CEL formation in chemical models, and among them, pectin and alginic acid were the most effective inhibitors. In roast fish patties, the addition of pectin and alginic acid at 0.9% reduced the content of CML by 43.6% and 44.9%, and CEL by 32.4% and 32.6%, respectively. Moreover, alginic acid plus a polyphenol epigallocatechin gallate (EGCG) showed stronger inhibitory effect against CML and CEL formation than alginic acid alone. Further study showed that alginic acid and pectin decreased the formation of glyoxal (GO) and methylglyoxal (MGO), two key intermediates of CML and CEL, in the chemical models and fish patties. In addition, compared with EGCG, the addition of alginic acid in fish patties showed less impact on color, odor, and sensory properties. These findings suggest that alginic acid is a potent inhibitor against the formation of AGEs with less impact on food quality.
研究领域:
食品科学
·
化学
·
营养学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）