Molecular Medicine Reports
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2024
·Vol. 29
·期 3
·1-12
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IF 3.4
Mi-Hua Liu,Xiao-Long Lin,Le-Le Xiao
Hyperphosphatemia or severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can promote cardiovascular adverse events in patients with chronic kidney disease. Hyperphosphatemia is associated with elevated inflammation and sterol regulatory element binding protein 2 (SREBP2) activation, but the underlying mechanisms in SARS‑CoV‑2 that are related to cardiovascular disease remain unclear. The present study aimed to elucidate the role of excess inorganic phosphate (PI) in SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation and the underlying mechanisms in vascular smooth muscle cells (VSMCs). The expression levels of SARS‑CoV‑2 N protein, SREBP cleavage‑activating protein (SCAP), mature N‑terminal SREBP2, NLRP3, procaspase‑1, cleaved caspase‑1, IL‑1β and IL‑18 were examined by western blotting. The expression levels of SREBP2, HMG‑CoA reductase, HMGCS1, low density lipoprotein receptor, proprotein convertase subtilisin/kexin type 9 (PCSK9), SREBP1c, fatty acid synthase, stearyl coenzyme A desaturase 1, acetyl‑CoA carboxylase α and ATP‑citrate lyase were determined by reverse transcription‑quantitative PCR. The translocation of SCAP or NLRP3 from the endoplasmic reticulum to the Golgi was detected by confocal microscopy. The results showed that excess PI promoted SCAP‑SREBP and NLRP3 complex translocation to the Golgi, potentially leading to NLRP3 inflammasome activation and lipogenic gene expression. Furthermore, PI amplified SARS‑CoV‑2 N protein‑induced inflammation via the SCAP‑SREBP pathway, which facilitates NLRP3 inflammasome assembly and activation. Inhibition of phosphate uptake with phosphonoformate sodium alleviated NLRP3 inflammasome activation and reduced SREBP‑mediated lipogenic gene expression in VSMCs stimulated with PI and with SARS‑CoV‑2 N protein overexpression. Inhibition of SREBP2 or small interfering RNA‑induced silencing of SREBP2 effectively suppressed the effect of PI and SARS‑CoV‑2 N protein on NLRP3 inflammasome activation and lipogenic gene expression. In conclusion, the present study identified that PI amplified SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation and lipogenic gene expression via the SCAP‑SREBP signaling pathway.
研究领域:
心血管疾病
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传染病
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分子生物学
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细胞生物学
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PubMed
高影响因子
Cell Reports
·
2024
·
IF 7.5
Mingzhi Wu,Xiaojun Zhou,Xinyi Zhou,Genxin Wang,Yiqun Zeng,Jun Li,Edward V. Prochownik,Fubing Wang,Youjun Li
Cholesterol metabolism reprogramming plays essential roles in hepatocellular carcinoma (HCC). However, precisely how cholesterol metabolism is dysregulated is not clear. Here, we show that the palmitoyltransferase ZDHHC3 and depalmitoylase ABHD17A regulate HCC cell cholesterol biosynthesis by dynamically S-acylating SREBP cleavage-activating protein (SCAP). SCAP S-acylation by ZDHHC3 at C264 antagonizes HACE1-mediated SCAP ubiquitination. Intriguingly, SREBP2 transcriptionally upregulates ZDHHC3 to form a positive feedback loop, which explains why negative feedback regulation of SCAP/SREBP2 signaling fails in HCC. Increased cholesterol in the tumor microenvironment (TME) restrains CD4 + T cell cytotoxicity. Hence, the cholesterol metabolism reprogramming and cholesterol level alternation in the TME cooperate to promote HCC development. We identified a small-molecule inhibitor of ZDHHC3 that, combined with anti-PD-1 immunotherapy, inhibited diethyl nitrosamine (DEN)/CCl 4 -induced HCC growth in mice. ZDHHC3-mediated SCAP S-acylation reprograms cholesterol metabolism and promotes HCC immune escape. ZDHHC3 is thus identified as a rational chemotherapy target for HCC.
研究领域:
癌症生物学
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分子生物学
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免疫学
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代谢学
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PubMed
高影响因子
Autophagy
·
2020
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IF 9.77
Zu-Guo Zheng,Si-Tong Zhu,Hui-Min Cheng,Xin Zhang,Gang Cheng,Pyone Myat Thu,Supeng Perry Wang,Hui-Jun Li,Ming Ding,Lei Qiang,Xiao-Wei Chen,Qing Zhong,Ping Li,Xiaojun Xu
SCAP (SREBF chaperone) regulates SREBFs (sterol regulatory element binding transcription factors) processing and stability, and, thus, becomes an emerging drug target to treat dyslipidemia and fatty liver disease. However, the current known SCAP inhibitors, such as oxysterols, induce endoplasmic reticulum (ER) stress and NR1H3/LXRα (nuclear receptor subfamily 1 group H member 3)-SREBF1/SREBP-1 c-mediated hepatic steatosis, which severely limited the clinical application of this inhibitor. In this study, we identified a small molecule, lycorine, which binds to SCAP, which suppressed the SREBF pathway without inducing ER stress or activating NR1H3. Mechanistically, lycorine promotes SCAP lysosomal degradation in a macroautophagy/autophagy-independent pathway, a mechanism completely distinct from current SCAP inhibitors. Furthermore, we determined that SQSTM1 captured SCAP after its exit from the ER. The interaction of SCAP and SQSTM1 requires the WD40 domain of SCAP and the TB domain of SQSTM1. Interestingly, lycorine triggers the lysosome translocation of SCAP independent of autophagy. We termed this novel protein degradation pathway as the SQSTM1-mediated autophagy-independent lysosomal degradation (SMAILD) pathway. In vivo, lycorine ameliorates high-fat diet-induced hyperlipidemia, hepatic steatosis, and insulin resistance in mice. Our study demonstrated that the inhibition of SCAP through the SMAILD pathway could be employed as a useful therapeutic strategy for treating metabolic diseases.Abbreviation: 25-OHD: 25-hydroxyvitamin D; 3-MA: 3-methyladenine; ABCG5: ATP binding cassette subfamily G member 5; ABCG8: ATP binding cassette subfamily G member 8; ACACA: acetyl-CoA carboxylase alpha; AEBSF: 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride; AHI: anhydroicaritin; AKT/protein kinase B: AKT serine/threonine kinase; APOE: apolipoprotein E; ATF6: activating transcription factor 6; ATG: autophagy-related; BAT: brown adipose tissue; CD274/PD-L1: CD274 molecule; CETSA: cellular thermal shift assay; CMA: chaperone-mediated autophagy; COPII: cytoplasmic coat protein complex-II; CQ: chloroquine; DDIT3/CHOP: DNA damage inducible transcript 3; DNL: de novo lipogenesis; EE: energy expenditure; EGFR: epithelial growth factor receptor; eMI: endosomal microautophagy; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FADS2: fatty acid desaturase 2; FASN: fatty acid synthase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvate transaminase; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCS1: 3-hydroxy-3-methylglutaryl-CoA synthase 1; HSP90B1/GRP94: heat shock protein 90 beta family member 1; HSPA5/GRP78: heat hock protein family A (Hsp70) member 5; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; INSIG1: insulin induced gene 1; LAMP2A: lysosomal associated membrane protein 2A; LDLR: low density lipoprotein receptor; LyTACs: lysosome targeting chimeras; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MBTPS1: membrane bound transcription factor peptidase, site 1; MEF: mouse embryonic fibroblast; MST: microscale thermophoresis; MTOR: mechanistic target of rapamycin kinase; MVK: mevalonate kinase; PROTAC: proteolysis targeting chimera; RQ: respiratory quotient; SCAP: SREBF chaperone; SCD1: stearoyl-coenzemy A desaturase 1; SMAILD: sequestosome 1 mediated autophagy-independent lysosomal degradation; SQSTM1: sequestosome 1; SREBF: sterol regulatory element binding transcription factor; TNFRSF10B/DR5: TNF receptor superfamily member 10b; TRAF6: TNF receptor associated factor 6; UPR: unfolded protein response; WAT: white adipose tissue; XBP1: X-box binding protein 1
研究领域:
药理学
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代谢
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 3
·
IF 7.7
Jiaqi Huang,Yuejue Wang,Fei Li,Nan Zhang,Guoxiong Tian,Dongyu Guo,Yanqi Guo,Zhengyuan Liu,Yinfang Wu,Xiaoping Li,Fei Xu,Zhongnan Qin,Ruixin Jia,Lingling Dong,Shenwei Gao,Jinkang Yu,Jian Lou,Songmin Ying,Daniel H. Scharf,Wen Li,Zhihua Chen
