MOLECULAR AND CELLULAR BIOCHEMISTRY
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2018
·Vol. 447
·期 1
·137-149
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IF 2.561
Wu Weiche,Wang Sisi,Xu Ziye,Wang Xinxia,Feng Jie,Shan Tizhong,Wang Yizhen
Betaine, a neutral zwitterionic compound, could regulate intramuscular fat (IMF) deposition and meat quality. However, the efficacy is controversial. Moreover, the regulatory mechanism of betaine on lipid metabolism in skeletal muscle cells remains unclear. Therefore, in this study, we examined the effects and regulatory mechanism of betaine on lipid accumulation in adipogenic-differentiated C2C12 cells. We found that adipogenic-induced C2C12 cells treated with 10 mM betaine for 24 and 48 h had more lipid accumulation than the control group. Real-time PCR and Western blot results revealed that betaine treatment did not alter the expression of lipolysis and lipid oxidation-related genes, but dramatically increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes such as fatty acid binding protein 4 (aP2), fatty acid synthase (FAS) and lipoprteinlipase (LPL). Furthermore, betaine combined with PPARγ inhibitor GW9662 treatment showed that betaine elevated C2C12 lipid accumulation through upregulation of PPARγ. Mechanistically, we found that betaine promoted PPARγ expression and lipid accumulation through inhibition of extracellular regulated protein kinases1/2 (ERK1/2) signalling pathway. These results demonstrate that betaine acts through ERK1/2-PPARγ signalling pathway to regulate lipid metabolism in adipogenic-differentiated skeletal muscle cells, which could provide some useful information for controlling muscle lipid accumulation by manipulating ERK1/2 and PPARγ signalling pathway.
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INFLAMMATION
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2018
·Vol. 41
·期 4
·1384-1395
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IF 2.884
Su Yang,Lu Jingxiao,Chen Xianguo,Liang Chaozhao,Luo Pengcheng,Qin Cong,Zhang Jie
Chronic prostatitis (CP) is a clinically common disease with high morbidity. It affects the patients’ quality of life (QoL) as well as physical and mental health seriously due to the recurring symptoms of lower urinary tract and genitalia. As the opinions about the etiology of CP are still not uniform, it is very difficult to be treated or even cured. Autophagy is a highly conserved physiological function which is widely found in eukaryotic cells. In general, cells maintain a certain level of autophagy under physiological conditions, and the basal level of autophagy can be regulated by a variety of autophagy-related genes under stress such as hunger, infection, trauma, and other circumstances. Therefore, the main purpose of this study is to investigate the role of autophagy in chronic nonbacterial prostatitis (CNP, also called CP). In this paper, we established the CNP model via hypodermic injection of 17β-estradiol and subsequently abdominal rapamycin (a common autophagy inducer) treatment based on castrated rats. Then, the expression of nuclear factor-κB (NF-κB), interleukin-1β (IL-1β), and autophagy-related markers as well as autophagosome formation in prostate tissues, peripheral blood mononuclear cells (PBMCs), and serum of rats were evaluated respectively. In addition to some histological changes in the prostate tissues, we found the levels of NF-κB and IL-1β were significantly increased in the model group, along with significantly suppressed autophagy, whereas rapamycin could reverse these effects which involved in the mTOR/ULK1/ATG13 signaling pathway. In conclusion, our results suggested that rapamycin could ameliorate hormone imbalance-induced CNP by activating autophagy.
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Lipids in Health and Disease
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2021
·Vol. 20
·期 1
·1-11
·
IF 3.876
Zha Yiwen,Lu Yaoyao,Zhang Ting,Yan Kunning,Zhuang Wenwen,Liang Jingyan,Cheng Yong,Wang Yingge
Background High levels of apolipoprotein C3 (APOC3) can lead to hypertriglyceridemia, which increases the risk of cardiovascular disease. We aim to create APOC3-knockout (KO) rabbits and explore the effects of APOC3 deletion on the occurrence and development of atherosclerosis.Methods An sgRNA anchored to exon 2 of APOC3 was designed to edit embryo genomes using the CRISPR/Cas9 system. The founder rabbits were sequenced, and their lipid profile, inflammatory cytokines, and atherosclerotic plaques were analyzed.Results When given a normal chow (NC) diet, all APOC3-KO rabbits had 50% lower triglyceride (TG) levels than those of the matched age control group. Additionally, their plasma lipoprotein lipase increased. When fed a high-fat diet, APOC3 deficiency was observed to be more conducive to the maintenance of plasma TG, total cholesterol, and low-density lipoprotein cholesterol levels, and the inhibition of the inflammatory response and the protection against atherosclerosis in rabbits.Conclusion APOC3 deficiency can delay the formation of atherosclerosis-induced HFD in rabbits, indicating this is a novel therapeutic target to treat atherosclerosis.
