BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2024
·
IF 4.2
Chunmeng Ding,Zhenguo Shen,Ruonan Xu,Yajing Liu,Mengyue Xu,Chenyu Fan,Dongyue Hu,Tian Xing
Aim To investigate the impact of exosomes released by Porphyromonas gingivalis -Lipopolysaccharide activated THP-1 macrophages and human periodontal ligament fibroblasts on hepatocyte fat metabolism. Results The liver of rats with experimental periodontitis showed obvious steatosis and inflammation compared with control rats. The culture supernatant of macrophages and human periodontal ligament fibroblasts (hPDLFs), when stimulated with Pg-LPS, induced lipogenesis in HepG2 cells. Furthermore, the lipid-promoting effect was effectively inhibited by the addition of the exosome inhibitor GW4869. Subsequently, we isolated exosomes from cells associated with periodontitis. Exosomes released by Pg-LPS-stimulated macrophages and hPDLFs are taken up by hepatocytes, causing mRNA expression related to fat synthesis, promoting triglyceride synthesis, and aggravating NAFLD progression. Finally, two sets of exosomes were injected into mice through the tail vein. In vivo experiments have also demonstrated that periodontitis-associated exosomes promote the development of hepatic injury and steatosis, upregulate SCD-1 expression and inhibit the AMPK signaling pathway. Conclusions In conclusion, we found that exosomes associated with periodontitis promote hepatocyte adipogenesis by increasing the expression of SCD-1 and suppressing the AMPK pathway, which indicates that close monitoring of the progression of stomatopathy associated extra-oral disorders is important and establishes a theoretical foundation for the prevention and management of fatty liver disease linked to periodontitis.
研究领域:
分子生物学
·
细胞生物学
·
病理学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
STEM CELLS AND DEVELOPMENT
·
2024
·
IF 2.5
Yaping Xu,Xiangli Zhang,Zhikun Fu,Yan Dong,Yuexin Yu,Yingtian Liu,Ziyu Liu,Jinfu Chen,Yao Yao,Yan Chen,Jer Ping Ooi,Bakiah Shaharuddin,Bin Yang,Jun Jie Tan,zhikun Guo
Heart failure is still the main cause of mortality worldwide. This study investigated the characteristics of human pericardial fluid-derived cells (hPFCs) and their effects in treating doxorubicin (DOX)-induced heart failure (HF) rats through intrapericardial injection. hPFCs were isolated from patients who underwent heart transplantation (N=5). These cells that primarily expressed SCA-1, NANOG, mesenchymal markers CD90, CD105 and CD73, were able to form adipocytes, osteoblasts, and cardiomyocytes in vitro. Passage 3 hPFCs (2.5 ×105 cells/heart) were injected into the pericardial cavity of the doxorubicin (DOX)-injured rat hearts, significantly improving cardiac functions after 4 weeks. The tracked and engrafted RFP-tagged hPFCs co-expressed cardiac troponin T and connexin 43 after 4 weeks in the host myocardium. This observation was also coupled with a significant reduction in cardiac fibrosis following hPFCs treatment (P<0.0001 versus untreated). The elevated inflammatory cytokine IL-6, IL-10, and TNF-α in the DOX-treated hearts were found to have significantly reduced (P<0.001 versus untreated), while the regional pro-angiogenic vascular endothelial growth factor A (VEGFA) level was increased in the hPFCs-treated group after 4 weeks (P<0.05 versus untreated). hPFCs possess stem cell characteristics and can improve cardiac functions of DOX-induced heart failure rats after 4 weeks through pericardial administration. The improvements were attributed to a significant reduction in cardiac fibrosis, inflammation, and elevated regional pro-angiogenesis factor VEGFA, with evidence of cellular engraftment and differentiation in the host myocardium.
