CELL
·
2024
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IF 45.5
Qixing Nie,Xi Luo,Kai Wang,Yong Ding,Shumi Jia,Qixiang Zhao,Meng Li,Jinxin Zhang,Yingying Zhuo,Jun Lin,Chenghao Guo,Zhiwei Zhang,Huiying Liu,Guangyi Zeng,Jie You,Lulu Sun,Hua Lu,Ming Ma,Yanxing Jia,Ming-Hua Zheng,Yanli Pang,Jie Qiao,Changtao Jiang
The gut microbiota has been found to play an important role in the progression of metabolic dysfunction-associated steatohepatitis (MASH), but the mechanisms have not been established. Here, by developing a click-chemistry-based enrichment strategy, we identified several microbial-derived bile acids, including the previously uncharacterized 3-succinylated cholic acid (3-sucCA), which is negatively correlated with liver damage in patients with liver-tissue-biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). By screening human bacterial isolates, we identified Bacteroides uniformis strains as effective producers of 3-sucCA both in vitro and in vivo . By activity-based protein purification and identification, we identified an enzyme annotated as β-lactamase in B. uniformis responsible for 3-sucCA biosynthesis. Furthermore, we found that 3-sucCA is a lumen-restricted metabolite and alleviates MASH by promoting the growth of Akkermansia muciniphila . Together, our data offer new insights into the gut microbiota-liver axis that may be leveraged to augment the management of MASH.
研究领域:
医学
·
微生物学
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DOI
PubMed
高影响因子
GENE
·
2021
·
IF 3.688
Ming Deng,Ping Xie,Zhonghui Chen,Yan Zhou,Junqi Liu,Jianghua Ming,Jianwei Yang
Background Spinal cord injury (SCI) leads to severe motor and sensory dysfunctions. Neural stem cells (NSCs) transplantation therapy plays a positive role in functional recovery after SCI, but the effectiveness of this therapy is limited by inadequate differentiation ability of transplanted NSCs. Mammalian achaete-scute homologue-1 (Mash-1) has been reported to improve differentiation of NSCs. Thus, this study modified NSCs with Mash-1 to repair SCI. Methods NSCs isolated from rat embryo hippocampus were cultured and identified in vitro and further transfected with the lentiviral vectors (Lv-Mash-1). After establishing a SCI rat model, the rats were transplanted with Mash-1 modified NSCs, the histopathological changes of rat spinal cord were detected by hematoxylin-eosin (HE) staining, and the locomotor activity of rats was evaluated with the Basso, Beattie and Bresnahan (BBB) scale. The NSCs cultured in vitro or extracted from SCI rat spinal cord were identified by immunofluorescence (IF). Mash-1, β3-Tubulin, and NeuN expressions in those cells were determined by Western blotting and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Results NSCs isolated from rat embryo hippocampus were Nestin- and NeuN-positive. NSC transplantation modified by Mash-1 increased BBB score of SCI rats and promoted recovery in lesion site of SCI rats. Mash-1 overexpression also promoted β3-Tubulin and NeuN expressions in NSCs cultured in vitro or extracted from spinal cord of SCI rats. Conclusion Mash-1 overexpression promoted NSC differentiation into neurons, and further improved locomotor functional recovery of SCI rats.
研究领域:
神经科学
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干细胞研究
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再生医学
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DOI
PubMed
高影响因子
Hepatology International
·
2026
·
IF 7.8
Lim Daniel Yan Zheng,Leow Wei Qiang,Allende Daniela S.,Seto Wai Kay,Yip Terry Cheuk-Fung,Goh George Boon Bee
Introduction Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common liver diseases, but thus far only two drugs (resmetirom and semaglutide) have received conditional approval for use. Successful MASH trials are thus highly desired to fill the therapeutic and evidence gap. Concurrently, AI has powered advances in multiple areas of medicine. We consider in this review the potential applications of AI to enhance MASH trials. Methods We conduct a narrative review of AI uses in MASH, with a focus on current and potential applications in MASH trials. Results We describe current digital pathology and AI technologies for MASH grading, a mature application where specific models have been qualified by the FDA and EMA for endpoint determination in MASH trials. We also cover the use of contemporary AI risk models to facilitate patient enrollment, and large language models to facilitate patient interactions including recruitment and retention. Finally, we consider lessons from innovative uses of AI in other medical domains, and how current guidelines shape our thinking about the use of AI in MASH trials.
Conclusion AI has made inroads into the world of MASH trials and shows high potential to further enhance their safety, efficacy, and scientific validity.
