MOLECULAR BIOLOGY REPORTS
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2024
·Vol. 51
·期 1
·1-11
·
IF 2.6
Wang Miao,Hong Ling,Cai Luyi,Zhang Ziyi,Jiang Ningdong,Chen Yijing,Ying Qian,Kong Lingpeng,Wei Zhiyun,Xu Yao,Jin Liping
Background Familial hypercholesterolemia (FH) is an autosomal dominant disease of lipid metabolism mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Genetic detection of patients with FH help with precise diagnosis and treatment, thus reducing the risk of coronary heart disease (CHD) and other related diseases. The study aimed to identify the causative gene mutations in a Chinese FH family and reveal the pathogenicity and the mechanism of these mutations. Methods and results Whole exome sequencing was performed in a patient with severe lipid metabolism dysfunction seeking fertility guidance from a Chinese FH family. Two LDLR variants c.1875 C > G (p.N625K; novel variant) and c.1448G > A (p.W483*) were identified in the family. Wildtype and mutant LDLR constructs were established by the site-direct mutagenesis technique. Functional studies were carried out by cell transfection to evaluate the impact of detected variants on LDLR activity. The two variants were proven to affect LDL uptake and binding, resulting in cholesterol clearance reduction to different degrees. According to The American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines, the W483* variant was classified as “Pathogenic”, while the N625K variant as “VUS”. Conclusions Our results provide novel experimental evidence of functional alteration by LDLR variants identified in our study and expand the mutational spectrum of LDLR mutation induced FH.
研究领域:
医学遗传学
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脂质代谢
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心血管疾病
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PubMed
高影响因子
JOURNAL OF FOOD BIOCHEMISTRY
·
2025
·Vol. 2025
·期 1
·8349248
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IF 4.2
Yuanjie Wu,Yuntian Zhang,Xike Wu,Ziyan Zhang,Junhui Shen,Nan Tian,Chunlei Fan
This study investigated the effects of tanshinone IIA combined with rutin and squalene (RTS) on atherosclerosis (AS) associated with hyperlipidemia and the underlying mechanisms. Female New Zealand rabbits were subjected to a hyperlipidemia and AS model. Treatment with RTS for 4 weeks reduced the weight, and some serum lipid levels include serum TC, serum TG, serum LDL-C. RTS also improved lesions of the liver and aorta. In vitro analyses showed that RTS significantly activated LDLR-mediated hepatic lipid endocytosis, but blocking LDLR activation with si-SREBP2 attenuated the therapeutic effect, which demonstrated that RTS can activate the SREBP2/LDLR pathway mediating liver clearance of blood lipids. This study highlights the therapeutic potential of RTS in hyperlipidemia and AS. As a convenient form of a combination drug, RTS has shown considerable potential in the improvement of hyperlipidemia combined with AS.
研究领域:
药理学
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心血管病学
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分子生物学
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DOI
高影响因子
Food & Function
·
2023
·Vol. 14
·期 7
·3269-3278
·
IF 6.1
Ye-Wei Huang,Li-Tian Wang,Meng Zhang,Yan Nie,Jin-Bo Yang,Wen-Luer Meng,Xuan-Jun Wang,Jun Sheng
Increasing low-density lipoprotein receptor (LDLR) protein levels represents a key strategy for the prevention and treatment. Berberine can reportedly alleviate non-alcoholic fatty liver disease (NAFLD) by increasing the LDLR expression in an ERK1/2 signaling-dependent manner of NAFLD. Studies have shown that caffeine can inhibit fat deposition in the livers of mice; however, caffeine has not been reported to alleviate NAFLD by augmenting the LDLR expression via targeting EGFR. Here, an MTT assay, western blotting, RT-qPCR, immunohistochemistry, and surface plasmon resonance (SPR) analysis were used to investigate the role of caffeine in low-density lipoprotein cholesterol (LDL-C) clearance both in vitro and in vivo. In vitro, we found that caffeine could activate the EGFR-ERK1/2 signaling pathway in HepG2 cells, leading to increased LDLR mRNA and protein expression, and this effect could be inhibited by cetuximab. The SPR assay results have indicated that caffeine may increase the LDLR expression by directly binding to the EGFR extracellular domain and activating the EGFR-ERK1/2 signaling pathway. In vivo, caffeine markedly improved fatty liver and related blood indices in ApoE KO mice with high-fat-diet-induced NAFLD. Consistent with our in vitro results, we found that caffeine could also activate EGFR-ERK1/2 signaling and promote the LDLR expression in ApoE KO mice. In summary, caffeine can enhance the LDLR expression by directly binding to EGFR and activating the EGFR-ERK1/2 signaling pathway. EGFR signaling may represent a novel target for the prevention and treatment of NAFLD.
研究领域:
药理学
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分子生物学
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细胞生物学
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病理生理学
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DOI
PubMed
高影响因子
PLoS Pathogens
·
2026
·Vol. 22
·期 7
·e1014453
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IF 4.9
Xiangshu Qiu,Rongguang Lu,Jiaxin Tian,He Zhang,Jiyong Zhou,Mengsi Sun,Xinyu Cao,Xiangyu Zhu,Bocheng Liu,Qihui Yu,Yuanyuan Li,Hualei Wang,Ningyi Jin,Huijun Lu,Ning Shi
Getah virus (GETV), a mosquito-borne alphavirus, poses an emerging threat to public health with its increasingly broad host spectrum. While glycosaminoglycans (GAGs) serve as critical attachment factors for many alphaviruses and the low-density lipoprotein receptor (LDLR) facilitates the cellular entry of several members, the precise viral determinants governing these interactions and their implications for viral virulence remain poorly defined. Here, we introduced an H86Y substitution, a potential adaptive mutation site, within the E2 glycoprotein of GETV using reverse genetics. The H86Y mutant replicated more efficiently in mosquito C6/36 cells but was consistently attenuated across several mammalian cell lines. In susceptible mouse models, H86Y infection led to reduced viral loads, milder histopathology, and lower inflammatory responses compared with the parental virus, yet still elicited robust protective immunity in adult mice. Mechanistically, a series of functional assays, including infection in GAG-deficient cells, decoy inhibition, co-immunoprecipitation, receptor overexpression and knockdown, and biolayer interferometry, demonstrated that the residue 86 in E2 glycoprotein is a critical determinant for GETV binding to both GAGs and LDLR. The H86Y mutation concurrently reduces these interactions, contributing the impairment of virus attachment and entry into mammalian cells. Furthermore, the GAG-binding site functionally overlaps with the LDLR interaction interface. In LDLR-deficient suckling mice, the impaired replication of H86Y persisted in examined tissues. However, pre-treatment with heparinase nearly completely eliminated this attenuation phenotype, further confirming that LDLR and GAG are the key host factors mediating attenuation phenotype for H86Y. In summary, the residue 86 of the GETV E2 glycoprotein represents a determinant of viral virulence, and an H86Y mutation attenuates GAGs and LDLR-dependent infection, providing mechanistic insights into alphavirus-host interactions and a potential target for antiviral and vaccine development.
Getah virus is an emerging mosquito-borne alphavirus. We investigated a naturally occurring substitution in the viral E2 glycoprotein, where histidine at position 86 is replaced by tyrosine. This single change, which we call H86Y, weakened the virus in mammalian cells and mice but unexpectedly enhanced its ability to infect mosquito cells. This host-specific switch may explain why the mutation persists in nature despite reducing disease severity in animals. Mechanistically, the attenuation was linked to impaired viral attachment and entry, resulting from a specific reduction in binding affinity for two critical host molecules, the attachment factor GAGs and the cellular entry receptor LDLR. Also, the GAG-binding site functionally overlaps with the LDLR interaction interface. Multiple mouse models supported that LDLR and GAGs are the key host factors mediating attenuation phenotype for H86Y. Despite being weakened, the mutant virus still triggered strong protective immunity, making it a promising vaccine candidate. Together, our findings identify E2 residue 86 as a key virulence determinant that modulates receptor usage, offering a precise target for antiviral and vaccine development against alphaviruses.
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DOI
PubMed
高影响因子
ACS Omega
·
2025
·
IF 4.3
Kaiyue Zuo,Naiyu Liu,Peng Zhou,Yingrui Wei,Jian Lin,Xinjie Zhu
Low-density lipoprotein receptor (LDLR), which serves as one of the most major entry receptors for many viruses in both human and mouse cells, plays a vital role in virus infection. However, there are no effective small molecules available to inhibit LDLR expression and exhibit antiviral effects. Here, we screened Bruceine A (BA), a natural product derived from the major constituents in Brucea javanica(L.) Merr. which inhibited vesicular stomatitis virus (VSV) infection in vitro. Mechanistically, BA blocked viral adsorption and internalization, facilitating antiviral effects through lysosome-mediated degradation of LDLR. Genetic knockdown of Ldlr exhibited strong antiviral effects. To the best of our knowledge, BA is the first LDLR-selective inhibitor, and our findings reveal that BA may serve as a potent and broad-spectrum virus entry inhibitor based on LDLR entry receptor.
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
·
IF 5.7
Jingyi Ren,Jinshi Zuo,Bowen Yin,Dan Huang,Rui Wen,Huanting Pei,Jiarui Liu,Yadong Zhang,Siqi Zhu,Shuman Zhen,Yuxia Ma
Perfluorooctanesulfonate (PFOS) is a widespread, persistent environmental pollutant that exerts apparent liver toxicity. Flaxseed oil (FO), a dietary oil rich in α-linolenic acid, has been demonstrated to possess a diverse array of health benefits. However, whether FO protects against PFOS-induced liver injury and its underlying mechanisms remain unclear. C57/BL6 mice were orally treated with different concentrations of FO alone or in combination with 10 mg/kg of PFOS for 28 consecutive days. Blood and liver tissues were collected for proteomic, histopathological, biochemical, immunohistochemical, and molecular examinations. Results demonstrated that FO supplementation reduced PFOS-induced liver injury, as evidenced by a decrease in histopathological changes, serum transaminase (ALT and AST) levels, levels of oxidative stress, and inflammatory cytokine (TNF-α, IL-1β, and IL-6) levels. Proteomic analyses showed that differentially expressed proteins were enriched in cholesterol metabolic pathways when comparing the PFOS group to the FO supplementation groups. The expression of cholesterol metabolism-related proteins was also subsequently measured, revealing that FO supplementation decreased the protein expressions of SREBP2, HMGCR, and LDLR while increasing the expression of CYP7A1. This study demonstrates that FO can alleviate PFOS-induced hepatotoxicity by regulating hepatic cholesterol metabolism, indicating that FO may serve as an effective dietary intervention for preventing liver injury caused by PFOS.
研究领域:
毒理学
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营养学
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分子生物学
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肝病学
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DOI
PubMed
高影响因子
FITOTERAPIA
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2023
·
IF 3.4
Shuai-Nan Zhang,Qi Liu,Xu-Zhao Li,Wu-De Yang,Ying Zhou
Ancient Chinese medicine literature and modern pharmacological studies show that Sophora tonkinensis Gagnep. (ST) has a protective effect on the heart. A biolabel research based on omics and bioinformatics and experimental validation were used to explore the application value of ST in the treatment of heart diseases. Therapeutic potential, mechanism of action, and material basis of ST in treating heart diseases were analyzed by proteomics, metabolomics, bioinformatics, and molecular docking. Cardioprotective effects and mechanisms of ST and active compounds were verified by echocardiography, HE and Masson staining, biochemical analysis, and ELISA in the isoproterenol hydrochloride-induced myocardial ischemia (MI) mice model. The biolabel research suggested that the therapeutic potential of ST for MI may be particularly significant among the heart diseases it may treat. In the isoprenaline hydrochloride-induced MI mice model, ST and its five active compounds (caffeic acid, gallic acid , betulinic acid , esculetin , and cinnamic acid) showed significant protective effects against echocardiographic changes and histopathological damages of the ischemic myocardial tissue. Meanwhile, they showed a tendency to correct mitochondrial structure and function damage and the abnormal expression of 12 biolables (DCTN1, DCTN3, and SCARB2, etc.) in the vesicle-mediated transport pathway, inflammatory cytokines (IL-1β, IL-6, and IL-10, etc.), and low density lipoprotein receptor (LDLR). The biolabel research identifies a new application value of ST in the treatment of heart diseases. ST and its active compounds inhibit mitochondrial impairments, inflammation, and LDLR deficiency through regulating the vesicle-mediated transport pathway, thus achieving the purpose of treating MI.
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PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-20
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IF 14.7
Chen Jinyong,Ren Tanchen,Xie Lan,Hu Haochang,Li Xu,Maitusong Miribani,Zhou Xuhao,Hu Wangxing,Xu Dilin,Qian Yi,Cheng Si,Yu Kaixiang,Wang Jian`an,Liu Xianbao
Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. Hence, an efficient drug delivery system could serve as a valuable tool in drug screening and potentially enhance therapeutic efficacy. However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. Accordingly, we develop a magnetic nanocarrier functionalized with PAR2-targeting hexapeptide for dual-active targeting drug delivery. We show that the nanocarriers effectively deliver XCT790—an anti-calcification drug—to the calcified aortic valve under extra magnetic field navigation. We demonstrate that the nano-cargoes consequently inhibit the osteogenic differentiation of valvular interstitial cells, and alleviate aortic valve calcification and stenosis in a high-fat diet-fed low-density lipoprotein receptor-deficient ( Ldlr −/− ) mouse model. This work combining PAR2- and magnetic-targeting presents an effective targeted drug delivery system for treating calcific aortic valve disease in a murine model, promising future clinical translation.
研究领域:
心血管疾病
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药物递送
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纳米技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHIMIE
·
2023
·
IF 3.9
Ya-nan Ou-Yang,Fen-fen Deng,Yun-jia Wang,Meng Chen,Peng-fei Yang,Zhe Yang,Zhongmin Tian
A high-salt diet is known to increase serum cholesterol levels; however, the underlying mechanism of salt - induced dyslipidemia in patients with salt-sensitivity remains poorly understood. We aimed to investigate whether high-salt diet (HSD) can induce dyslipidemia and elucidate the underlying mechanism of salt-induced dyslipidemia in Dahl salt - sensitive (SS) rats. Metabolomic and biochemical analyses revealed that the consumption of an HSD (8 % NaCl) significantly increased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL - C) in SS rats. The enzyme-linked immunosorbent assay demonstrated an increase in circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, accompanied by a decrease in hepatic low-density lipoprotein receptor (LDLR) levels due to HSD consumption. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis revealed that HSD consumption activated sterol regulatory element-binding protein-2 (SREBP2) expression in the liver and kidney, resulting in upregulation of PCSK9 at the transcriptional level in the liver and at the translational level in the kidney, ultimately increasing circulating PCSK9 levels. The combined effects of HSD on the liver and kidney contributed to the development of hypercholesterolemia. Furthermore, an in vitro assay confirmed that high-salt exposure led to an increase in the protein expression of SREBP2 and PCSK9 secretion, thereby reducing low-density lipoprotein (LDL) uptake. This study, for the first time, shows that an HSD induces dyslipidemia through activation of the SREBP2/PCSK9 pathway, providing new insights into the prevention and treatment of dyslipidemia in patients with salt sensitivity.
研究领域:
营养学
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心血管疾病
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分子生物学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
CELL BIOLOGY AND TOXICOLOGY
·
2023
·
IF 6.1
Xie Wenqing,Shan Yue,Wu Zhuonan,Liu Nan,Yang Jinjin,Zhang Hanlin,Sun Shiming,Chi Jufang,Feng Weizhong,Lin Hui,Guo Hangyuan
Objectives To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in hcy-induced calcific aortic valve disease (CAVD). Background The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited. Methods In vivo, we use the low-density lipoprotein receptor (LDLR) and Herpud1 double knockout (LDLR−/−/Herpud1−/−) mice and used high methionine diet (HMD) to assess of aortic valve calcification lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). In vitro, the role of Herpud1 in the Hcy-related osteogenic differentiation of AVICs was investigated by manipulating of Herpud1 expression. Results Herpud1 was highly expressed in calcified human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. Herpud1 deficiency inhibited hcy-induced CAVD in vitro and in vivo. Herpud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. ERS inhibitor 4-phenyl butyric acid (4-PBA) significantly attenuated aortic valve calcification in HMD-fed low-density lipoprotein receptor−/− (LDLR−/−) mice by suppressing ERS and subsequent Herpud1 biosynthesis. Conclusions These findings identify a previously unknown mechanism of Herpud1 upregulation in Hcy-related CAVD, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression. Highlights • Herpud1 is upregulated in the leaflets of Hcy-treated mice and patients with CAVD. • In mice, global knockout of Herpud1 alleviates aortic valve calcification and Herpud1 silencing activates cell autophagy, inhibiting osteogenic differentiation of AVICs induced by Hcy. • 4-PBA suppressed Herpud1 expression to alleviate AVIC calcification in Hcy treated AVICs and to mitigate aortic valve calcification in mice. Graphical Abstract
研究领域:
心血管疾病
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分子生物学
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细胞生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
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2022
·
IF 16.874
Ting Dai,Wenming He,Shuangshuang Tu,Jinru Han,Bo Yuan,Chenyang Yao,Wenzhi Ren,Aiguo Wu
Given that apoptosis increases the risk of plaque rupture, strategies that reduce intracellular lipid levels without killing foam cells are warranted for safe and effective treatment of atherosclerosis. In this study, a mild phototherapy strategy is carried out to achieve the hypothesis. Foam cell-targeted nanoprobes that allow photothermal therapy (PTT) and/or photodynamic therapy (PDT) were prepared by loading hyaluronan and porphine onto black TiO 2 nanoparticles. The results showed that when temperatures below 45 °C, PTT alone and PTT + PDT significantly reduced the intracellular lipid burden without inducing evidently apoptosis or necrosis. In contrast, the use of PDT alone resulted in only a slight reduction in lipid levels and induced massive apoptosis or necrosis. The protective effect against apoptosis or necrosis after mild-temperature PTT and PTT + PDT was correlated with the upregulation of heat shock protein 27. Further, mild-temperature PTT and PTT + PDT attenuated intracellular cholesterol biosynthesis and excess cholesterol uptake via the SREBP2/LDLR pathway, and also triggered ABCA1-mediated cholesterol efflux, ultimately inhibiting lipid accumulation in foam cells. Our results offer new insights into the mechanism of lipid regulation in foam cells and indicate that the black TiO 2 nanoprobes could allow safer and more effective phototherapy of atherosclerosis.
研究领域:
纳米技术
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光疗
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心血管疾病
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脂质代谢
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
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2024
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IF 5.1
Sijia Zhu,Jiyu Yang,Pengkui Xia,Sha Li,Qi Wang,Kaikai Li,Bin Li,Jing Li
Konjac glucomannan (KGM) is a dietary fiber supplement that exhibits multiple biological activities, including weight control and regulation of glucose and lipid metabolism. Currently, KGM intake patterns in practical applications include KGM sol, thermal irreversible gel, and frozen thermal irreversible gel. In this study, four intake patterns of KGM, namely KGM sol (KS), deacetylated KGM (DK), KGM gel (KG) and frozen KGM gel (FKG), were used as materials to explore the effects of KGM intake patterns on glucose and lipid metabolism and intestinal flora of obese mice induced by high fat diet under the same dose. Results showed that any type of KGM intake could reduce body weight, fat mass, lipid levels, and insulin resistance in obese mice, as well as partially alleviating liver damage and inflammation caused by obesity. However, KS has the most significant effect on controlling blood glucose and blood lipid in obese mice. Additionally, it was found that KS, DK, KG and FKG can increase the α-diversity of intestinal microflora in high-fat mice, and improve the microflora disorder in high-fat mice. Finally, KS may increase the levels of fasting appetite hormones GLP-1 and PYY in mice, up-regulate the expression of LDLR, GCK and G-6-pase mRNA, and increase the production of short-chain fatty acids (SCFAs) in the intestinal flora of mice, thus regulating glucose and lipid metabolism . This study systematically investigated the effects of different intake forms of KGM on metabolism and intestinal flora in obese mice, which is of great significance for further understanding the role of KGM in the prevention and treatment of obesity metabolic diseases, and for developing targeted dietary interventions.
研究领域:
营养学
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代谢研究
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肥胖研究
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肠道微生物
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）