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Nature Communications
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2025
·
IF 15.7
Bowen Liu,Yue Han,Yuan Jin,Meng Ye,Zeliang Yang,Jingyi Yang,Minglu Zhu,Xuyang Zhao,Yan Jin,Yuxin Yin
The quality control network in type 2 alveolar epithelial cells (AEC2s) is essential to respond to intrinsic and extrinsic challenges. However, the mechanisms that regulate AEC2 mitochondrial homeostasis remain unclear understood. Here, we report a role of G protein-coupled receptor class C group 5 member A (GPRC5A) in mitochondrial quality control in AEC2s through promoting mitochondrial secretion in extracellular vesicles (EVs). Utilizing mice models, we demonstrate that the disruption of GPRC5A specifically in AEC2s aggravates lung injuries. We further observe that GPRC5A deficiency in AEC2s reduces secretion of mitochondrial components in small-EVs and disrupts mitochondrial functions both in vitro and in vivo. Mechanistically, we determine that the GPRC5A-MIRO2 pathway facilitates the transfer of mitochondrial fragments into late endosomes. Collectively, our findings provide evidence of the shedding of mitochondrial components dependent on GPRC5A as a pathway of mitochondrial quality control in AEC2s, which is crucial in the maintenance of epithelial physiological activities and lung tissue homeostasis. The authors provide evidence of the secretion of mitochondrial components in extracellular vesicles dependent on GPRC5A as a pathway of mitochondrial quality control in AEC2s, which is essential for lung homeostasis maintenance.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 24
·期 1
·103
·
IF 12.6
Zhang Yixun,Wang Xuehua,Zhang Hongli,Zhou Xin,He Huichan,Zou Fen,Zhuo Yangjia,Cai Zhouda,Xu Qianfeng,Xie Wenjie,Lin Jundong,Chen Muqi,Zheng Wenlian,Chen Jianwei,Liu Jinsheng,Yang Huikang,Zhong Weide,Yang Ronghua
Melanoma has a high incidence and mortality, and current therapies are limited. Here, we developed TCPC, an ER-targeted nanomedicine guided by omics analysis. It consists of curcumin-loaded PEG–PCL nanomicelles coated with a Tannic acid–Cu metal–polyphenol network. Guided by clinical transcriptome mining, we identified ER-stress vulnerabilities to inform material design. RNA-seq and imaging confirmed that TCPC preferentially accumulates in melanoma cells and localizes to the ER. TCPC markedly elevates CHOP expression, which triggers ER Ca²⁺ release, mitochondrial dysfunction, ROS accumulation, and apoptosis. Functionally, TCPC significantly suppresses cell viability, migration, and invasion in vitro. In melanoma xenografts, systemic TCPC treatment slows tumor growth, enhances intratumoral CHOP and Cleaved caspase-3, and induces apoptosis without systemic toxicity. Moreover, pharmacogenomic analyses revealed that CHOP upregulation correlates with increased sensitivity to several agents, and molecular docking highlighted Irinotecan and JQ1 as potential synergistic partners with TCPC. Collectively, this work demonstrates that nanomedicine guided by omics can couple organelle-specific delivery with ER-stress amplification to achieve potent antitumor efficacy. Overall, this work establishes an omics-guided materials strategy that integrates organelle-targeted delivery with ER-stress amplification for effective melanoma therapy. Graphical abstract
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Stem Cell Research & Therapy
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2025
·
IF 7.3
Zhang Qinyao,Huang Shuwei,Liu Xiaoqian,Zhang Meijiu,Sun Jun,Liu Mingzhu,Nie Hemin,Lei Lei
Aim During the tooth-root elongation phase, dental epithelial stem cells (DESCs) cluster together and release various signaling molecules, facilitating the differentiation of stem cells from the apical papilla (SCAPs) into odontoblasts. This study aimed to investigate the regulatory mechanism of secretory proteins from DESCs cultured in a spherical system mimicking the in vivo microenvironment on the odontoblastic differentiation of SCAPs during root development, providing theoretical foundations and potential targets for dentin regeneration therapy based on epithelial-mesenchymal interactions. Methodology DESCs were isolated from the root tips of rodent incisors and cultured using low-attachment surface to mimic their in vivo clustering. The effects of spheroid culture (versus monolayer culture) on SCAPs viability and odontoblastic differentiation potential were systematically compared. Label-free mass spectrometry and bioinformatics