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高影响因子
International Journal of Nanomedicine
·
2025
·
IF 6.5
Shuying He,Yuerong Lv,Zixian Gao,Liang Peng
Objective The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing because people’s dietary habits are dominated by high caloric intake and sedentary lifestyles, leading to the accumulation of lipid, reactive oxygen species (ROS) and inflammation. However, treating MASH remains a challenge.Methods Two-dimensional (2D) niobium carbide (Nb4C3) MXene nanoenzymes (MXenzymes) possess both antioxidant and anti-inflammatory properties and have attracted considerable attention in the tumor and engineering fields. The Nb4C3 MXenzyme was developed for MASH therapy and exhibited biosafety and antilipid peroxidation activity.Results Nb4C3 reduced excessive ROS and proinflammatory cytokine levels through its antilipid peroxidation activities, resulting in the inhibition of hepatocyte lipid accumulation and inflammation in a methionine–choline-deficient diet (MCD)-induced murine MASH model. Mechanistically, Nb4C3 not only inhibited lipid accumulation and disrupted lipid metabolism in hepatocytes but also attenuated fatty acid-induced cell death by reducing intracellular ROS levels, which significantly promoted the polarization of M1 macrophages to M2 macrophages by alleviating oxidative stress and suppressing inflammatory factor expression.Conclusion The Nb4C3 MXenzyme can be used as a multifunctional bioactive material to alleviate hepatic steatosis and inflammation in MASH mice through its robust antioxidant and anti-inflammatory activities.
研究领域:
生物医学工程
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肝脏疾病研究
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DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Qianrang Lu,Meiching Ong,Xuewen Yi,Muqiong Xing,Xinyao Tian,Ke Zhang,Ling Lu,Hao Wang,Xiaohan Lin,Jun Fang,Aibo Mu,Jiaying Cao,Jingyu Jiang,Feng Gao,Hongjun Li,Baohong Wang,Qi Ling
Macrophages are central mediators of hepatic inflammation and fibrosis in metabolic-associated steatohepatitis (MASH), yet the mechanisms driving their activation remain unclear. Integration of four human single-nucleus transcriptomic datasets identified Coagulation Factor XIII-A (F13A1)-positive macrophages as the predominant subset in MASH livers, a finding validated in patient samples and murine models. Lipid-stressed hepatocytes induce F13A1 expression through a sphingosine-1-phosphate (S1P)-dependent mechanism. Silencing F13A1 suppressed the pro-inflammatory phenotype and alleviated hepatic injury in vivo. Mechanistically, F13A1 directly interacted with pyruvate kinase M2 (PKM2), promoting its dimerization, a process enhanced by intracellular calcium levels. Dimerized PKM2 translocated into the nucleus and upregulates interleukin-1 beta (IL1B) expression via the PKM2/HIF1A (Hypoxia-inducible factor 1-alpha) axis. In addition, F13A1 enhanced the Warburg effect in macrophages through PKM2-mediated metabolic reprogramming. Pharmacologic activation of PKM2 with DASA-58 abrogated F13A1-driven inflammation, and PEG-PLA micelle-mediated delivery of DASA-58 ameliorated hepatic inflammation in vivo. These findings establish F13A1 as a critical driver of macrophage-mediated inflammation in MASH and highlight the F13A1/PKM2/HIF1A pathway as a promising therapeutic target.
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DOI
高影响因子
Cell Reports Medicine
·
2024
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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
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代谢性疾病
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分子生物学
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细胞信号传导
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高影响因子
LIVER INTERNATIONAL
·
2025
·Vol. 45
·期 4
·e70053
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IF 5.2
Peng Ma,Hao Ou,Junze Cai,Yuanli Zhang,Yu Ou
Background & Aims G protein-coupled receptors (GPCRs) are important potential drug targets for the treatment of metabolic disorders. The D2 dopamine receptor (DRD2), a GPCR receptor, is a member of the dopamine receptor family. However, the role of DRD2 in regulating lipid metabolism, especially in hepatic steatosis, is unclear. Methods Eight-week male mice were fed HFHC/MCD to induce the MASH model. AAV2/8 containing the TBG promoter was used to knock down and overexpress DRD2 in mouse liver. Co-immunoprecipitation, Western lotting, immunofluorescence, and immunohistochemistry were used to investigate the mechanisms and screen DRD2 antagonists. Results The study found that activation of PKC leads to the elevation and internalisation of DRD2 in a high-fat environment. Knockdown of DRD2 in mouse liver can effectively interfere with the progression of MASH, while overexpression of DRD2 significantly aggravates the process of MASH. The study on the mechanism of DRD2 regulating lipid metabolism found that the internalisation of DRD2 could lead to dephosphorylation of pAKT (T308) by binding to β-arrestin2 and pAKT, thereby inducing ubiquitin-dependent degradation of AMPK and exacerbating steatosis. L-741626, a DRD2 antagonist, was found to interfere with the internalisation of DRD2 in a high-fat environment. It has been shown that L-741626 can treat MASH by regulating the AKT-AMPK signalling axis in vitro and in vivo. Conclusions In conclusion, this study demonstrated that internalisation of DRD2 in a high-fat environment aggravated MASH progression through the AKT-AMPK signalling axis. Furthermore, L-741626, as a DRD2 antagonist, has the potential to treat MASH.