Fungal infection induces substantial but poorly understood metabolic reprogramming in macrophages. We demonstrate that fungal stimulation reduces Scap levels in human monocytes and murine bone-marrow-derived macrophages (BMDMs), and Scap deficiency impairs cytokine production and phagocytosis, leading to more severe fungal infections. Although Scap canonically regulates lipid synthesis, pharmacological inhibition of lipid synthesis and genetic ablation of SREBP1/2 reveal that Scap-dependent anti-fungal immunity is largely independent of this pathway. Instead, Scap interacts with and stabilizes PKM2, a key glycolysis enzyme, by competitively inhibiting STUB1-mediated ubiquitination and degradation of PKM2 at Lys-311. PKM2 agonist DASA58 enhances fungus-induced production of pro-inflammatory cytokines and phagocytic activity in wild-type BMDMs and partially rescues these functions in Scap-deficient macrophages, whereas myeloid-specific deletion of PKM2 recapitulates the effects of Scap deficiency. These results identify Scap as a critical regulator of PKM2-mediated glycolysis and demonstrate its potential as a therapeutic target for modulation of anti-fungal immunity.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Yu Su,Haobo Wen,Ke Hu,Cuiping Wen,Ping Wang,Lulu Zhao,Gang Zou,Wei Jiang,Yaxi Chen,Yunfei Zhao,Qiu Li
The multifaceted pathogenesis and multi-cellular involvement of diabetic nephropathy (DN) stand in stark contrast to the inadequacy of conventional single-target therapeutic strategies. This disparity underscores the urgent need for novel drugs with comprehensive targeting capabilities. Herein, the SREBP cleavage-activating protein/sterol regulatory element-binding proteins (SCAP/SREBPs) pathway was identified as a central driver in DN, where its activation in key renal parenchymal cells promotes lipid metabolic disorders and inflammation, thereby exacerbating renal injury. Guided by this discovery, we screened a 245-member nanoparticle library comprising SCAP inhibitors self-assembled with chitosan, and identified chitosan-lycorine nanoparticles (CLNPs) as the optimal candidate. Owing to its efficient intestinal absorption and significant accumulation in mesangial and proximal tubular epithelial cells, oral CLNPs strongly alleviated renal injury in a murine model of DN by counteracting lipid accumulation and inflammation, consistent with SCAP/SREBPs pathway inhibition. Critically, CLNPs prevented hepatotoxicity from free lycorine, which reduced mortality and enabled safer prolonged therapy. Together, our findings demonstrate the viability of CLNPs for DN, thereby offering a generalizable strategy for combating complex diseases through a single combinatorial agent that counters multiple co-existing pathological injuries.
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INTERNATIONAL ENDODONTIC JOURNAL
·
2025
·
IF 7.1
Xiaolin Li,Sanjun Zhao,Yao Liu,Yu Gu,Lihong Qiu,Xu Chen,Alastair J. Sloan,Bing Song
Aim This study examined the impact of direct current electric fields (DCEFs) on the biological properties of stem cells derived from the apical papilla (SCAP) and further elucidated the underlying mechanisms involved in odontogenic differentiation induced by DCEFs stimulation. Methodology The measurement of endogenous currents in wounded dentine was achieved using a non-invasive vibrating probe system. Two-dimensional (2D) and three-dimensional (3D) systems were developed to apply DCEFs of varying strengths. The migration direction and trajectories of SCAP within DCEFs were analysed using time-lapse imaging. Cell proliferation was assessed through Hoechst staining and the CCK-8 assay. Changes in cell morphology, arrangement, and polarization were examined using fluorescence staining. The odontogenic differentiation of SCAP in vitro was assessed using quantitative polymerase chain reaction (qPCR), western blot analysis, alkaline phosphatase staining, and Alizarin Red S staining. In vivo evaluation was conducted through Haematoxylin and eosin staining, immunohistochemistry staining, and Sirius Red staining after transplantation experiments. Results Injured dentine demonstrated a significantly increased outward current, and DCEFs facilitated the migration of SCAP towards the anode. DCEFs at a magnitude of 100 mV/mm promoted SCAP proliferation, whereas DCEFs at 200 mV/mm enhanced both polarization and odontogenic differentiation of SCAP. The application of cytoskeletal polymerization inhibitors mitigated the odontogenic differentiation induced by DCEFs. In vivo studies confirmed that DCEFs promoted the differentiation of SCAP into odontoblast-like cells in an orderly arrangement, as well as the formation of collagen fibres and dentine-like tissue. Conclusions DCEFs of varying intensities exhibited an enhanced capacity for migration, proliferation, odontogenic differentiation, and polarization in SCAP. These findings provide substantial insights for the advancement of innovative therapeutic strategies targeting the repair and regeneration of immature permanent teeth and dentine damage.
