JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2020
·Vol. 24
·期 9
·5168-5184
·
IF 4.486
Huan Nie,Yuanjun Deng,Chuiyang Zheng,Maoxing Pan,Jiqian Xie,Yupei Zhang,Qinhe Yang
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is still not fully understood, and currently, no effective pharmacotherapy is available. Nuclear receptors (NRs) are important biological participants in NAFLD that exhibit great therapeutic potential. Chaihu Shugan powder (CSP) is a traditional Chinese medicine (TCM) formula that has a wide therapeutic spectrum including NAFLD, but the effective components and functional mechanisms of CSP are unclear. We adopted a network pharmacology approach using multiple databases for Gene Ontology (GO) enrichment analysis and the molecular complex detection (MCODE) method for a protein-protein interaction (PPI) analysis, and we used molecular docking method to screen the NR targets and determine the corresponding CSP components. The screening results were validated through a NAFLD rat model that was used to explain the possible relationship between CSP and NAFLD. Finally, we screened PPARγ, FXR, PPARα, RARα and PPARδ as target genes and quercetin , kaempferol , naringenin , isorhamnetin and nobiletin as target compounds. The five components were detected through high-performance liquid chromatography-mass spectrometry (HPLC-MS), the results of which aligned with the docking experiments of PPARγ, PPARα and PPARδ. After CSP intervention, the NAFLD rat model showed ameliorated effects in terms of bodyweight, hepatic histopathology, and serum and liver lipids, and the mRNA levels of PPARγ, FXR, PPARα and RARα were significantly changed. The results from this study indicate that CSP exhibits healing effects in an NAFLD model and that the network pharmacology approach to screening NR targets and determining the corresponding CSP components is a practical strategy for explaining the mechanism by which CSP ameliorates NAFLD.
研究领域:
药理学
·
中药学
·
分子生物学
·
病理学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2024
·
IF 7.6
Ping Li,Bin Liu,Shu-Wen He,Ling Liu,Zhi-Hua Li
Triphenyltin (TPT), a widely used environmental contaminant in antifouling paints, is known for its neurotoxic effects. To investigate the multigenerational impacts of long-term exposure (6 weeks) to environmental concentrations of TPT (100 ng/L) on either parent, we performed mixed mating between control and exposed groups (males or females). Although there was no direct contact with TPT in the subsequent generations, both the first and second generations displayed behavioral abnormalities, including reduced activity and impaired cognitive function, with pronounced gender differences and anxiety-like behaviors. Females were more susceptible than males, displaying a significantly increased time spent in the mirror-proximal zone in both F1 and F2 generations. Additionally, F0 females exhibited a marked reduction in the time spent in the bright area, further supporting the role of sex differences in behavioral responses. Notably, the maternal contribution of marine medaka ( Oryzias melastigma ) played a more significant role in the inheritance of TPT-induced cognitive deficits. A reduction in DA levels and AChE activity was observed across generations, regardless of gender, underscoring the critical role of DA-AChE balance in maintaining cognitive function. Additionally, gender differences and the hereditary effects of TPT exposure on anxiety-like behaviors were strongly associated with the transcriptional regulation of pparγ and gst . Impaired transcription of key genes in the dopaminergic system resulted in reduced DA levels, with the intergenerational transmission of mao being closely linked to behavioral impairments. In summary, TPT-induced neurotoxicity presents both hereditary effects and gender-specific differences, emphasizing the maternal influence in the inheritance of cognitive abilities and shedding light on the genetic impact of parental exposure.
