BACKGROUND AND AIMS:TREM2-expressing scar-associated macrophages (SAMs) are integral to the pathogenesis of hepatic fibrosis; however, the limited understanding of their differentiation and pro-fibrotic functions impedes the advancement of targeted therapeutic strategies. APPROACH AND RESULTS:Integrated multi-omics analysis, including transcriptomics, 4D proteomics, CUT&Tag, and WGCNA of human and mouse fibrotic livers, coupled with single-cell RNA sequencing, identified SAMs with high TREM2 expression as key drivers of fibrosis. These TREM2high macrophages serve as essential mediators for the reception and transmission of TGF-β signaling. In the context of a fibrotic microenvironment, TGF-β activates HIF-1α-mediated glycolysis and lactate production, leading to an increase in histone lactylation, particularly the p300-catalyzed lactylation of histone H4 at lysine 12 (H4K12la). Importantly, the enrichment of H4K12la at the TREM2 promoter facilitates an upregulation of TREM2 transcription, thereby promoting the differentiation of monocytes into the pro-fibrotic TREM2high macrophage phenotype. Furthermore, the TREM2 protein directly interacted with lactate dehydrogenase A (LDHA), stabilizing its expression and reinforcing lactate production, thereby establishing a complete TREM2/LDHA/H4K12la positive-feedback loop that promotes the differentiation of TREM2high macrophages. In murine models, the knockout of TREM2, macrophage-specific knockdown, and overexpression all disrupted this regulatory loop, inhibited glycolysis and H4K12la modification, and ultimately mitigated liver fibrosis. CONCLUSIONS:H4K12 lactylation facilitates the differentiation of monocytes into TREM2high macrophages within the context of liver fibrosis. This lactylation event enhances and maintains a crucial TREM2/LDHA positive-feedback loop. Intervening in this H4K12la-TREM2 pathway significantly mitigates liver fibrosis, thus presenting a novel potential target for therapeutic intervention in hepatic fibrogenesis.

Astragaloside IV (AS-IV), a principal bioactive constituent of the medicinal and edible herb Radix astragali, exerts protective effects against ulcerative colitis (UC). This study investigated its underlying mechanisms in dextran sulfate sodium (DSS)-induced colitis using 16S rRNA sequencing, untargeted fecal metabolomics, and label-free proteomics. AS-IV intervention remodeled intestinal microbiota composition by markedly increasing Akkermansia abundance. Fecal metabolomic analysis revealed enhanced tryptophan (Trp) metabolism and elevated levels of kynurenic acid, 5-hydroxyindoleacetic acid and indole-3-acetic acid, which were significantly positively correlated with Akkermansia abundance. Proteomic analysis further identified Trp metabolism as a key pathway. Indoleamine 2,3-dioxygenase 1 (IDO1) and dopa decarboxylase (DDC) were recognized as differentially expressed proteins in colonic tissues. AS-IV ameliorated colitis by downregulating IDO1 expression, while upregulating the expression of tryptophan hydroxylase 1 (TPH1), DDC, monoamine oxidase A (MAO-A), and the aryl hydrocarbon receptor (AhR), as well as inhibiting NF-κB p65 phosphorylation. Collectively, these findings indicate that AS-IV enhances intestinal barrier function and mitigates colonic inflammation in DSS-induced UC. These beneficial effects are associated with the regulation of host-gut Trp metabolism, altered AhR expression, and suppressed NF-κB p65 activation. This study underscores the potential of AS-IV as a candidate functional food ingredient for the management of UC.

