ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2025
·
IF 3
Yuqi Wang,Hao Wu,Xun Hu
Background The significance of serine and glycine metabolism in cancer cells is increasingly acknowledged, yet the quantification of their metabolic flux remains incomplete, impeding a comprehensive understanding. This study aimed to quantify the metabolic flux of serine and glycine in cancer cells, focusing on their inputs and outputs, by means of Combinations of C-13 Isotopes Tracing and mathematical delineation, alongside Isotopically Nonstationary Metabolic Flux Analysis. Results In HeLa cells, serine uptake, the serine synthesis pathway (SSP), and other sources (e.g., protein degradation) contribute 71.2 %, 24.0 %, and 5.7 %, respectively, to serine inputs. Conversely, glycine inputs stem from uptake (45.6 %), conversion from serine (45.1 %), and other sources (9.4 %). Serine input flux surpasses glycine by 7.3-fold. Serine predominantly directs a major fraction (94.7 %) to phospholipid, sphingolipid, and protein synthesis, with only a minor fraction (5.3 %) directing towards one-carbon unit and glycine production. Glycine mainly supports protein and nucleotide synthesis (100 %), without conversion back to serine. Serine output rate exceeds glycine output rate by 7.3-fold. Serine deprivation mainly impairs output to synthesis of phospholipid and sphingolipid, crucial for cell growth, while other outputs unaffected. AGS cells exhibit comparable serine and glycine flux to HeLa cells, albeit lacking SSP activity. Serine deprivation in AGS cells halts output flux to phospholipid, sphingolipid, protein synthesis, completely inhibiting cell growth. Conclusions By providing quantitative insights into serine and glycine metabolism, this study delineates the association of serine flux to different metabolic pathway with cancer cell growth and offers potential targets for therapeutic intervention, highlighting the importance of serine flux to pathway for the synthesis of phospholipids and sphingolipids in cancer cells growth.
研究领域:
生物化学
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肿瘤学
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代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Science & Nutrition
·
2024
·
IF 3.5
Jia Hao,Shaohui Beng,Zifeng Ma,Hongmei Xu,Ting Yang,Qiman Yang,Yunduan Wang,Wenhui Zheng,Yisha Ma,Shuo Zhang,Liangde Kuang,Wei Fu
This study aimed to investigate the effects of short-term exposure of Bisphenol A (BPA) on the growth and lactation performance, blood parameters, and milk composition of lactating rabbits and explore its potential molecular mechanisms. Eight lactating rabbits with similar body weight were selected and randomly divided into the experimental group (BPA) and the control group (Ctrl). The group BPA was orally administered 80 mg/kg/day BPA on the 15th day postpartum, while the group Ctrl received a corresponding volume of vehicle. Blood and milk samples were collected after 7 days treatment. The results showed that short-term ingestion of BPA did not obviously alter the body weight, feed intake, or milk yield of the lactating rabbits. ELISA assays indicated that BPA did not significantly affect the plasma levels of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), creatinine (CRE), alanine aminotransferase (ALT), aspartate aminotransferase (AST), uric acid (UA), and urea. Utilizing untargeted metabolomics, we first depicted the metabolomic profile of rabbit milk, and identified 277 differential metabolites (DMs), with 141 DMs upregulated (e.g., BPA, and its metabolites including Cetirizine N-oxide) and 136 DMs downregulated (e.g., Oleamide, Tiglic acid, PC O-38:4) in the group BPA. KEGG analysis revealed that the DMs were mainly enriched in pathways comprising fatty acid metabolism, fatty acid degradation, and phosphatidylinositol signaling system, emphasizing the effect of BPA on milk fat metabolism. Hence, we established the BPA-induced MAC-T model, and the results showed that BPA significantly reduced cell viability and impacted lipid synthesis, as evidenced by reduced lipid droplets (BODIPY and Oil Red O staining) and decreased expression of genes related to lipid synthesis (e.g., PPARγ , ACACA , LPL ). In summary, we first drew the metabolomic profile of rabbit milk and confirmed that short-term BPA exposure impacted mammary lipid synthesis, thereby reducing the milk quality of lactating rabbits and providing fundamental data for resolving the toxicological mechanisms of BPA on mammal lactation.