研究领域:
环境毒理学
·
神经科学
·
海洋生物学
·
遗传学
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2020
·
IF 5.115
Shuping Wei,Chaoli Xu,Yidan Zhang,Zhongqing Shi,Min Wu,Bin Yang
Objective To investigate the antifibrotic effect of the combination of a PPARγ agonist-loaded nanoparticle-microbubble complex with ultrasound (US) exposure on renal interstitial fibrosis (RIF). Materials and Methods Polylactide-co-glycolide (PLGA) nanoparticles were used to load PPARγ agonist (rosiglitazone, RSG) and prepare PLGA-RSG nanoparticles (PLNPs-RSG); then, a novel complex between PLNPs-RSG and SonoVue microbubbles (MBs) (PLNPs-RSG-MBs) was prepared. The size distribution, zeta potentials, RSG-loading capacity and entrapment efficiency were measured, and the release of RSG was assessed using a UV-vis spectrophotometer. The in vitro cytotoxicity and in vivo systemic toxicity assays were performed. The cellular uptake assessment was performed using a confocal laser scanning microscope (CLSM). The in vivo biodistribution assessment was performed using fluorescence imaging with a near-infrared (NIR) imaging system. Furthermore, this complex was administered to a unilateral ureteral obstruction (UUO) rat model with the assistance of US exposure to investigate the antifibrotic effect. Results This PLNPs-RSG-MBs complex had a size of 2199.5± 988.1 nm and a drug-loading efficiency of 28.5%. In vitro cytotoxicity and in vivo systemic toxicity assays indicated that the PLNPs-RSG-MBs complex displayed excellent biocompatibility. In addition, the complex showed high cellular uptake efficiency in vitro and kidney-targeting ability in vivo. In a UUO rat model, the combination of the PLNPs-RSG-MBs complex with US exposure significantly reduced collagen deposition and successfully attenuated renal fibrosis. Conclusion The combination of the PLNPs-RSG-MBs complex with US exposure may be a promising approach for the treatment of RIF.
研究领域:
药理学
·
纳米技术
·
医学影像学
·
肾脏疾病
✓ 已验证
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Lei Wang,Yufeng Tao,Xuesong Wang,Yuhan Gan,Yuting Zeng,Shasha Li,Qing Zhu
Phellinus igniarius is an important medicinal and edible fungus with diverse biological activities. This study aimed to investigate the effects of aqueous extract from P. igniarius (API) on the treatment of hyperuricemia (HUA) and related kidney damage. The chemical constituents of API were determined. The therapeutic effects of API on HUA and renal injury were assessed in adenine/potassium oxonate (PO)-treated mice. The constituent analysis of API revealed a predominance of polysaccharides (33.4 %), followed by total flavonoids (9.1 %), and total triterpenoids (3.5 %). Compared to control, the adenine/PO treatment greatly elevated serum uric acid (UA) levels but this elevation was attenuated by API. In the liver, the expression and activity of xanthine oxidase (XOD) were increased by HUA which were diminished by API. Furthermore, API was found to enhance the expression of UA transporter ABCG2 in the kidney and intestine of HUA mice, suggesting elevating UA excretion. Additionally, API ameliorated HUA-induced renal injury, as indicated by reduced serum BUN/creatinine levels, decreased glomerular and tubular damage, and lowered fibrotic levels. Network pharmacology analysis predicted that P. igniarius may regulate mitochondrial function to improve HUA-related renal injury. This prediction was then substantialized by the API-induced upregulation of NAD+/NADH ratio, ATP level, SOD2 activity, and expression of SOD2/PCG-1α/PPARγ in the kidney of HUA mice. Our results demonstrate that API may effectively ameliorate HUA by reducing UA production in the liver and enhancing UA excretion in the kidney and intestine, and it might be a potential therapy to HUA-related renal injury.
研究领域:
药理学
·
医学
·
生物化学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2019
·
IF 4.784
Jixu Wu,Huarong Shao,Jinhua Zhang,Yong Ying,Yanling Cheng,Dan Zhao,Xixi Dou,Huimin Lv,Shuaiguang Li,Fei Liu,Peixue Ling
We isolated and characterized a Mussel polysaccharide, α -D-glucan (MP-A), from Mytilus coruscus earlier. In this work, the pharmacological activity and mechanisms of MP-A as an oral supplement for non-alcoholic fatty liver disease (NAFLD) were explored. High fat diet (HFD) was utilized to induce NAFLD in Sprague Dawley male rats and MP-A (0.6 g/kg) was supplemented for 4 weeks. The results showed that MP-A supplementation reduced blood lipid levels, intrahepatic lipid accumulation and NAFLD activity score in HFD-fed rats. Additionally, the analysis of 16S rDNA sequencing on gut microbiota samples revealed that HFD could induce microbial dysbiosis. However, MP-A supplementation could remodel gut microbiota structure, inhibit LPS-TLR4-NF- κ B pathway activation, and restrain subsequent inflammation factors secretion. Furthermore, MP-A regulated the lipid metabolism by promoting the production of short chain fatty acids and suppressing PPAR γ and SREBP-1c expression. Our results support that MP-A can prevent against NAFLD and act as an oral supplementation for hepatoprotection via modulating gut microbiota and related gut-liver axis signaling pathways.