Chronic obstructive pulmonary disease (COPD) remains a significant global health challenge, which urges the discovery of novel drugs. In this article, we investigated the therapeutic potential and action mechanism of a new benzoxazolone derivative, 4-(5'-dimethylamino)-naphthalenesulfonyl-2(3H)-benzoxazolone (W3D), synthesized by our research team, against COPD both in vivo and in vitro. The results demonstrated that W3D could down-regulate inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and MMP-9, thereby reducing airway inflammation and improving lung function, which together alleviated lung injury in COPD. Meanwhile, W3D increased the expression of tight junction proteins claudin-1 and occludin and attenuated the activation of the Toll-like receptor 4/nuclear factor kappa B (TLR4)/NF-κB) signaling pathway to maintain the integrity of bronchial epithelial cells. Additionally, W3D restored the expression of glycolytic enzymes such as LDHA, PKM2, and HK2 to modulate lactate levels, thereby correcting glycolytic pathway dysregulation. W3D decreased intracellular lactate content, down-regulated global Kla levels and H3K18la expression, and regulated macrophage polarization in cigarette smoke extract (CSE)-induced macrophages. Furthermore, these therapeutic effects of W3D were compromised in the presence of the glycolytic inhibitor 2-deoxy-d-glucose (2-DG), indicating that W3D regulated macrophage polarization by inhibiting glycolysis. Our results demonstrated that glycolysis was activated in macrophages exposed to CSE and served as a key role in the macrophage polarization process. Inhibiting glycolysis in macrophages might be a potential therapeutic direction for COPD. In addition, given the confirmed protective effect against COPD, W3D could serve as a promising lead compound for further structural modifications of innovative drugs.

Background: Inonotus obliquus, a fungus known for its edible and medicinal properties, has traditionally been used as a herbal tea to relieve gastrointestinal disorders. Melanin, a major active constituent of this fungus, exhibits antioxidant, anti-inflammatory, and immune-modulating effects. This study aimed to investigate the therapeutic potential and mechanisms of Inonotus obliquus crude melanin (IOM) in treating dextran sulfate sodium (DSS)-induced colitis in mice. Methods: The study assessed colonic inflammation, mucosal damage, and intestinal barrier integrity. It also measured the levels of proinflammatory cytokines and oxidative stress markers. Gut microbiota composition was analyzed using 16S rRNA gene sequencing following IOM treatment. Additionally, label-free quantitative proteomic analysis was performed to explore the underlying mechanisms. Results: IOM administration significantly ameliorated colitis symptoms, strengthened the intestinal barrier, and reduced inflammation and oxidative stress in a dose-dependent manner. Furthermore, IOM modulated gut microbiota composition by increasing the relative abundance of Lactobacillus and Muribaculaceae, while reducing that of Bacteroides, Escherichia-Shigella, and Romboutsia. Proteomic analyses revealed that IOM treatment regulated the neutrophil pro-NETotic signaling pathway, which was further verified by immunohistochemistry or Western blot analysis of key pro-NETotic markers (e.g., PAD4, CitH3, MPO). Importantly, the relative abundances of these bacterial taxa were significantly correlated with the ulcerative colitis (UC) progression and neutrophil pro-NETotic activation. Conclusions: IOM mitigates DSS-induced colitis alongside the modulation of gut microbiota and the suppression of neutrophil pro-NETotic activation, suggesting its potential as a functional food ingredient for the management of UC.

The identification of natural compounds with therapeutic efficacy for acute lung injury has consistently represented a critical area of research. Dulcitol, a natural product isolated from plants, is extensively used in the food and medical industries as a sweetener. Herein, we investigated whether dulcitol exerts an anti-inflammatory effect on LPS-induced acute lung injury (ALI) in mice. In our study, ICR mice were pretreated with dulcitol at dose of 6, 12 and 24 mg/kg for seven consecutive days, followed by intratracheally instilled with LPS (10 mg/kg) to induce acute lung injury. In vitro, RAW264.7 and A549 cells were incubated with LPS in the presence of dulcitol to investigate the anti-inflammatory activity and mechanism. The results demonstrated that dulcitol effectively inhibited the infiltration of inflammatory cells and reduced the excessive production of pro-inflammatory cytokines triggered by LPS to ameliorates acute lung injury in mice. Additionally, in vitro experiments indicated that dulcitol suppressed the release of NO, IL-6 and TNF-alpha while reducing mRNA expression levels of IL-1 beta, IL-6, COX-2, iNOS and TNF-alpha in RAW264.7 and A549 cells in a dose-dependent manner. Furthermore, dulcitol significantly decreased TLR4, MyD88, and TRIF levels and inhibited the translocation of NF-kappa B from the cytoplasm to the nucleus. Our finding suggested that dulcitol could serve as a protective agent against LPS-induced acute lung injury by inhibiting the TLR-4/NF-kappa B signaling pathway.