研究领域:
毒理学
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动物科学
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代谢组学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2023
·Vol. 8
·期 1
·1-21
·
IF 39.3
Wei Wenxia,Qin Baifu,Wen Weijie,Zhang Boyu,Luo Haidan,Wang Yuzhi,Xu Hui,Xie Xiaoshan,Liu Sicheng,Jiang Xin,Wang Mengan,Tang Qin,Zhang Jiayu,Yang Runxiang,Fan Zongmin,Lyu Haiwen,Lin Junzhong,Li Kai,Lee Mong-Hong
Continuous de novo fatty acid synthesis is required for the biosynthetic demands of tumor. FBXW7 is a highly mutated gene in CRC, but its biological functions in cancer are not fully characterized. Here, we report that FBXW7β, a FBXW7 isoform located in the cytoplasm and frequently mutated in CRC, is an E3 ligase of fatty acid synthase (FASN). Cancer-specific FBXW7β mutations that could not degrade FASN can lead to sustained lipogenesis in CRC. COP9 signalosome subunit 6 (CSN6), an oncogenic marker of CRC, increases lipogenesis via interacting with and stabilizing FASN. Mechanistic studies show that CSN6 associates with both FBXW7β and FASN, and antagonizes FBXW7β’s activity by enhancing FBXW7β autoubiquitination and degradation, which in turn prevents FBXW7β-mediated FASN ubiquitination and degradation, thereby regulating lipogenesis positively. Both CSN6 and FASN are positively correlated in CRC, and CSN6-FASN axis, regulated by EGF, is responsible for poor prognosis of CRC. The EGF-CSN6-FASN axis promotes tumor growth and implies a treatment strategy of combination of orlistat and cetuximab. Patient-derived xenograft experiments prove the effectiveness of employing orlistat and cetuximab combination in suppressing tumor growth for CSN6/FASN-high CRC. Thus, CSN6-FASN axis reprograms lipogenesis to promote tumor growth and is a target for cancer intervening strategy in CRC.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Guanlin Wu,Yan Zhang,Bo Liang,Lianhong Yin,Meng Gao,Han Zhang,Youwei Xu,Xu Han,Yan Qi,Fang Liu,Lina Xu
Investigating and identifying pathogenic molecules of non-alcoholic fatty liver disease (NAFLD) has become imperative, which would serve as effective targets in the future. We established high-fat diet (HFD)-induced NAFLD model in mice and palmitic acid (PA)-induced model in mouse AML12 cells. The level of miR-218-5p was examined by qRT-PCR, and Elovl5 was identified as the potential target gene of miR-218-5p . The binding relationship between miR-218-5p and Elovl5 was validated by double luciferase reporter gene assay, and inhibition/overexpression of miR-218-5p in vitro . The functional mechanisms of miR-218-5p / Elovl5 in regulating lipogenesis in NAFLD were investigated in vivo and in vitro through gain- and loss-of-function studies. MiR-218-5p was significantly increased, and Elovl5 was decreased in model group. According to the double luciferase reporter and gene interference experiments in AML12 cells, Elovl5 was a target gene of miR-218-5p and its expression was regulated by miR-218-5p . The SREBP1-mediated lipogenesis signaling pathway regulated by Elovl5 was upregulated in model group. Moreover, silencing of miR-218-5p significantly upregulated Elovl5 expression, and suppressed SREBP1 signaling pathway in PA-induced AML-12 cells. Correspondingly, the cell injury, elevated TC, TG contents and lipid droplet accumulation were ameliorated. Furthermore, the effect of miR-218-5p on lipogenesis in vitro and in vivo was obstructed by si-Elovl5 , implicating that miR-218-5p promotes lipogenesis by targeting ELOVL5 in NAFLD. miR-218-5p could promote fatty acid synthesis by targeting Elovl5 , thereby accelerating the development of NAFLD, which is one of the key pathogenic mechanisms of NAFLD and provides a new molecular target for the management of NAFLD.
研究领域:
分子生物学
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肝病学
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病理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED MICROBIOLOGY
·
2019
·Vol. 127
·期 5
·1546-1555
·
IF 2.683
Song B.,Zhong Y.Z.,Zheng C.B.,Li F.N.,Duan Y.H.,Deng J.P.