研究领域:
药理学
·
胃肠病学
·
微生物学
·
代谢学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2022
·
IF 16.744
Mingxin Qiao,Zhengyi Xu,Xibo Pei,Yanhua Liu,Jian Wang,Junyu Chen,Zhou Zhu,Qianbing Wan
Hyperlipidemia negatively affects osteogenesis, thereby impairing bone healing. However, few biomaterials have been developed for bone tissue engineering to solve this problem. Herein, the preparation of specific biomaterials that can promote osteogenesis and suppress adipogenesis holds great promise for reconstructive bone defect treatment. In this study, we propose the construction of a nano simvastatin-laden zeolitic imidazolate framework-8 (nano [email protected] ) modified injectable high-intensity biohydrogel, composed of poly (ethylene glycol) diacrylate (PEGDA) and sodium alginate (SA) to form nano [email protected] /PEGDA/SA (defined as nSZPS), which can stimulate osteogenic differentiation and inhibit adipogenic differentiation. The characterization and drug loading efficiency of the nanoparticles were examined to confirm the successful synthesis of nano [email protected] Within the PEGDA/SA delivery platform, nSZPS showed excellent injectability and mechanical strength through rheological and mechanical tests. Moreover, owing to the sustained release of SIM and bioactive Zn ions, nSZPS not only possessed excellent biocompatibility but also significantly enhanced the osteogenic differentiation ability and inhibited the adipogenic efficacy of BMSCs in vitro. Furthermore, nSZPS showed excellent osseointegration and lipid-lowering abilities in healing bone defects of hyperlipidemic rats by decreasing PPARγ expression and increasing RUNX2 expression in vivo. In addition, the bidirectional regulatory mechanisms of nSZPS in bone defects may be closely related to the mutual regulation of the PPARγ and Wnt/β-CATENIN pathways. In summary, this nano [email protected] modified injectable high-intensity biohydrogel might be a promising strategy for complex bone regeneration, especially in hyperlipidemic microenvironments.
研究领域:
生物材料
·
组织工程
·
骨再生
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
ENVIRONMENTAL RESEARCH
·
2025
·
IF 7.7
Yinling He,Zhendong Sun,Ning Wu,Chuanhai Li,Qunfang Zhou,Ligang Hu,Chunyang Liao,Guibin Jiang
Mounting evidence suggests that certain environmental contaminants can influence adipogenesis and function as obesogens, many of which act by activating the key regulator peroxisome proliferator-activated receptor γ (PPARγ). Synthetic phenolic antioxidants (SPAs) are ubiquitously detected in both environmental matrices and human samples, whereas their potential effects on lipid metabolism and the underlying molecular mechanisms remain largely unexplored. In this study, we aimed to assess the agonistic effects of SPAs on PPARγ, glucocorticoid receptor (GR), and retinoid X receptor α (RXRα), as well as their adipogenic potential. Luciferase reporter gene assays showed that among the ten commonly used SPAs evaluated, only 2,4,6-tri- tert -butylphenol (AO 246) exhibited efficacious agonistic activity toward RXRα. Environmentally relevant level exposure to AO 246 significantly promoted adipogenesis in 3T3-L1 cells, as evidenced by increased lipid accumulation and adipogenic gene expression, which could be alleviated by the RXRα antagonist UVI 3003. Further analysis revealed that the early stage of differentiation (Days 0–2) was the critical window for AO 246 to enhance adipogenesis and modify the gene expression profile. This study first demonstrated the adipogenic effects of AO 246 by activating RXRα but not PPARγ or GR, emphasizing its possible implications in obesity and associated health risks.
