FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Ru Li,Yimei Ma,Anqi He,Yamin Pu,Xuanting Wan,Hongbao Sun,Ningyu Wang,Min Luo,Guan Wang,Yong Xia
The multi-kinase inhibitor sorafenib has shown potential to inhibit tumor cell growth and intra-tumoral angiogenesis by targeting several kinases, including VEGFR2 and RAF. Abnormal activation of the Ras/Raf/MAPK/ERK kinase cascade and the VEGF pathway is a common feature in breast cancer. However, the efficacy of sorafenib in breast cancer treatment remains limited. Recently, fasting has emerged as a promising non-pharmacological approach to modulate cancer metabolism and enhance the effectiveness of cancer therapies. In this study, we found that fasting significantly enhances the anti-cancer effects of sorafenib monotherapy and its combination with immunotherapy in breast cancer models without causing obvious side effects. This combined treatment effectively inhibits tumor cell proliferation and intra-tumoral angiogenesis. The fasting-induced reduction in peripheral blood glucose levels strongly correlated with enhanced sensitivity to sorafenib. Mechanistically, the combined treatment induced mitophagy, characterized by mitochondrial dysfunction and activation of the PINK1-Parkin pathway. Consequently, increased mitochondrial ROS levels promoted p53 expression, amplifying cell cycle arrest and apoptosis in breast cancer cells. Furthermore, fasting reduced lactate levels within the tumor, and the consequent glucose limitation synergized with sorafenib to activate AMPK, which in turn elevated PD-L1 expression in tumor cells, potentially enhancing their sensitivity to immunotherapy. In summary, our findings demonstrate that fasting and sorafenib, as a rational combination therapy, induce mitophagy, thereby enhancing sorafenib's efficacy in treating breast cancer through the ROS-driven p53 pathway. This study underscores the potential of fasting in breast cancer therapy and provides a foundation for optimizing the clinical application of sorafenib.
研究领域:
肿瘤学
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分子生物学
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代谢研究
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DOI
PubMed
高影响因子
Cell Metabolism
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2025
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IF 30.9
Shujun Cui,Danyang Chong,Yi-Xin Wang,Huixian Tong,Minggui Wang,Guo-Ping Zhao,Liang-Dong Lyu
Fasting metabolism is a commonly observed motivational response to acute infections and is conceptualized as being beneficial for host survival. Here, we show that fasting potentiates antibiotic treatment for murine sepsis caused by Salmonella Typhimurium, Klebsiella pneumoniae , and Enterobacter cloacae , resulting in increased bacterial clearance and improved host immune responses and survival. This effect is mediated by fasting-induced ketogenesis and could be alternatively implemented by combination therapy with antibiotics and ketone bodies. We show that the ketone body acetoacetate is an effector that sensitizes bacteria to antibiotic treatment by increasing antibiotic lethality and outer and inner membrane permeability. Our results demonstrate that acetoacetate depletes bacterial amino acids, particularly positively charged amino acids and putrescine, leading to cell membrane malfunctions and redox-related lethality. This study reveals an unrecognized role of ketogenesis in antibiotic treatment and a potential ketone body-based treatment strategy for bacterial sepsis.
