Open Medicine
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2023
·Vol. 18
·期 1
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IF 2.1
Haibin Li,Chunyan Zhang,Qiang Liu
Adverse cardiovascular events are associated with vascular calcification (VC) process, where vascular smooth muscle cells (VSMCs) differentiate into osteoblastic phenotype and deposit hydroxyapatite crystals. Microtubule-associated protein kinesin family member 2C (KIF2C) expression is decreased obviously in VSMC during calcification induction. Accordingly, we investigate the role and potential mechanism of KIF2C on VSMC calcification. The effects of β-glycerophosphate (β-GP)/KIF2C/lumican (LUM) on calcification, calcium content, alkaline phosphatase (ALP) activity, calcification-related markers, Tubulin, the ratio of polymerized (Po) to free (Fr) tubulin, as well as levels of LUM, apolipoprotein B (APOB), and KIF2C were assessed by Alizarin red S staining, calcium assay kit, ALP assay kit, Western blot, immunofluorescence, and quantitative real-time PCR. The interplay between LUM and APOB was estimated using co-immunoprecipitation and immunofluorescence. As a result, β-GP promoted calcification of human VMSCs (HVMSCs) and repressed KIF2C expression. KIF2C overexpression reversed the effect of β-GP on HVSMCs. LUM silencing attenuated β-GP-induced promotion on HVSMC calcification and increased KIF2C expression by interacting with APOB. Collectively, LUM silencing can alleviate β-GP-induced VSMC calcification through mitigating the repression of APOB on KIF2C expression.
研究领域:
心血管疾病
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Communications Biology
·
2026
·Vol. 9
·期 1
·390
·
IF 5.8
Li Keying,Zhao Xinying,Xie Zhuoyi,Wu Qiuchen,Jia Wenlu,Zhou Xiangrong,Gao Xiang,Zeng Ping,Li Jing,Niu Qiao,Qi Zhipeng,Cui Mengqiao,Song Weiyi
Lanthanum (La), the second most produced rare earth element, is detected in various environmental and human samples. Epidemiological studies have reported a strong association between La exposure and liver injury. However, the effects of early La exposure on liver development and underlying mechanisms remain limited. Here, we evaluate the hepatotoxicity of LaCl 3 at environmentally relevant concentrations using zebrafish larvae. Embryonic LaCl 3 exposure causes concentration-dependent hepatic steatosis, which cannot be reversed after exposure cessation. Metabolomic profiling reveals that very-low-density lipoprotein (VLDL) and its multiple downstream metabolites are consistently downregulated upon LaCl 3 treatment, together with increased triglycerides (TG) level, indicating impaired TG-VLDL biosynthesis. In addition, transcriptomics suggest that genes related to the PPAR α signaling pathway are significantly downregulated, especially those involved in TG-VLDL biosynthesis ( mttp and all apob subtypes). Further studies show that LaCl 3 can inhibit the transcriptional regulatory activity of PPAR α . The upregulation of the PPAR α signaling pathway corresponding genes of ppara , mttp , and apob effectively rescues LaCl 3 -induced liver impairments. Subsequently, a subcellular localization assay finds that increased ApoB degradation in the endoplasmic reticulum contributes to LaCl 3 -triggered lipid droplet accumulation. Overall, our findings fill critical research gaps regarding LaCl 3 -induced hepatotoxicity and provide important evidence for the environmental risk assessment of La.
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高影响因子
RSC Advances
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2017
·Vol. 7
·期 15
·8823-8831
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IF 3.108
Tsogzolmaa Ganbold,Gerile Gerile,Hai Xiao,Huricha Baigude
RNA interference (RNAi) has shown great potential for clinical treatment of a variety of diseases. As an effective post-transcriptional regulation, RNAi induces degradation of specific target mRNA, leading to a decreased level of disease related gene product, which could be resistant to conventional small molecule therapeutics. Because of the relatively small size of short interfering RNA (siRNA) as well as it's robustness in the design of efficient 20–22 nucleotide sequences targeting any known gene, delivery of siRNA in vitro and in vivo has achieved tremendous success by the design and fabrication of various carrier materials including peptides, lipids, and polymers. While siRNA delivery efficiency of these materials proved to be appreciable, their tissue specificity, biocompatibility and cytotoxicity still need much improvement. We report a novel siRNA delivery material designed by optimization of our previously reported peptidomimetic based lipoplex. The novel lipoplex, which bears a D-amino acid based dipeptide head group, possesses an ideal balance of increased stability in a tissue environment, and enhanced efficiency of tissue specific delivery as well as minimized cytotoxicity. The novel lipoplex carrying siRNA efficiently targeted mouse liver, initiated RNAi and knocked down the apoB dose dependently, which is confirmed by both RT-qPCR and Western blotting. Moreover, the novel lipoplex does not induce any apparent cytotoxicity, as confirmed by the measurement of liver enzyme levels in serum.