研究领域:
环境毒理学
·
分子生物学
·
药理学
·
内分泌学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Qing Zheng,Hanghang Liu,Hao Zhang,Yaobao Han,Jiaxin Yuan,Tingting Wang,Yifan Gao,Zhen Li
Mitochondrial dysfunction of neurons is the core pathogenesis of incurable Parkinson's disease (PD). It is crucial to ameliorate the mitochondrial dysfunction of neurons for boosting the therapy of PD. Herein, the remarkable promotion of mitochondrial biogenesis to ameliorate mitochondrial dysfunction of neurons and improve the treatment of PD by using mitochondria-targeted biomimetic nanoparticles, which are Cu 2- x Se-based nanoparticles functionalized with curcumin and wrapped with DSPE-PEG 2000 -TPP-modified macrophage membrane (denoted as CSCCT NPs), is reported. These nanoparticles can efficiently target mitochondria of damaged neurons in an inflammatory environment, and mediate the signaling pathway of NAD + /SIRT1/PGC-1 α /PPAR γ /NRF1/TFAM to alleviate 1-methyl-4-phenylpyridinium (MPP + )-induced neuronal toxicity. They can reduce the mitochondrial reactive oxygen species, restore mitochondrial membrane potential (MMP), protect the integrity of mitochondrial respiratory chain, and ameliorate mitochondrial dysfunction via promoting mitochondrial biogenesis, which synergistically improve the motor disorders and anxiety behavior of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. This study demonstrates that targeting mitochondrial biogenesis to ameliorate mitochondrial dysfunction has a great potential in the treatment of PD and mitochondria-related diseases.
研究领域:
神经科学
·
纳米技术
·
药理学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AMB Express
·
2024
·Vol. 14
·期 1
·1-16
·
IF 3.5
Yan Yan,Yuan Haisheng,Yang Fan,Na Heiya,Yu Xiuling,Liu Jingran,Wang Yuzhen
Non-alcoholic fatty liver disease (NAFLD) is becoming a significant global public health threat. Seabuckthorn ( Hippophae rhamnoides L.) has been used in traditional Chinese medicine (TCM). The hypolipidemic effects of Seabuckthorn polysaccharides (SP) against high-fat diets (HFD)-induced NAFLD were systematically explored and compared with that of Bifidobacterium lactis V9 ( B. Lactis V9). Results showed that HFD-induced alanine transaminase (ALT) and aspartate aminotransferase (AST) levels decreased by 2.8-fold and 4.5-fold, respectively, after SP supplementation. Moreover, the alleviating effect on hepatic lipid accumulation is better than that of B. Lactis V9. The ACC and FASN mRNA levels were significantly reduced by 1.8 fold ( P < 0.05) and 2.3 folds ( P < 0.05), respectively, while the CPT1α and PPARα mRNA levels was significantly increased by 2.3 fold ( P < 0.05) and 1.6 fold ( P < 0.05), respectively, after SP administration. SP activated phosphorylated-AMPK and inhibited PPARγ protein expression, improved serum oxidative stress and inflammation ( P < 0.05). SP supplementation leads to increased hepatic expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and Superoxide dismutase-2 (SOD-2). Furthermore, SP treatment improved HFD-induced intestinal dysbiosis. Lentisphaerae , Firmicutes , Tenericutes and Peptococcus sp., RC9_gut_group sp., and Parabacteroides sp. of the gut microbiota were significantly associated with hepatic steatosis and indicators related to oxidative stress and inflammation. Therefore, SP can mitigate hepatic lipid accumulation by regulating Nrf-2/HO-1 signaling pathways and gut microbiota. This study offers new evidence supporting the use of SP as a prebiotic treatment for NAFLD.
研究领域:
药理学
·
肝病学
·
营养学
·
微生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DAIRY SCIENCE
·
2023
·
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
·
分子生物学
·
生物化学
·
动物生理学
✓ 已验证
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）