研究领域:
微生物学
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医学
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感染病学
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DOI
PubMed
高影响因子
Cancers
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2022
·Vol. 14
·期 2
·345
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IF 6.575
Hui Chen,Han Zhang,Lixing Cao,Jinling Cui,Xuan Ma,Chong Zhao,Shutao Yin,Hongbo Hu
Simple SummarySelenite, a representative inorganic form of selenium, is preferentially accumulated in tumors. The therapeutic potential of sodium selenite in tumors has received significant attention. However, the effect of sodium selenite in the treatment of established tumors is hampered by its systemic toxicities. In this study, we found selenite exerted a stronger lethality to the cancer cells under the condition of glucose limitation in vitro and an enhanced inhibitory effect on tumor growth when combined with intermittent fasting in vivo. In addition, this treatment showed no obvious toxicity to normal cells and mice. The findings of the present study provide an effective and practical approach for increasing the therapeutic window of selenite and imply that combination of selenite and fasting holds promising potential to be developed a clinically useful regimen for treating certain types of cancer.AbstractCombination of intermittent fasting and chemotherapy has been drawn an increasing attention because of the encouraging efficacy. In this study, we evaluated the anti-cancer effect of combination of glucose limitation and selenite (Se), a representative inorganic form of selenium, that is preferentially accumulated in tumors. Results showed that cytotoxic effect of selenite on cancer cells, but not on normal cells, was significantly enhanced in response to the combination of selenite and glucose limitation. Furthermore, in vivo therapeutic efficacy of combining selenite with fasting was dramatically improved in xenograft models of lung and colon cancer. Mechanistically, we found that SLC7A11 expression in cancer cells was up-regulated by selenite both in vitro and in vivo. The elevated SLC7A11 led to cystine accumulation, NADPH depletion and the conversion of cystine to cysteine inhibition, which in turn boosted selenite-mediated reactive oxygen species (ROS), followed by enhancement of selenite-mediated cytotoxic effect. The findings of the present study provide an effective and practical approach for increasing the therapeutic window of selenite and imply that combination of selenite and fasting holds promising potential to be developed a clinically useful regimen for treating certain types of cancer.Keywords:selenite;glucose limitation;SLC7A11;NADPH;ROS
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
Fishes
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2023
·Vol. 8
·期 3
·170
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IF 2.3
Lei Zhang,Peng Shi,Lin Zhang,Yajun Wang,Jilin Xu,Xiaojun Yan,Kai Liao
Ghrelin, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY) are potent hormones mediating food intake according to the nutritional status in fish. However, limited information is available on these genes and their expression in response to nutrition in silver pomfret (Pampus argenteus). A comparison analysis revealed thatghrelinand GLP-1 were relatively conserved in marine fish. PYYa and PYYb shared a low identity and were clustered to different PYY branches.Ghrelin,pyya, andpyybmRNAs were highly expressed in the brain, whileglp-1was highly expressed in the gills and liver. TheghrelinmRNA expression was relatively high an hour post-feeding and decreased after 3 to 72 h of fasting. Theglp-1mRNA expression was increased after 6 to 24 h of fasting. ThepyyamRNA expression was increased after 72 h of fasting, while thepyybexpression remained stable during fasting. The diet with 14% lipid promoted the expressions ofglp-1,pyya, andpyyb, but inhibited theghrelinexpression. Theghrelinexpression in the intestine was increased after palmitic acid, oleic acid (OA), linoleic acid (LA), α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) incubation. OA decreased the expression ofglp-1and increased the expression ofpyya. The expression ofpyybwas downregulated by LA, DHA, and EPA. These results suggest the importance ofghrelin,glp-1, andpyyin coordinating food intake in response to fasting, dietary lipid concentration, and fatty acids in silver pomfret.Keywords:ghrelin;glp-1;pyy;fasting;lipid content;fatty acids;silver pomfretKey Contribution:This study provides insight into howghrelin,glp-1, andpyyrespond to fasting, dietary lipid concentration, and fatty acids in silver pomfret.
研究领域:
海洋生物学
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分子生物学
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营养学
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DOI
高影响因子
CELL
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2024
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IF 45.5
Han Chen,Chao Liu,Shiyao Cui,Yingqian Xia,Ke Zhang,Hanxiao Cheng,Jingyu Peng,Xiaoling Yu,Luyang Li,Hualin Yu,Jufang Zhang,Ju-Sheng Zheng,Bing Zhang
Intermittent fasting has gained global popularity for its potential health benefits, although its impact on somatic stem cells and tissue biology remains elusive. Here, we report that commonly used intermittent fasting regimens inhibit hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). This effect is independent of calorie reduction, circadian rhythm alterations, or the mTORC1 cellular nutrient-sensing mechanism. Instead, fasting activates crosstalk between adrenal glands and dermal adipocytes in the skin, triggering the rapid release of free fatty acids into the niche, which in turn disrupts the normal metabolism of HFSCs and elevates their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. A randomized clinical trial (NCT05800730) indicates that intermittent fasting inhibits human hair growth. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration and identifies interorgan communication that eliminates activated HFSCs and halts tissue regeneration during periods of unstable nutrient supply.
研究领域:
干细胞生物学
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组织再生
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营养科学
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细胞代谢
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器官间通讯
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DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2023
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IF 6.2
Fen Xiong,Kaiyuan Jiang,Yali Wu,Cong Lou,Chengjie Ding,Wenli Zhang,Xi Zhang,Chen Li,Hong Zheng,Hongchang Gao
Intermittent fasting (IF) is an ecological strategy to control various metabolic disorder symptoms, but its protective effect on type 1 diabetes (T1D)-induced cognitive dysfunction and the underlying mechanisms remain poorly defined. Herein, we examined the efficacy of IF in altering the behaviors and brain metabolome in T1D mice and investigated the potential molecular mechanisms. We demonstrated that IF remarkably improved frontal cortical-dependent memory in T1D mice and reduced the loss of neuronal cells. Metabolomics and targeted mass spectrometry assays showed that IF reprogrammed the composition of the frontal cortical metabolome in T1D mice, including activating the aspartate and glutamate pathway and reversing glycerophospholipid and sphingolipid depositions. Mechanistically, IF attenuated the levels of oxidative stress proteins, like NOX2, NOX4, 8-OHdG, and 4-HNE, and inhibited the levels of pro-apoptotic factors Bax and cleaved Caspase-3, ultimately improving the memory ability of T1D mice. In vitro studies confirmed the protective effect of the supplemented N -acetylaspartate, a pivotal metabolite involved in IF-regulated T1D-induced cognitive dysfunction, in high glucose-stimulated SH-SY5Y cells by eliminating toxic lipids accumulation, oxidative stress, and apoptosis. To conclude, the frontal cortical metabolites mediated the protective effects of IF against T1D-induced cognitive dysfunction by attenuating oxidative stress and apoptotic signaling. Thus, IF can be a potential therapeutic strategy for T1D-induced cognitive dysfunction.
研究领域:
神经科学
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代谢疾病
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糖尿病研究
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认知科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
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2024
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IF 4.8
Li-Li Zhang,Jia-Ying Xu,Wei Wei,Zhi-Qiang Hu,Yan Zhou,Jia-Yang Zheng,Yu Sha,Lin Zhao,Jing Yang,Qi Sun,Li-Qiang Qin
Background Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy, limiting the clinical application of this treatment. Evidence shows the potential benefits of dietary restriction in improving metabolic profiles and age-related diseases. The present study investigated the effects and mechanisms of dietary restriction in radiation-induced intestinal injury. Methods The mice were randomly divided into the control group, 10 Gy total abdominal irradiation (TAI) group, and groups pretreated with 30% caloric restriction (CR) for 7 days or 24h fasting before TAI. After radiation, the mice were returned to ad libitum. The mice were sacrificed 3.5 days after radiation, and tissue samples were collected. Results CR and fasting reduced radiation-induced intestinal damage and promoted intestinal recovery by restoring the shortened colon length, improving the impaired intestinal structure and permeability, and remodeling gut microbial structure. CR and fasting also significantly reduced mitochondrial damage and DNA damage, which in turn reduced activation of the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) pathway and the production of type I interferon and other chemokines in the jejunum. Since the cGAS/STING pathway is linked with innate immunity, we further showed that CR and fasting induced polarization to immunosuppressive M2 macrophage, decreased CD8 + cytotoxic T lymphocytes, and downregulated proinflammatory factors in the jejunum. Conclusions Our findings indicated that CR and fasting alleviate radiation-induced intestinal damage by reducing cGAS/STING-mediated harmful immune responses.
研究领域:
放射生物学
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免疫学
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胃肠病学
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营养学
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DOI
PubMed
高影响因子
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