研究领域:
分子生物学
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药学
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生物技术
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高影响因子
JOURNAL OF DAIRY SCIENCE
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2023
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IF 3.5
Shendong Zhou,Mengru Chen,Meijuan Meng,Nana Ma,Wan Xie,Xiangzhen Shen,Zhixin Li,Guangjun Chang
ABSTRACT Ketosis is a metabolic disease that often occurs in dairy cows postpartum and results from disordered lipid metabolism. Acetyl-coenzyme A (CoA) acetyltransferase 2 ( ACAT2 ) is important for balancing cholesterol and triglyceride ( TG ) metabolism; however, its role in subclinical ketotic dairy cows is unclear. This study aimed to explore the potential correlation between ACAT2 and lipid metabolism disorders in subclinical ketotic cows through in vitro and in vivo experiments. In the in vivo experiment, liver tissue and blood samples were collected from healthy cows ( CON , n = 6, β-hydroxybutyric acid [ BHBA ] concentration < 1.0 mM) and subclinical ketotic cows (subclinical ketosis [ SCK] , n = 6, BHBA concentration = 1.2–3.0 mM) to explore the effect of ACAT2 on lipid metabolism disorders in SCK cows. For the in vitro experiment, bovine hepatocytes ( BHEC ) were used as the model. The effects of BHBA on ACAT2 and lipid metabolism were investigated via BHBA concentration gradient experiments. Subsequently, the relation between ACAT2 and lipid metabolism disorder was explored by transfection with siRNA of ACAT2. Transcriptomics showed an upregulation of differentially expression genes ( DEGs ) during lipid metabolism and significantly lower ACAT2 mRNA levels in the SCK group. Compared with the CON group in vivo, the SCK group showed significantly higher expression levels of peroxisome proliferator–activated receptor γ ( PPARγ ) and sterol regulator element binding protein 1c ( SREBP1c ) and significantly lower expression levels of peroxisome proliferator-activated receptor α ( PPARα ), carnitine palmitoyl-transferase 1A ( CPT1A ), sterol regulatory element binding transcription factor 2 ( SREBP2 ), and 3-hydroxy-3-methylglutaryl-CoA reductase ( HMGCR ). Moreover, the SCK group had a significantly higher liver TG content and significantly lower plasma total cholesterol ( TC ) and free cholesterol ( FC ) content. These results were indicative of TG and cholesterol metabolism disorders in the liver of dairy cows with SCK. Additionally, the SCK group showed an increased expression of Perilipin-2 ( PLIN2 ), decreased expression of apolipoprotein B ( APOB ), and decreased plasma concentration of very low-density lipoproteins ( VLDL ) and low-density lipoproteins-cholesterol ( LDL-C ) by downregulating ACAT2, which indicated an accumulation of TG in liver. I n vitro experiments showed that BHBA induced an increase in the TG content of BHEC, decreased content TC, increased expression of PPARγ and SREBP1c, and decreased expression of PPARα, CPT1A, SREBP2, and HMGCR. Additionally, BHBA increased the expression of PLIN2 in BHEC, decreased the expression and fluorescence intensity of ACAT2, and decreased the VLDL and LDL-C contents. Furthermore, silencing ACAT2 expression increased the TG content; decreased the TC, VLDL, and LDL-C contents; decreased the expression of HMGCR and SREBP2; and increased the expression of SREBP1c; but had no effect on the expression of PLIN2. These results suggest that ACAT2 downregulation in BHEC promotes TG accumulation and inhibits cholesterol synthesis, leading to TG and cholesterol metabolic disorders. In conclusion, ACAT2 downregulation in the SCK group inhibited cholesterol synthesis, increased TG synthesis, and reduced the contents of VLDL and LDL-C, eventually leading to disordered TG and cholesterol metabolism.
研究领域:
兽医学
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分子生物学
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生物化学
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动物生理学
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PubMed
高影响因子
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