Cardiac metabolism relies on glycogen conversion by glycolysis. Glycolysis intersects fatty acid oxidation and often directs a signal crosstalk between redox metabolites. Myocardium with ischemia/reperfusion significantly diverts from normal metabolism. Prospectively, peroxisome lies central to metabolism and redox changes, but mechanisms underlying in ischemia/reperfusion remain undefined. This work aims at investigating the potential effects and mechanisms of Salvianolic acid B (Sal B) in cardioprotection through metabolic remodeling. Following experiments, we found that Sal B is absorbed in blood and rat hearts and its cardiac absorption prevents ischemia/reperfusion injury. Sal B cardioprotection relates to gluconeogenesis activation and peroxisomal redox remodeling. Gluconeogenesis compensates glycogen synthesis through upregulating pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase. Gluconeogenic PC activity drives peroxisomal Pex2/Pex3 expressions and promotes the proliferation of peroxisome. Peroxisome quality control is enhanced with Pex5/Pex14/Pex13/Pex2 transcriptions. Nono, a non-POU domain-containing octamer-binding protein, promotes upregulation of gluconeogenic PC and peroxisomal gene transcripts through transcriptionally splicing their pre-RNAs at octamer duplex. Nono also controls the expression of SARM1/PARP1/sirtuin1 for catalyzing nicotinamide adenine dinucleotide (NAD+) consumption, leading to endurable redox capacities of peroxisome. Peroxisomal redox remodeling alters reactive oxygen species (ROS) and NAD+ contents, following which NAD+ affects cardiac accumulation of physiologically harmful glucocorticoid. In the tests of Sal B combinational treatments, results indicate ROS upregulation whereas NAD+ downregulation with glucocorticoid, ROS scavenging and glucocorticoid elimination with NAD+ precursor, and NAD+ promotion with ROS scavenger, respectively. This metabolite signal crosstalk alternatively antagonizes/agonizes Sal B cardioprotective functions on electrocardiographic output and infarction. Taken together, we reported a cardiac metabolism regulation with Sal B, capable of preventing myocardium from ischemia/reperfusion injury. The metabolite signal crosstalk was achieved by coupling reaction cascades between gluconeogenesis and peroxisomal redox remodeling.

The electrochemical oxidation of small molecules is a promising approach in chemical synthesis, but catalyst deactivation due to the accumulation of poorly soluble products on the surface remains a significant challenge. To address this, we propose an in situ cleaning method using an additional oxygen evolution reaction (OER) to regenerate degraded catalysts. The OER facilitates the removal of insoluble products, thereby restoring active sites. Taking the electrochemical oxidation of tetrahydroisoquinoline (THIQ) to dihydroisoquinoline (DHIQ) as an example, we develop a highly active γ-Ni(Co)OOH anode. The OER generates oxygen, promoting the oxidation of DHIQ to IQ, which is more soluble, thus effectively removing DHIQ from the catalyst surface. After 120 cycles in a small-scale pilot test, the current stability exceeds 98%, and the product selectivity reaches 95%. This method demonstrates the highest stability to date, outperforming previous catalysts 15-fold, and can be applied to other electrocatalytic systems facing similar deactivation issues.