研究领域:
牙齿再生医学
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干细胞生物学
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组织工程
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高影响因子
iScience
·
2025
·
IF 4.1
Zizheng Liu,Huiming Jiang,Zhaofeng Zhang,Ruiyang Jiang,Rongliang Wang,Jiawei Li,Weitong Li,Guihua Tan,Yuxiang Fei,Zhongyang Lv,Hu Guo,Ziyin Sun,Rui Wu,Hongfei Shi,Dongquan Shi
Chondrocytes experience adverse lipid metabolism disorders during the degeneration of cartilage in osteoarthritis (OA), while the underlying mechanisms remain poorly understood. SESN2, a highly conserved stress-inducible protein, plays a crucial role in regulating lipid metabolism. This study aims to investigate the role of SESN2 in the regulation of fatty acid metabolism in chondrocytes and elucidate the underlying molecular mechanisms in OA. The expression of SESN2 was significantly decreased in OA-affected human cartilage, and this decrease correlated with the upregulation of lipogenic enzymes. Sesn2 inhibited lipogenic enzyme expression in chondrocytes and improved cartilage homeostasis. Mechanistically, SESN2 inhibited the expression of SREBP1 and interacted with SCAP to deactivate SREBP1-mediated transcription for lipogenesis. Finally, overexpression of Sesn2 in mice undergoing DMM surgery ameliorated OA pathological manifestations and improved behavioral experiments performance through inhibiting fatty acid synthesis. Our findings revealed that SESN2 suppresses SREBP1-mediated transcription for lipogenic enzyme in chondrocytes and ameliorates OA progression. These results highlighted that targeting SESN2 may serve as a promising therapeutic strategy for OA.
研究领域:
分子生物学
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生物化学
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细胞生物学
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骨科
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医学研究
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PubMed
高影响因子
Cell Reports Medicine
·
2024
·
IF 11.7
Weize Zhu,Ying Hong,Zhaowei Tong,Xiaofang He,Yan Li,Hao Wang,Xinxin Gao,Pengtao Song,Xianshan Zhang,Xiaochang Wu,Zhenhua Tan,Wenjin Huang,Zekun Liu,Yiyang Bao,Junli Ma,Ningning Zheng,Cen Xie,Xisong Ke,Wen Zhou,Wei Jia,Mingxiao Li,Jing Zhong,Lili Sheng,Houkai Li
Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A 1 R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A 1 R in MAFLD remains unclear. Here, we report that liver-specific depletion of A 1 R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A 1 R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A 1 R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A 1 R agonists attenuate MAFL/MASH in an A 1 R-dependent manner. These results highlight that hepatic A 1 R is a potential target for MAFL/MASH therapy.
研究领域:
肝病学
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药理学
·
代谢性疾病
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分子生物学
·
细胞信号传导
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DOI
高影响因子
JOURNAL OF PHARMACOLOGICAL SCIENCES
·
2019
·
IF 2.439
Jinying Che,Shuo Yang,Zijing Qiao,He Li,Jinghui Sun,Wenyue Zhuang,Jianguang Chen,Chunmei Wang
Schisandra chinensis is a hepatoprotective herb that has been used for centuries in China. Polysaccharide is one of the major active components in S. chinensis , which has been reported to improve liver injuries induced by carbon tetrachloride, alcohol, or high-fat diet. In this study, we observed the effects and corresponding mechanisms of the secondary component of Schisandra polysaccharide (acidic polysaccharide, SCAP) on a murine model of severe acute liver injury induced by acetaminophen (APAP). SCAP significantly decreased the serum alanine aminotransferase (ALT), aspartate aminotransferas (AST), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels, and was found to alleviate hepatic pathological alterations in the mouse model. Meanwhile, SCAP revealed a protective effects on the liver injury-related enzymes and factors, such as significantly diminished malondialdehyde (MDA) levels and glutathione (GSH) depletion, reduced ratio of B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax)/Bcl-2, prohibited cleaved caspase-3 expression, and elevated the expression of p-AMPK, p-Akt, p-glycogen synthase kinase 3β (GSK 3β), nuclear factor erythroid 2–derived-like 2 (Nrf 2) and heme oxygenase-1 (HO-1) proteins in the liver tissues of the mouse model. In conclusion, we speculated that the protective activities of SCAP on the APAP-induced mouse model of acute liver injury might be related to its antioxidation, anti-inflammation and anti-apoptosis properties.
研究领域:
药理学
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肝病学
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免疫学
·
分子生物学
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DOI
PubMed
高影响因子
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