研究领域:
心脏病学
·
干细胞生物学
·
再生医学
✓ 已验证
DOI
PubMed
高影响因子
STEM CELLS AND DEVELOPMENT
·
2023
·
IF 4
Mr. Genghua Xu,Ms. Nuoya Liu,Ms. Yaqing Qiu,Ms. Jiayu Qi,Prof. Danyan Zhu
The histamine H3 receptor, prominently expressed in neurons with a minor presence in glial cells, acts as both an autoreceptor and an alloreceptor, controlling the release of histamine and other neurotransmitters. The receptor impacts various essential physiological processes. Our team's initial investigations had demonstrated that the histamine H3 receptor antagonists could facilitate the nerve regeneration via promoting the histamine H1 receptors on primary neural stem cells in the traumatic brain injury mouse, which suggested the potential of histamine H3 receptor as a promising target for treating neurological disorders and promoting nerve regeneration. Pitolisant (PITO) is the only histamine H3 receptor antagonist approved by the FDA for treating narcolepsy. However, there are no reports on Pitolisant in neural development or regeneration, and it is urgent to be further studied in strong biological activity models in vitro. The embryonic stem (ES) cells were differentiated into neural cells in vitro, which replicated the neurodevelopmental processes that occur in vivo. It also provided an alternative model for studying neurodevelopmental processes and testing drugs for neurological conditions. Therefore, we aimed to elucidate the regulatory role of Pitolisant in the early differentiation of ES cells into neural cells. Our results demonstrated that Pitolisant could promote the differentiation of ES cells towards neural stem cells (NSCs) and stimulated the formation of growth cones. Furthermore, Pitolisant was capable of inducing the polarization of NSCs through the cAMP-LKB1-SAD/MARK2 pathway, but had no significant effect on later neuronal maturation. Pitolisant altered mitochondrial morphology and up-regulated the levels of mitochondrial-related proteins TOM20, Drp1, and p-Drp1, and reversed the inhibitory effect of Mdivi-1 on mitochondrial fission during the early neural differentiation of ES cells. Additionally, Pitolisant induced the increase in cytosolic Ca2+. Our study provided an experimental foundation for the potential application of histamine H3 receptor-targeted modulators in the field of neuroregeneration.
研究领域:
神经科学
·
干细胞生物学
·
药理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
STEM CELLS AND DEVELOPMENT
·
2023
·
IF 4
Ziqiu Xiao,Yue Zhang,Guohua Yuan,Guobin Yang
Tooth dentin is a crucial tooth structure. The biological process of odontoblast differentiation is essential for formation of normal dentin. Accumulation of reactive oxygen species (ROS) leads to oxidative stress, which can influence the differentiation of several cells. As a member of the importin-β superfamily, importin 7 (IPO7) is essential for nucleocytoplasmic transport and plays an important role in the processes of odontoblast differentiation and oxidative stress. Nevertheless, the association between ROS, IPO7, and odontoblast differentiation in mouse dental papilla cells (mDPCs) and the underlying mechanisms remain to be elucidated. In this study, we confirmed that ROS suppressed odontoblastic differentiation of mDPCs as well as the expression and nucleocytoplasmic shuttle of IPO7 in cells, while overexpression of IPO7 can rescue these effects. ROS resulted in increased phosphorylation of p38 and cytoplasmic aggregation of phosphorylated p38 (p-p38), which was able to be reversed by overexpression of IPO7. p-p38 interacted with IPO7 in mDPCs without hydrogen peroxide (H2O2) treatment, but in the presence of H2O2, the interaction between p-p38 and IPO7 was significantly decreased. Inhibition of IPO7 increased the expression level and nuclear translocation of p53, which are mediated by cytoplasmic aggregation of p-p38. In conclusion, ROS inhibited odontoblastic differentiation of mDPCs, which is mediated by downregulation and damaged nucleocytoplasmic shuttle of IPO7.
研究领域:
牙齿生物学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
STEM CELLS AND DEVELOPMENT
·
2019
·Vol. 28
·期 13
·871-881
·
IF 3.147
Lin Li,Lisheng Chu,Cuicui Ren,Jun Wang,Siqi Sun,Tianyi Li,Yuanjun Yin
Bone marrow-derived mesenchymal stem cells (BMSCs) hold great promise for treating ischemic stroke owing to their capacity to secrete various trophic factors with potent angiogenic and neurogenic potentials. However, the relatively poor migratory capacity of BMSCs toward infarcted regions limits effective therapies for the treatment of stroke. The combination of BMSCs and pharmacological agent can promote the migration of BMSCs toward infarcted regions and improve the therapeutic effects after stroke. In this study, we aimed to investigate whether BMSCs combined with tetramethylpyrazine (TMP) enhanced BMSC migration into the ischemic brain, which had better therapeutic effect in the treatment of stroke. In a rat stroke model, we found that combination treatment significantly upregulated ischemic brain stromal-derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) expressions, and promoted BMSCs homing toward the ischemic regions than BMSC monotherapy. Moreover, BMSCs combined with TMP synergistically increased the expression of vascular endothelial growth factor and brain-derived neurotrophic factor, promoted angiogenesis and neurogenesis, and improved functional outcome after stroke. These results suggest that combination treatment could not only enhance the migration of BMSCs into the ischemic brain but also act in a synergistic way to potentiate endogenous repair processes and functional recovery after ischemic stroke.
研究领域:
神经科学
·
药理学
·
再生医学
·
干细胞治疗
✓ 已验证
DOI
PubMed
高影响因子
STEM CELLS AND DEVELOPMENT
·
2021
·Vol. 30
·期 10
·526-536
·
IF 3.272
Chaoqun Hu,Yun He,Daijiang Liu,Li Zhao,Shuyu Fang,Bin Tan,Shifang Dong,Yi Wang,Tongchuan He,Yang Bi
Our previous studies reported that urine-derived stem cells (USCs) possess a strong self-renewal ability and multidirectional differentiation potential and thus are an ideal candidate cell source for hepatocellular transplantation. USC transplantation may repair the pathological changes of chronic liver injury to a certain extent, and hypoxia pretreatment may improve the recovery efficiency of USCs. Therefore, the present study aimed to investigate the possible mechanism of the improved recovery efficiency of hypoxia-pretreated USCs. A chronic liver injury model was established by intraperitoneal injection of carbon tetrachloride into nude mice. USCs were transplanted via caudal vein injection. Hematoxylin and eosin staining and Masson's staining were performed to determine the pathology of the liver. Immunofluorescence and frozen section biopsy were performed to determine differentiation and cell fusion in vivo. Cell coculture was used to detect cell fusion in vitro. The proliferative ability of USCs was evaluated using cell viability and colony formation assays, and the migratory functions of USCs were evaluated using wound healing and transwell assays. The degeneration of hepatocytes and the level of fibrosis in the hypoxia transplantation group were improved compared with the normoxia transplantation group. It was found that exogenous USCs may be differentiated into functional hepatocytes or fused with hepatocytes in vivo. C-X-C motif chemokine (CXC) ligand 12 (CXCL12) expression levels in liver tissue of the chronic liver injury model were upregulated compared with those in the control group. The expression of CXC receptor 4 (CXCR4) in hypoxia-pretreated USCs was also significantly upregulated. The results suggested that USCs fused with different types of liver cells and that hypoxia treatment promoted the fusion rate in vitro by upregulating CXCR4 signaling. Furthermore, hypoxia pretreatment promoted cell proliferation, migration, and cell fusion by inducing CXCR4 signaling, leading to USC-elicited liver tissue recovery following injury in vivo.
研究领域:
干细胞生物学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
STEM CELLS AND DEVELOPMENT
·
2021
·Vol. 30
·期 22
·1126-1138
·
IF 3.272
Nannan Zhang,Li Zhao,Daijiang Liu,Chaoqun Hu,Yi Wang,Tongchuan He,Yang Bi,Yun He
Urine-derived stem cells (USCs) are adult stem cells isolated from urine with strong proliferative ability and differentiation potentials. Cell transplantation of USCs could partly repair liver injury. It has been reported that the proliferative ability of bone mesenchymal stem cells in patients with chronic liver failure is significantly lower than in patients without liver disease. The aim of this study was therefore to evaluate the biological characteristics of USCs from end-stage liver disease patients (LD-USCs, USCs from patients with liver disease) compared with those from normal healthy individuals (N-USCs, USCs from normal individuals), with a view to determining whether autologous USCs can be applied to the treatment of liver disease. In this study USCs were isolated from urine samples of male patients with end-stage liver disease. Adherent USCs exhibit a spindle- or rice grain-like morphology, and express CD24, CD29, CD73, CD90, and CD146 surface markers, but not CD31, CD34, CD45, and CD105. We observed no differences in cell morphology or cell surface marker profile between LD-USCs and N-USCs. LD-USCs exhibited similar proliferative, colony-forming, apoptotic, and migratory abilities to N-USCs. Both USCs demonstrated similar capacities for osteogenic, adipogenic, and chondrogenic differentiation. When USCs were transplanted into CCl4 treatment-induced acute and chronic liver fibrosis mouse models, we observed a decrease in liver index, recovery of alanine aminotransferase and aspartate aminotransferase levels, alleviation of liver tissue injury, and dramatic improvement of liver tissue structure. USC transplantation can effectively recover liver function and improve liver tissue damage in acute or chronic liver injury mouse models. According to the results, we concluded that the biological characteristics of LD-USCs are not affected by basic liver disease. This study provides further evidence of the stem cell characteristics and liver repair function of LD-USCs, which may serve as a theoretical and experimental foundation for autologous USC transplantation technology in the treatment of liver failure and end-stage liver diseases.
研究领域:
干细胞生物学
·
肝病学
·
再生医学
·
细胞治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Fang Wang,Yan Qing Liu,Jun Nan Wei,Xiao Fen Wang,Feng Qin Li,Xiu Jia Tian,Dan Li,Yu Xuan Gao,Xin Zhi Guo,Xue Yan Li,Ping Luo
Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disorder characterized by intrahepatic lipid accumulation, oxidative stress, and inflammatory responses, underscoring the urgent need for effective therapeutic strategies. D-limonene, a cyclic monoterpenoid primarily derived from citrus fruits, possesses well-documented antioxidant, anti-fibrotic, and wound-healing properties. However, its therapeutic potential in MASLD remains largely unexplored. Methods To evaluate the therapeutic efficacy of D-limonene, a rat model of MASLD was established using a high-fat diet (HFD). An integrated approach combining metabolomics, transcriptomics, and network analysis was employed to identify key signaling pathways and molecular targets. The expression levels of candidate targets were validated by RT-qPCR and Western blotting. Molecular docking simulations were performed to predict the binding affinity between D-limonene and the target proteins. Furthermore, a cellular thermal shift assay (CETSA) was conducted to confirm direct binding and protein stabilization. In parallel, cellular experiments using BRL-3A and HepG2 cells were carried out to assess the effect of D-limonene on lipid accumulation. Results D-limonene treatment significantly ameliorated liver injury, reduced excessive lipid deposition, attenuated inflammation, and suppressed oxidative stress in HFD-induced rats. Integrated multi-omics and network analyses identified the PPAR signaling pathway as the core pathway mediating the regulatory effects of D-limonene on lipid metabolism, with PPARγ and SCD-1 pinpointed as key downstream targets. RT-qPCR and Western blot analyses confirmed that D-limonene significantly downregulated the expression of both PPARγ and SCD-1. Molecular docking simulations revealed stable binding of D-limonene to PPARγ and SCD-1. Importantly, CETSA further demonstrated that D-limonene directly binds to and stabilizes these two proteins. Consistently, cellular assays showed that D-limonene significantly reduced lipid accumulation in BRL-3A and HepG2 cells by inhibiting the PPARγ/SCD-1 axis. Conclusion Collectively, these findings suggest that D-limonene alleviates HFD-induced MASLD, and its protective effects may be mediated, at least in part, through inhibition of the PPARγ/SCD-1 axis. This study provides preliminary evidence supporting the potential development of D-limonene as a targeted therapeutic agent for MASLD. Further studies are warranted to validate these findings and elucidate additional underlying mechanisms.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2021
·
IF 7.514
Pei Yu,Yini Yang,Jinyuan Sun,Xiao Jia,Chang Zheng,Qi Zhou,Fenghong Huang
Volatile sulfur-containing compounds (VSCs) provide an important contribution to foods due to their special odors. In this study, VSCs in 21 cold-pressed rapeseed oils (CROs) from 9 regions in China were extracted and separated by headspace solid-phase microextraction combined with gas chromatography coupled with sulfur chemiluminescence detection. 19 VSCs were identified by authentic standards, and the total concentration of VSCs in all CROs ranged from 49.0 to 18129 μg/kg. Dimethyl sulfide (DMS), with its high odor activity value (7–14574), was the most significant aroma contributor to the CROs. Furthermore, S-methylmethionine (SMM) in rapeseed was first affirmed by ultra-performance liquid chromatography–tandem mass spectrometry and isotope quantitation. The positive correlation coefficient between DMS and SMM was 0.793 ( p < 0.05), which confirmed SMM as a crucial precursor of DMS in CROs. This study provided a theoretical basis for selecting rapeseed materials by the distribution of essential VSCs and the source of DMS.
研究领域:
食品科学
·
分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2019
·
IF 3.061
Jianying Bai,Zhen He,Yaofu Li,Xuexia Jiang,Hongmei Yu,Qing Tan
Mono-2-ethylhexyl phthalate (MEHP) is a major bioactive metabolite in the widely used industrial plasticizer diethylhexyl phthalate (DEHP) that has been found to be toxic to the liver. The aim of this study is to determine whether MEHP exposure can change the expression of fatty acid metabolism-related genes in HepG2 cells, which might be related to non-alcoholic fatty liver disease (NAFLD). The results revealed that exposure to MEHP promoted lipid accumulation in HepG2 cells. The levels of intracellular triglycerides in the hepatocytes increased after exposure to 0.8–100 μM MEHP for 24 h and 48 h. The genetic expressions of SREBP-1c, ChREBP, ACC1, FASN, and SCD significantly increased at 6 h after exposure to MEHP. At 24 h, the expression of the SREBP-1c and ChREBP genes remained increased, while the expression of the FASN and SCD genes decreased. At 48 h, the expression of SREBP-1c, ChREBP, ACC1, FASN, and SCD decreased. Furthermore, the levels of proteins including ACC1, FASN, SCD, and ChREBP (except SREBP-1c) increased at 24 h. These findings suggest that MEHP exposure can promote fatty acid synthesis in hepatocytes by regulating the expression of relevant genes and proteins, contributing to NAFLD.
研究领域:
毒理学
·
细胞生物学
·
分子生物学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2023
·
IF 5.6
Ritian Jin,Jude Juventus Aweya,Rong Lin,Wuyin Weng,Jiaqi Shang,Dangfeng Wang,Yiling Fan,Shen Yang
VLATSGPG (VLA) was a DPP-IV inhibitory peptide isolated from salmon ( Salmo Salar ) skin. Here, we demonstrated that VLA inhibited the activation of PERK through the AKT signaling pathway. Furthermore, we investigated the effect of VLA on free fatty acid (FFA)-induced lipid accumulation disorder and inflammation in HepG2 cells, elucidating the potential regulatory mechanism in this nonalcoholic fatty liver disease cell model. VLA reduced the mRNA expression of adipogenic factors FAS, ACC, and SCD-1 through the PERK/eIF2α pathway and the level of apolipoprotein B-100 secretion. These may contribute to the reducing FFA-induced lipid accumulation in cells and reducing intracellular lipid levels. In addition, VLA increased IκBα mRNA expression via the PERK/IκBα pathway, inhibited the NF-κB p65 activation, and thus inhibited cell inflammation.
研究领域:
分子生物学
·
细胞生物学
·
药理学
·
生物化学
✓ 已验证
产品关联
DOI
高影响因子
Chinese Herbal Medicines
·
2019
·
IF 0
Ya-yun Liu,Jiao-jiao You,Wei Xu,Ting Zhai,Chun-yuan Du,Yong Chen,Feng-mei Han
Objective The present work was to investigate the protective effects of the aqueous extract of Gynura procumbens (GPAE) against nonalcoholic steatohepatitis (NASH) in mice and NCTC-1469 cells. Methods C57BL/6J mice were fed with methionine and choline-deficient (MCD) diet and administered simultaneously with GPAE (500 and 1000 mg/kg/d, respectively) by gavage for six weeks. The biomarkers of NASH in serum and liver were determined. NCTC-1469 cells were pretreated with 0.25 mmol/L palmitic acid (PA) plus 0.5 mmol/L oleic acid (OA) for 24 h or treated with adenovirus expressing short-hairpin RNA against CFLAR (Ad-shCFLAR) for 24 h and then treated with GPAE (80 and 160 µg/mL, respectively) for 24 h, and the content of cellular biomarkers of NASH was detected. Results In mice treated with MCD , GPAE could decrease the levels of serum ALT , AST, the content of hepatic TG , TC and MDA , repress the activities and protein expression of CYP2E1 and CYP4A and the phosphorylation of JNK, increase the activities of HO-1, CAT and GSH-Px, up-regulate the mRNA expression of PPARα, FABP5, CPT1α, ACOX, SCD-1, mGPAT, MTTP and the protein expression of CFLAR and NRF2. In NCTC-1469 cells treated with PA and OA, GPAE could decrease the content of cellular TG and ROS , promote the uptake of 2-NBDG, up-regulate the protein expression of CFLAR and NRF2. In NCTC-1469 cells treated with Ad-sh CFLAR , GPAE up-regulated the mRNA and protein expression of CFLAR, down-regulated the phosphorylation of JNK, and increased the protein expression of NRF2 and pIRS1 . Conclusion These results indicated that the activation on CFLAR-JNK pathway might be the main anti-NASH mechanism of GPAE, which on the one hand promote the β-oxidation and efflux of fatty acids in liver, and finally reduce hepatic lipid accumulation , on the other hand increase the activities of anti-oxidant enzymes and inhibit the activities of ROS generation enzymes by activating NRF2, and therefore attenuates hepatic oxidative stress damage.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
危险品化学品经营许可证（带存储）