Pharmaceutically active compounds have garnered increased attention as emerging contaminants due to their widespread presence and potential ecological impacts. This study conducted a field evaluation under varied rainfall conditions, assessing the effects of rainfall intensity and duration on pharmaceutical concentrations. Grab sampling was complemented by the deployment of diffusive gradients in thin films (DGT) passive samplers along two urban rivers in Beijing, China. Twenty-four target pharmaceuticals were detected, with concentrations ranging from 370 to 686 ng/L in the Beixiao River and 376 to 610 ng/L in the Qing River. Rainfall influenced pharmaceutical concentrations through either dilution or enhancement, depending on local factors. Rainfall had a minimal impact on DGT performance, while biofouling showed compound-specific effects. For about 70 % of the pharmaceuticals, hydrophilic poly tetrafluoroethylene (PTFE) membranes used over 9-15 days effectively minimized biofouling influence (M-biofouled/M-clean > 0.8). The effectiveness of DGT for long-term monitoring depended on the biofilm formation time. Overall, DGT proved to be a reliable tool for accurately characterizing pharmaceutical concentrations in dynamic water systems. This study represents the first attempt to evaluate DGT performance for pharmaceuticals under fluctuating concentration scenarios in the field, providing valuable insights into the occurrence and environmental behavior of these contaminants.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease in which macrophages produce cytokines that enhance inflammation and contribute to the destruction of cartilage and bone.Additive Sishen decoction (ASSD) is a widely used traditional Chinese medicine for the treatment of RA; however, its active ingredients and the mechanism of its therapeutic effects remain unclear.Methods: To predict the ingredients and key targets of ASSD, we constructed "drug-ingredient-target-disease" and protein-protein interaction networks.Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to explore the potential mechanism.The activity of the predicted key ingredients was verified in lipopolysaccharide-stimulated macrophages.The binding mode between the key ingredients and key targets was elucidated using molecular docking and molecular dynamics simulation.Results: In all, 75 ASSD active ingredients and 1258 RA targets were analyzed, of which kaempferol, luteolin, and quercetin were considered key components that mainly act through inflammation-related pathways, such as the PI3K-AKT, TNF, and IL-17 signaling pathways, to ameliorate RA.Transcriptome sequencing suggested that kaempferol-, luteolin-, and quercetin-mediated inhibition of glycolysis reduced the lipopolysaccharide-induced production of proinflammatory factors.In vitro experiments indicated that kaempferol, luteolin, and quercetin decreased Glut1 and LDHA expression by diminishing PI3K-AKT signaling to inhibit glycolysis.Molecular dynamic simulation revealed that kaempferol, luteolin, and quercetin stably occupied the hydrophobic pocket of PI3Kδ.Conclusion: Our results show that the PI3Kδ-mediated anti-inflammatory responses elicited by kaempferol, luteolin, and quercetin are crucial for the therapeutic efficacy of ASSD against RA.

We have previously identified sitravatinib as a potent inhibitor of FLT3, capable of overcoming resistance to gilteritinib in the treatment of acute myeloid leukemia (AML). The combination of venetoclax and FLT3 inhibitors gilteritinib and quizartinib has shown promising results in reducing leukemia burden and improving survival in pre-clinical studies and clinical trials of AML with FLT3 mutation. In this study, we aimed to investigate the therapeutic effect of treating AML with sitravatinib combined with venetoclax. Our findings indicated that the combination of sitravatinib and venetoclax significantly decreased cell viability and increased cell apoptosis in AML cell lines harboring FLT3 mutation, more so than either treatment alone. These two agents exerted strong synergistic effects in FLT3-ITD AML cell lines and patient bone marrow cells in vitro. The activation of MAPK/ERK signaling are common causes that weaken the efficacy of FLT3 inhibitors, while the upregulation of anti-apoptotic proteins including BCL-xL and MCL-1 leads to venetoclax resistance. Our data demonstrated that sitravatinib plus venetoclax further suppressed the phosphorylation of AKT and ERK as well as downregulated MCL-1 and BCL-xL, which mechanically explain the synergistic effect. Finally, we tested the potential application of sitravatinib plus venetoclax in vivo using patient-derived xenografts, and found that the combined therapy was significantly more effective in inhibiting leukemia cell expansion, reducing infiltration in the spleen, and prolonging survival time compared to a single administration. Our study demonstrates the potential use of sitravatinib plus venetoclax as an alternative therapeutic strategy to treat AML patients with FLT3-ITD mutation.

In this study, nine novel carvacrol/thymol derivatives incorporating carbamate groups were designed, synthesized, and evaluated as multifunctional anti-AD agents. These derivatives displayed superior BuChE inhibitory and anti-inflammatory characteristics compared to the parent compounds. While the derivatives exhibited AChE IC50 values exceeding the detectable limit (>100 μM), they demonstrated high potency as BuChE inhibitors, with IC50 values ranging from 0.05 to 9.62 μM. In an inflammation model of BV2 microglial cells induced by lipopolysaccharide (LPS), the derivatives effectively reduced the levels of the pro-inflammatory cytokine interleukin-1β (IL1β), with inhibition rates of IL1β exceeding 50 % at 10 μM. Notably, compound SXF3 ‌attained the highest BuChE inhibition efficacy (eqBuChE IC50 = 0.05 ± 0.003 μM, hBuChE IC50 = 0.04 ± 0.001 μM), the highest selectivity for BuChE (with a selectivity index, SI, exceeding 2000, calculated as the ratio of eeAChE IC50 to eqBuChE IC50) and high anti-inflammatory activity (inhibition of IL1β, IC50 = 8.33 ± 0.08 μM). In a scopolamine-induced AD mouse model, SXF3 (15 mg/kg) significantly reduced the latency to the platform and attenuated memory deficits. Biochemical analysis confirmed that SXF3 significantly increased acetylcholine (ACh) levels in the mice hippocampus, primarily due to the inhibition of BuChE rather than AChE, and that SXF3 significantly reduced IL1β levels to normal, further confirming its anti-inflammatory activities. Hence, the selective BuChE inhibitory properties and anti-inflammatory attributes of SXF3 render it a promising candidate for further investigation in the treatment of AD.

Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates both oxidative stress and mitochondrial biogenesis. Our previous study reported the cardioprotection of calycosin against triptolide toxicity through promoting mitochondrial biogenesis by activating nuclear respiratory factor 1 (NRF1), a coregulatory effect contributed by Nrf2 was not fully elucidated. This work aimed at investigating the involvement of Nrf2 in mitochondrial protection and elucidating Nrf2/NRF1 signaling crosstalk on amplifying the detoxification of calycosin. Results indicated that calycosin inhibited cardiomyocytes apoptosis and F-actin depolymerization following triptolide exposure. Cardiac contraction was improved by calycosin through increasing both fractional shortening (FS

This study aimed to investigate the inhibitory effect of astragaloside IV (AS-IV) on enterovirus 71 (EV71)-induced pyroptosis. The results indicated that AST-IV inhibited EV71-induced pyroptosis in normal human gastric epithelial (GES-1) cells. Therefore, we investigated the mechanisms underlying pyroptosis inhibition by AST-IV. We found that EV71 inhibited the Nrf2-Keap1 pathway, whereas AST-IV treatment activated it. Overexpression of Nrf2 led to the inhibition of EV71-induced pyroptosis. EV71 infection and AST-IV treatment upregulated and downregulated thioredoxin interacting protein (TXNIP), respectively. Downregulation of TXNIP activated the Keap1/Nrf2 signaling pathway and inhibited EV71-induced pyroptosis. Furthermore, transcription factor 12 (TCF12) reduced the protein and mRNA levels of TXNIP, and AST-IV treatment upregulated TCF12. These results demonstrate that the TCF12-TXNIP-Keap1/Nrf2 axis participates in the inhibition of pyroptosis by AST-IV in EV71-infected GES-1 cells, suggesting that AST-IV could be used as a dietary supplement to alleviate EV71-induced pyroptosis.

Background: According to traditional Chinese medicine (TCM), drugs supplementing the vital energy, Qi, can eliminate tumors by restoring host immunity. The objective of this study is to investigate the underlying immune mechanisms of anti-tumor activity associated with Qi-supplementing herbs, specifically the paired use of Huangqi and Danggui. Methods: Analysis of compatibility regularity was conducted to screen the combination of Qi-supplementing TCMs. Using the MTT assay and a transplanted tumor mice model, the anti-tumor effects of combination TCMs were investigated in vitro and in vivo. High content analysis and flow cytometry were then used to evaluate cellular immunity, followed by network pharmacology and molecular docking to dissect the significant active compounds and potential mechanisms. Finally, the anti-tumor activity and the mechanism of the active ingredients were verified by molecular experiments. Results: There is an optimal combination of Huangqi and Danggui that, administered as an aqueous extract, can activate immunity to suppress tumor and is more effective than each drug on its own in vitro and in vivo. Based on network pharmacology analysis, PIK3R1 is the core target for the anti-tumor immunity activity of combined Huangqi and Danggui. Molecular docking analysis shows 6 components of the combined Danggui and Huangqi extract (quercetin, jaranol, isorhamnetin, kaempferol, calycosin, and suchilactone) that bind to PIK3R1. Jaranol is the most important component against breast cancer. The suchilactone/jaranol combination and, especially, the suchilactone/kaempferol combination are key for immunity enhancement and the anti-tumor effects of the extract. Conclusions: The combination of Huangqi and Danggui can activate immunity to suppress breast cancer and is more effective than the individual drugs alone.

Background Alcoholic liver disease (ALD) is a significant contributor to liver damage. However, the clinical options for the treatment of ALD are limited. