Nutrients
·
2023
·Vol. 15
·期 19
·4176
·
IF 5.9
Yuxu Chen,Zhiye Zhao,Shancheng Guo,Yaxian Li,Haiaolong Yin,Lei Tian,Guiguang Cheng,Ye Li
Alcoholic liver disease (ALD), leading to the most common chronic liver diseases, is increasingly emerging as a global health problem, which is intensifying the need to develop novel treatments. Herein, our work aimed to estimate the therapeutic efficacy of red rice (Oryza sativaL.) seed coat on ALD and further uncover the underlying mechanisms. Red rice seed coat extract (RRA) was obtained with citric acid–ethanol and analyzed via a widely targeted components approach. The potential targets of RRA to ALD were predicted by bioinformatics analysis. Drunken behavior, histopathological examination, liver function, gut microbiota composition and intestinal barrier integrity were used to assess the effects of RRA (RRAH, 600 mg/kg·body weight; RRAL, 200 mg/kg·body weight) on ALD. Oxidative stress, inflammation, apoptosis associated factors and signaling pathways were measured by corresponding kits, Western blot and immunofluorescence staining. In ALD model mice, RRA treatment increased sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate (S1P) levels, improved gut microbiota composition, restored intestinal barrier, decreased lipopolysaccharide (LPS) levels in plasma and the liver, cut down Toll-like receptor 4 (TLR4)/Nuclear factor kappa B (NF-κB) pathways, alleviated liver pathological injury and oxidative stress, attenuated inflammation and apoptosis and enhanced liver function. To sum up, RRA targeting SPHK2 can ameliorate ALD by repairing intestinal barrier damage and reducing liver LPS level via the TLR4/NF-κB pathway and intestinal microbiota, revealing that red rice seed coat holds potential as a functional food for the prevention and treatment of ALD.Keywords:red rice seed coat;alcoholic liver disease;SPHK2;gut microbiota;intestinal barrier
研究领域:
药理学
·
胃肠病学
·
微生物学
·
营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2024
·
IF 27.7
Xiaoqian Ji,Zihao Chen,Qiyuan Wang,Bin Li,Yan Wei,Yun Li,Jianqing Lin,Weisheng Cheng,Yijie Guo,Shilin Wu,Longkun Mao,Yuzhou Xiang,Tian Lan,Shanshan Gu,Meng Wei,Joe Z. Zhang,Lan Jiang,Jia Wang,Jin Xu,Nan Cao
Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.
研究领域:
心血管生物学
·
再生医学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Chanyuan Su,Hang Chen,Yuanming Yan,Beilei Li,Qin Chen,Zhaoyang Chen,Yukun Luo
Farnesol mitigates post-MI ventricular remodeling and fibrosis. • Multi-omics reveal farnesol upregulates the SPHK2/S1P pathway. • Increased S1P synthesis blunts pro-fibrotic SMAD3 signaling. • Pharmacological SPHK2 blockade in vivo reverses these benefits. • Modulating SPHK2 offers a potential post-MI therapeutic strategy. Pathological ventricular remodeling following myocardial infarction (MI) is driven by dysregulated pro-fibrotic signaling and metabolic maladaptation. This study aimed to investigate whether farnesol, an endogenous mevalonate pathway intermediate with cardioprotective properties, mitigates post-MI fibrotic remodeling by pharmacologically modulating sphingolipid metabolism. MI was induced in C57BL/6 mice via permanent coronary artery ligation, followed by daily intragastric administration of farnesol (2 mg/kg) for 14 days. Cardiac structural and functional indices, alongside inflammatory and fibrotic cascades, were evaluated. The underlying molecular mechanisms were elucidated using transcriptomic and untargeted metabolomic profiling. In vivo target validation was achieved through pharmacological blockade of sphingosine kinase 2 (SPHK2) using opaganib. Farnesol treatment significantly preserved left ventricular systolic function and attenuated interstitial fibrosis. At the cellular level, farnesol facilitated inflammatory resolution by reducing acute neutrophil infiltration and promoting reparative M2 macrophage polarization, while restraining aberrant myofibroblast activation. Multi-omics integration revealed that farnesol modulated sphingolipid metabolism by selectively upregulating SPHK2 and increasing sphingosine-1-phosphate (S1P) synthesis. Activation of the SPHK2/S1P axis subsequently attenuated pro-fibrotic signaling via transforming growth factor-beta (TGF-β)/SMAD3. Crucially, targeted in vivo inhibition of SPHK2 with opaganib substantially reversed farnesol-induced suppression of SMAD3 and its downstream cardioprotective effects. These findings suggest that farnesol confers cardioprotection against post-MI remodeling, an effect closely associated with the pharmacological upregulation of the SPHK2/S1P axis and the subsequent attenuation of TGF-β/SMAD3-mediated fibrogenesis. Together, these findings highlight crosstalk between the mevalonate and sphingolipid pathways, supporting modulation of SPHK2 as a potential therapeutic strategy for the clinical management of post-MI heart failure. Farnesol attenuates post-MI ventricular remodeling through targeted modulation of sphingolipid metabolism. By upregulating the SPHK2/S1P axis, farnesol blocks pro-fibrotic TGF-β/SMAD3 signaling and subsequent fibrotic gene transcription. This metabolic intervention facilitates inflammatory resolution, restrains myofibroblast activation, and ultimately preserves left ventricular systolic function. Download: Download high-res image (276KB) Download: Download full-size image
✓ 已验证
DOI
高影响因子
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