研究领域:
代谢性疾病
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肝病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
EXPERIMENTAL AND MOLECULAR MEDICINE
·
2026
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IF 17.5
Gao Jun,Yang Meng,Duan Rui,Huang Tongling,Li Pengda,Gao Lu,Lu Zhaocheng,Wong Chi-Wai,Geng Chang-An,Guan Min
Lactate has been recognized as a major fuel substrate and also a lactyl-group donor for histone lysine lactylation. Hepatocytes act as lactate-consuming cells owing the high oxidative capability especially during exercise, a primary nonpharmacological intervention for alleviating metabolic dysfunction-associated steatotic liver diseases including steatohepatitis (MASLD/MASH). However, little is known regarding how lactate links the metabolic–epigenetic axis in hepatocytes. Here we show that declined estrogen-related receptor α (ESRRA) expression occur in MASLD/MASH accompanied with elevated levels of lactate and histone lactylation, particularly H3K18la. Such dysregulation can be partially rescued by chronic exercise in aged mice or exacerbated by genetic ablation of hepatocyte ESRRA. Mechanistically, exercise-induced ESRRA/PPARGC1A facilitates lactate consumption through transcriptional regulation of lactate dehydrogenase B and glucose-6-phosphatase catalytic subunit 1, rewiring lactate from a lactyl donor to gluconeogenic precursor in hepatocytes. Hepatocyte-specific ESRRA overexpression counteracts MASLD/MASH progression in mice, rectifying aberrant H3K18la accumulation and its marked gene transcripts that are involved in liver pathology. Our findings reveal that ESRRA functions as an exercise executor linking metabolism with epigenetic modification, highlighting a gluconeogenic–epigenetic regulatory axis that could be fine-tuned to mitigate risk factors of MASLD/MASH such as aging, menopause, a sedentary lifestyle and malnutrition. The alternative text for this image may have been generated using AI.
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Shaoyong Weike,Jiang Shouchuan,Wang Yingqian,Li Wei,Wang Zilong,Yang Yixiao,Du Juan,Liu Zhongjie
Chronic exposure of the liver to diverse insults can lead to metabolic dysfunction-associated steatohepatitis (MASH), a complex metabolic disorder characterized by hepatic steatosis and inflammation, often accompanied by progressive fibrosis, intestinal barrier dysfunction, and intestinal endocrine imbalance. No approved pharmacotherapies effectively treat MASH largely because of the difficulty in reversing fibrosis and restoring extracellular matrix homeostasis. Managing intestinal barrier dysfunction and GLP1 secretion has emerged as a promising therapeutic strategy against the progression of metabolic-associated fatty liver (MAFL) to MASH. This study presents MSN@HTL, fabricated using trehalose and temsirolimus on mesoporous silica nanoparticles (MSNs) and encapsulated with sodium alginate using an electrostatic spraying system. After oral administration, MSN@HTL protects against intestinal barrier injury and GLP1 secretion, consequently inhibiting the progression of MAFL. MSN@HTL stimulated intestinal stem cell self-renewal, proliferation, and GLP1 secretion. Mechanistically, MSN@HTL induces lysosomal autophagy to recycle disrupted mitochondria, increasing mitochondrial fusion and energy metabolism, elevating cAMP concentration, and inducing PKA phosphorylation-mediated intestinal barrier revision and GLP1 secretion, thereby impairing MAFL-to-MASH progression. Given its availability and functionality, our study demonstrates the potential of MSN@HTL as a pharmaceutical agent for managing MAFL-to-MASH progression via the mitochondria/cAMP/PKA signaling pathway in humans. Graphical
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高影响因子
npj Science of Food
·
2025
·Vol. 9
·期 1
·1-13
·
IF 7.8
Liao Yingyi,Xie Xingyu,Lin Zixin,Huang Ning,Wei Guilan,Wu Jiazhen,Li Yucui,Chen Jiannan,Su Ziren,Yu Xiuting,Chen Liping,Liu Yuhong
Visceral adiposity is an important characteristic of metabolic dysfunction-associated steatohepatitis (MASH) that affects its development. Curcumin (Cur) attenuates MASH through microbial biotransformation. However, antibiotics (Abx) do not weaken but rather enhance the resistance to weight gain of Cur on MASH rats. The resistance to weight gain mechanism of Cur is different from its anti-MASH effect, which may relate to alleviate visceral adiposity. Here we investigated the mechanism of Cur against visceral adiposity in high-fat diet-induced MASH rats. The results demonstrated that Cur and Abx reduced body, liver and visceral fat weights of MASH rats. Unlike Abx, which induces resistance to weight gain by reducing appetite, Cur mainly reduced the weight of visceral fat, especially that of perirenal fat. Intriguingly, the reduction in perirenal fat caused by Cur was attributed to its specific inhibition of gastric inhibitory polypeptide (GIP) release. The Cur-induced decrease in intestinal GIP release inhibited the activation of GIP receptors to alleviate adipogenesis and inflammation in perirenal adipose tissue. Moreover, Cur alleviated intestinal epithelium and vascular barrier disruption-mediated hypoxia to inhibit GIP release. In summary, the pharmacological effects of Cur on visceral adiposity were mainly contributed by inhibiting gut barrier disruption-mediated hypoxia to attenuate GIP release.