AimsThe aims were to examine whether oral sodium propionate supplementation regulate lipid metabolism through modulating gut microbiota.Methods and ResultsICR male mice (26·98 ± 0·30 g) were randomly assigned to three groups (n = 10) and fed control diet (Con), high‐fat diet (HFD) and HFD plus propionate (Pro) respectively. In this study, we found that HFD increased the weight of final body, inguinal white adipose tissues (iWAT), epididymal white adipose tissue (eWAT) and perirenal white adipose tissue (pWAT), as well as the adipocyte mean area of iWAT and eWAT in mice (P < 0·05), whereas sodium propionate treatment reduced the weight of iWAT and pWAT as well as adipocyte mean area of iWAT in mice fed a HFD (P < 0·05). Moreover, in the iWAT, the mRNA expression of lipogenesis genes, including peroxisome proliferator activated receptor γ, acetyl‐CoA carboxylase and carnitine palmitoyl transferase‐1β, was upregulated by HFD challenge (P < 0·05), and the elevation of these genes was nearly reversed to the level of control diet‐fed mice by sodium propionate treatment. Meanwhile, sodium propionate treatment increased the hormone‐sensitive lipase mRNA expression in the iWAT of HFD‐fed mice (P < 0·05). High‐throughput pyrosequencing of the 16S rRNA demonstrated that sodium propionate treatment significantly recovered the gut microbiota dysbiosis in HFD‐fed mice, including the richness and diversity of microbiota and the ratio of Firmicutes to Bacteroidetes. Furthermore, the HFD‐induced reductions in colonic levels of butyrate and valerate were reversed by sodium propionate treatment, which also normalized the serum LPS level seen in HFD‐fed mice to the levels of the control diet‐fed mice.ConclusionsCollectively, these results indicated that sodium propionate treatment could improve lipid metabolism in HFD‐fed mice, and the potential mechanisms might be via regulating gut microbiota.Significance and Impact of the StudyWe demonstrated for the first time that oral sodium propionate significantly improved HFD‐induced dysbiosis of gut microbiota, indicating that the mitigative effect of propionate for HFD‐induced lipid dysmetabolism might be mediated by gut microbiota in mice.
研究领域:
营养学
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微生物学
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代谢学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ANIMAL SCIENCE
·
2024
·
IF 2.7
Ma Zifeng,Li Qiao,Xu Hongmei,Li Yueyue,Wang Shujin,Xiong Yan,Lan Daoliang,Li Jian,Xiong Xianrong,Fu Wei
Zearalenone (ZEN), a mycotoxin from Fusarium fungi, impairs fertility and milk production in female animals, however, the mechanisms remain poorly understood. Using the bovine mammary epithelial cells (MAC-T) as the model, this study investigated the impacts of ZEN on programmed cell death (PCD) and milk fat synthesis, and explored the underlying mechanism. We found that 10 ng/mL prolactin (PRL) notably enhanced the differentiation of MAC-T cells, promoting the expression of genes related to the synthesis of milk fat, protein, and lactose. Next, the toxic effects of different doses of ZEN on the differentiated MAC-T with PRL treatment were determined. 10 μM and 20 μM ZEN significantly reduced cell viability, induced oxidative stress, and triggered PCD (e.g. apoptosis and necrosis). Notably, ZEN exposure downregulated the mRNA/protein levels of critical factors involving in milk fat synthesis by disrupting the AKT-mTOR-PPARγ-ACSL4 pathway. Interestingly, melatonin (MT), known for its antioxidant properties, protected against the above ZEN-induced effects by enhancing the binding of PPARγ to the promoter regions of ACSL4, which led to the upregulated expression of ACSL4 gene. These results underscored the potential of MT to mitigate the adverse effects of ZEN on mammary cells, highlighting a way for potential therapeutic intervention.