analyses were employed to characterize the secretory protein profiles of DESCs under different culture conditions. In vitro and in vivo experiments validated the role of a key differential protein Lumican and its downstream signaling mechanisms. Results Compared to monolayer culture, spheroid culture significantly enhanced the secretion of Lumican by DESCs. Lumican demonstrated the ability to significantly promote dentin differentiation of SCAPs in vitro and in vivo. Mechanistic analysis revealed that Lumican binds specifically to integrin β1 (ITGβ1) on the SCAPs membrane, thereby activating the downstream ERK signaling pathway to mediate its pro-differentiation effects. Conclusion This study illustrates that spheroid culture can restore the epithelial microenvironment of DESCs, leading to the release of Lumican, which targets SCAPs. This research uncovers the crucial roles of Lumican and ITGβ1 in DESCs-SACPs interactions and paves the way for potential therapeutic strategies in dentin regeneration. Graphical abstract
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Scientific Reports
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2020
·Vol. 10
·期 1
·1-14
·
IF 3.998
Duan Huyang,Cao Chuanliang,Wang Xiaolei,Tao Jun,Li Chen,Xin Hongbo,Yang Jing,Song Yulin,Ai Fanrong
Various therapeutic platforms have been developed for repairing bone defects. However, scaffolds possess both cortical bone-matching mechanical properties and excellent osteoconductivity for load-bearing bone defects repair is still challenging in the clinic. In this study, inspired by the structure of the ferroconcrete, a high-strength bifunctional scaffold has been developed by combining surface-modified magnesium alloy as the internal load-bearing skeleton and bioglass-magnesium phosphate bone cement as the osteoconductive matrix. The scaffold combines the high mechanical strength and controllable biodegradability of surface-modified magnesium alloy with the excellent biocompatibility and osteoconductivity of bioglass-magnesium phosphate bone cement, thus providing support for load-bearing bone defects and subsequently bone regeneration. The scaffolds generate hydroxyapatite (HA) during the degrading in simulated body fluid (SBF), with the strength of the scaffold decreasing from 180 to 100 MPa in 6 weeks, which is still sufficient for load-bearing bone. Moreover, the scaffolds showed excellent osteoconductivity in vitro and in vivo. In a New Zealand White Rabbit radius defect model, the scaffolds degrade gradually and are replaced by highly matured new bone tissues, as assessed by image-based analyses (X-ray and Micro-CT) and histological analyses. The bone formation-related proteins such as BMP2, COL1a1 and OCN, all showed increased expression.
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PROTOPLASMA
·
2018
·Vol. 255
·期 4
·1039-1052
·
IF 2.457
Li Chao,Li Cheng,Wang Bingbing,Zhang Runqi,Fu Kaiyong,Gale William J.,Li Chunyan
Drought frequently occurs during wheat ( Triticum aestivum L.) grain filling. The objectives of this study were (i) to investigate the effect of post-anthesis drought on programmed cell death (PCD) in wheat endosperm cells and (ii) to examine the role of ethylene (ETH) receptors and abscisic acid (ABA) in regulating wheat endosperm PCD. Two winter wheat cultivars (‘Xindong 18’ and ‘Xindong 22’) were used in this study. Grain samples were collected from normal and drought stressed plants at 5-day intervals between 5 and 35 days post-anthesis. The samples were then compared with respect to cell viability, nuclear morphometry, cell ultrastructure, DNA integrity, nucleic acid content, and nuclease activity. Analysis was also conducted about gene transcripts related to PCD, ETH receptors, and ABA biosynthesis and degradation. Drought stress reduced cell viability, accelerated nuclear deformation, and increased mitochondrial dissolution. The activity of nucleic acid hydrolase was greater, and the nucleic acid concentrations were less in the drought treatments than in the control. As a result, the peak in DNA fragmentation occurred earlier in the drought treatment. Drought stress significantly increased the expression of four genes related to ABA ( nced1 , nced2 , ao1 , ao2 ) . In contrast, drought significantly reduced the expression of four genes related to ETH receptors ( ers1 , ers2 etr1 , etr2 ) and one gene related to PCD ( dad1 ). In summary, the results indicated that drought stress caused PCD to occur earlier in the endosperm of winter wheat.
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Cancer Cell International
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2021
·Vol. 21
·期 1
·1-15
·
IF 5.722
Lv Minchao,Xu Qingxin,Zhang Bei,Yang Zhiqiang,Xie Jun,Guo Jinku,He Feixiong,Wang Wei
Background Osteosarcoma is the third most common cancer in adolescence and the first common primary malignant tumor of bone. The long-term prognosis of osteosarcoma still remains unsatisfactory in the past decades. Therefore, development of novel therapeutic agents which are effective to osteosarcoma and are safe to normal tissue simultaneously is quite essential and urgent. Methods Firstly, MTT assay, cell colony formation assay, cell migration and invasion assays were conducted to evaluate the inhibitory effects of imperatorin towards human osteosarcoma cells. RNA-sequence assay and bioinformatic analysis were then performed to filtrate and assume the potential imperatorin-induced cell death route and signaling pathway. Moreover, quantitative real-time PCR assay, western blot assay and rescue experiments were conducted to confirm the assumptions of bioinformatic analysis. Finally, a subcutaneous tumor-transplanted nude mouse model was established and applied to evaluate the internal effect of imperatorin on osteosarcoma by HE and immunohistochemistry staining. Results Imperatorin triggered time-dependent and dose-dependent inhibition of tumor growth mainly by inducing autophagy promotion and G0/G1 phase arrest in vitro and in vivo. Besides, imperatorin treatment elevated the expression level of PTEN and p21, down-regulated the phosphorylation of AKT and mTOR. In contrast, the inhibition of PTEN using Bpv (HOpic), a potential and selective inhibitor of PTEN, concurrently rescued imperatorin-induced autophagy promotion, cell cycle arrest and inactivation of PTEN-PI3K-AKT-mTOR/p21 pathway. Conclusions This work firstly revealed that imperatorin induced autophagy and cell cycle arrest through PTEN-PI3K-AKT-mTOR/p21 signaling pathway by targeting and up-regulating PTEN in human osteosarcoma cells. Hence, imperatorin is a desirable candidate for clinical treatments of osteosarcoma.
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INFLAMMATION RESEARCH
·
2014
·Vol. 63
·期 7
·597-608
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IF 2.143
Pan Xiaolong,Cao Xiang,Li Na,Xu Yimiao,Wu Qiuyue,Bai Jing,Yin Zhimin,Luo Lan,Lan Lei
Objective Forsythin (FOR) is an active ingredient extracted from the fruit of the medicinal plant Forsythia suspensa (Thunb.) Vahl. Here, we investigated the effect of FOR on LPS-induced inflammatory response and the underlying molecular mechanisms in RAW264.7 macrophages. Materials and methods RAW264.7 cells were pre-treated with or without FOR and then stimulated with or without LPS. The productions of TNF-α, IL-1β, IL-6, PGE 2 and NO were determined by ELISA and nitrite analysis, respectively. The expressions of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were measured by Western blotting and RT-PCR analysis. The activations of signaling molecules were detected by Western blotting using phosphorylation specific antibodies. Reactive oxygen species (ROS) production was determined by ROS assay. Results LPS-induced productions of IL-1β, IL-6, TNF-α, NO and PGE 2 were inhibited by FOR in a dose-dependent manner. FOR also suppressed the LPS-elevated expressions of iNOS and COX-2. Further investigations revealed that FOR significantly inhibited the LPS-induced activations of JAK-STATs and p38 MAPKs, but not of IKKα/β in LPS-stimulated RAW264.7 cells. Additionally, FOR interfered with both JAK-STATs and p38 MAPKs signaling pathways to modulate the expressions of IL-1β, IL-6, TNF-α, iNOS and COX-2. Furthermore, FOR reduced the LPS-induced ROS accumulation, validating that FOR serves as an antioxidant. Conclusions Our data suggested that FOR exerts anti-inflammatory action, at least in part, via suppressing LPS-induced activation of JAK-STATs and p38 MAPKs signalings and production of ROS in macrophage cells.