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DOI
PubMed
高影响因子
Foods
·
2026
·Vol. 15
·期 2
·360
·
IF 5.1
Linli Dai,Xin Wang,Nurul Hawa Ahmad,Jae-Hyung Mah,Wen Qin,Xinyao Wei,Shuxiang Liu
Although fermented seasonings play a pivotal role in improving food quality, the high sodium content of many traditional products poses considerable public health concerns, including hypertension and cardiovascular disease. This study established a low-salt fermentation strategy for Mumashan chili by regulating water activity (aw) under NaCl concentrations ranging from 4 to 12% (w/w). The aw-regulated system effectively maintained awwithin ± 0.03 at both 25 and 40 °C, thereby sustaining stable microbial activity despite the reduced salt concentration. Compared with the control group 15% NaCl, the 4% NaCl treatments exhibited significantly higher total acidity (130–200 g/kg vs. 24–58 g/kg) and a faster consumption rate of reducing sugars, with MH12 achieving an 80% rate of reducing sugars by day 21. Sensory evaluation revealed a higher overall quality score for the low-salt chili mash (MH12, 7.7/10), which was associated with a balanced aroma profile and enhanced color stability (ΔE < 5). However, the elevated relative abundance of opportunistic pathogens (Klebsiellaapp., ~10%) highlights the necessity of strict raw material hygiene. Overall, these results validate the feasibility of awregulation for low-salt fermentation, elucidate the associations between microbial communities and flavor development, and provide a basis for future industrial applications.
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Manman Yuan,Jing Ye,Xiangqiao Sun,Zhiwu Tong,Tingting Wang,Renxiang Tan,Xingxin Wu
Acaudiolide ameliorates liver fibrosis in mice • Acaudiolide inhibits TGF-β1/SMAD signaling in HSCs • Acaudiolide inhibits the nuclear translocation of p-SMAD2/3 • Acaudiolide weakens the interaction between SMAD4 and p-SMAD2/3 • SMAD4 is a candidate covalent target of acaudiolide Hepatic stellate cell (HSC) activation is a central driver of fibrosis progression in metabolic dysfunction-associated steatohepatitis (MASH), yet effective antifibrotic pharmacotherapies remain limited. Here, we identify acaudiolide, a sulfur-bridged symmetric dimeric macrodiolide isolated from the fungus Acaulium sp. H-JQSF, as a natural-product lead that suppresses HSC activation and experimental liver fibrosis. In a Western diet (WD)/CCl 4 murine model of MASH, acaudiolide reduced collagen deposition, alpha-smooth muscle actin (α-SMA) expression and fibrogenic gene expression. Transcriptomic profiling of HSCs showed that acaudiolide antagonized transforming growth factor-β1 (TGF-β1)-driven profibrotic programs. Mechanistically, acaudiolide did not measurably alter SMAD2/3 phosphorylation but markedly reduced the nuclear accumulation of phosphorylated SMAD2/3 (p-SMAD2/3). Integration of Connectivity Map (CMap) analysis with isotopic tandem orthogonal proteolysis-activity-based protein profiling (isoTOP-ABPP) chemical proteomics nominated SMAD4 as a candidate covalent target of acaudiolide. Covalent docking suggested Cys363 as a potential engagement site, and co-immunoprecipitation showed that acaudiolide weakened the association of SMAD4 with p-SMAD2/3. These findings support a model in which acaudiolide interferes with SMAD complex assembly, thereby attenuating TGF-β-dependent profibrotic transcription and HSC activation. Collectively, our data nominate acaudiolide as a preclinical antifibrotic lead and SMAD4 as a potentially tractable downstream node for pharmacological modulation of TGF-β signaling in MASH-related fibrosis. Download: Download high-res image (386KB) Download: Download full-size image
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高影响因子
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