研究领域:
兽医学
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毒理学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2019
·
IF 4.259
Zhang Jian-Mei,Sun Yin-Shuang,Zhao Li-Qin,Chen Tian-Tian,Fan Mei-Na,Jiao Hong-Chao,Zhao Jing-Peng,Wang Xiao-Juan,Li Fu-Chang,Li Hai-Fang,Lin Hai
The impact of gut microbiota and its metabolites on fat metabolism have been widely reported in human and animals. However, the critical mediators and the signal transductions are not well demonstrated. As ovipara, chicken represents a specific case in lipid metabolism that liver is the main site of lipid synthesis. The aim of this study is to elucidate the linkage of gut microbiota and fat synthesis in broiler chickens. The broilers were subjected to dietary treatments of combined probiotics (Animal bifidobacterium: 4 × 108 cfu/kg; Lactobacillus plantarum: 2 × 108 cfu/kg; Enterococcus faecalis: 2 × 108 cfu/kg; Clostridium butyrate: 2 × 108 cfu/kg, PB) and guar gum (1 g/kg, GG), respectively. Results showed that dietary supplementation of PB and GG changed the cecal microbiota diversity, altered short chain fatty acids (SCFAs) contents, and suppressed lipogenesis. In intestinal epithelial cells (IECs), SCFAs (acetate, propionate, and butyrate) up-regulated the expression of glucagon-like peptide-1 (GLP-1) via mitogen-activated protein kinase (MAPK) pathways, mainly via the phospho - extracellular regulated protein kinase (ERK) and phospho-p38 mitogen activated protein kinase (p38 MAPK) pathways. GLP-1 suppressed lipid accumulation in primary hepatocytes with the involvement of (AMP)-activated protein kinase/Acetyl CoA carboxylase (AMPK/ACC) signaling. In conclusion, the result suggests that SCFAs-induced GLP-1 secretion via MAPK pathway, which links the regulation of gut microbiota on hepatic lipogenesis in chickens.
研究领域:
动物营养学
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微生物学
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分子生物学
·
生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AQUACULTURE
·
2021
·
IF 4.242
Jia Xu,Shiwei Xie,Shuyan Chi,Shuang Zhang,Junming Cao,Beiping Tan
The increasing aquaculture production brought about the extensive use of high-lipid diets and antibiotics as effective means to spare costly protein and treat diseases, respectively. However dietary antibiotics and high-lipid diets both influence the gut microbiome . We hypothesized that antibiotics could affect the lipid metabolism by altering the composition of intestinal microbiota in fish at medium- and high-lipid diets. We explored this hypothesis by a 6-day administration of antibiotics mixtures to the diet of hybrid grouper ( Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂). Four diet groups were designed: medium-lipid (control diet, CD, 8.27% lipids), CD supplemented with antibiotics (vancomycin, neomycin sulfate, metronidazole ; ACD), high-lipid diet (HD, 15.32% lipids), and HD with antibiotics (AHD). The ACD and AHD groups exhibited significantly decreased crude lipids, lipid droplets, triglycerides , and total cholesterol contents of the liver (compared to CD and HD). The antibiotics treatment mainly upregulated the expressions of genes associated with lipolysis at the medium-lipid diet and downregulated the expression of lipogenesis-associated genes at the high-lipid diet. The antibiotics treatment mainly inhibited the expression of lipogenesis-associated proteins in the high-lipid diet, and mainly facilitated lipolysis in the medium-lipid diet. The antibiotics treatment significantly reduced the abundance and diversity of microbes, the abundance of Firmicutes , and Firmicutes / Bacteroidetes ratio. In addition, antibiotics homogenized the intestinal microbiota, which in turn caused analogous effects in medium- and high-lipid diets in grouper. In conclusion, short-term dietary antibiotics treatment improved the accumulation of lipids and lipid metabolism by inhibiting lipogenesis at the high-lipid level and facilitating lipolysis at the medium-lipid level via affecting the composition, diversity and functional pathways of gut microbiota.
研究领域:
水产养殖
·
微生物学
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营养学
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分子生物学
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生理学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Xin Jiang,Ziqing Yuan,Tingbo Ding,Ker Yu,Jibin Dong
The massive infiltration of suppressor immune cells within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is a major cause of treatment resistance. Reducing this infiltration may represent a potentially effective therapeutic strategy. Sphingomyelin synthase 2 (SMS2) is a crucial enzyme for sphingomyelin synthesis, contributing significantly to the integrity and function of the plasma membrane. In this study, we developed a self-assembling SMS2 siRNA gene expression plasmid for in vivo delivery. The SMS2 siRNA specifically inhibits SMS2 expression while preserving the expression and activity of SMS1. Administration of the self-assembling SMS2 siRNA suppresses tumor growth in a murine model of Panc02 pancreatic carcinoma, modulates the polarization of tumor-associated macrophages (TAMs), and reduces the infiltration of tumor-associated neutrophils (TANs) by regulating the NF-κB/CXCL5 pathway. Consequently, utilizing SMS2 siRNA to improve the local immunosuppressive microenvironment holds promise for pancreatic cancer therapy.
研究领域:
癌症生物学
·
分子生物学
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免疫学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
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