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Cell and Bioscience
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2021
·Vol. 11
·期 1
·1-16
·
IF 7.133
Xu Hongfei,Wang Zhen,Chen Miao,Zhao Wenting,Tao Tingting,Ma Liang,Ni Yiming,Li Weidong
Background Pathological cardiac hypertrophy is a major contributor of heart failure (HF), which seriously threatens human’s health world widely. Deregulation of m6A RNA methylation, and m6A methyltransferases and de-methyltransferases have been demonstrated to act essential roles in cardiac hypertrophy and HF. Here, we studied the potential roles and its underlying mechanisms of m6A Reader YTHDF proteins in HF. In this study, we constructed HF mouse model by transverse aortic constriction surgery. Primary cardiomyocytes were isolated and stimulated with isoproterenol (ISO) or phenylephrine (PHE) to induce myocardial hypertrophy.Results Through single-cell RNA-seq analysis, immunofluorescent staining, HE staining, Western blotting, and real time-PCR detections, we found that YTHDF2 mRNA and protein level, but not YTHDF1 or YTHDF3, was significantly increased during HF development. YTHDF2 overexpression could efficiently alleviate cardiac hypertrophy. Furthermore, through immunoprecipitation accompanied with mass spectrometry analysis, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found that ISO stimulation did not evidently affect YTHDF2-interacting proteins. However, ISO or PHE stimulation significantly increased YTHDF2 protein interacting with Myh7 (beta-myosin heavy chain) mRNA, an important cardiac hypertrophy marker, in an m6A-dependent manner. Knockdown of Myh7 or deletion of the YTH domain of YTHDF2 reversed the protective effects of YTHDF2 on cardiac hypertrophy. Finally, we found that ISO or PHE stimulation promoted YTHDF2 protein expression through enhancing Ythdf2 mRNA stability in an m6A-dependent manner in cardiomyocytes.Conclusion sOverall, our results indicate that the m6A Reader YTHDF2 suppresses cardiac hypertrophy via Myh7 mRNA decoy in an m6A-dependent manner. This study highlights the functional importance of YTHDF2-dependent cardiac m6A mRNA regulation during cardiac hypertrophy, and provides a novel mechanistic insight into the therapeutic mechanisms of YTHDF2.
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Cell Death & Disease
·
2018
·Vol. 9
·期 6
·1-14
·
IF 5.638
Tao Liang,Lin Hongfa,Wen Jingjing,Sun Qi,Gao Yan,Xu Xi,Wang Junsong,Zhang Jianfa,Weng Dan
Endoplasmic reticulum (ER) stress contributes to the development and progression of many chronic inflammatory diseases, including type 2 diabetes, obesity, atherosclerosis, neurodegenerative diseases, and cancer. ER stress has been reported to induce inflammasome activation and release of mature IL-1β, which contributes to many inflammatory diseases. The molecular mechanisms that activate the inflammasome during ER stress are still poorly understood. Here we report that the kinase receptor-interacting protein 1 (RIP1) plays an important role in ER stress-induced activation of inflammasome. Inhibition of RIP1 kinase activity by Necrostatin-1 or siRNA-mediated RIP1 knockdown significantly reduced ER stress-induced caspase-1 cleavage and IL-1β secretion in both bone marrow-derived macrophages (BMDMs) and J774A.1 macrophages. We speculate that the mitochondria fission factor dynamin-related protein 1 (DRP1) and reactive oxygen species (ROS) might function as the effectors downstream of RIP1 to mediate inflammasome activation. Our study reveals a critical role for RIP1 in regulating ER stress-induced inflammation responses, and proposes RIP1 as a potential pharmaceutical target to treat diseases resulting from unresolved ER stress-related inflammation.
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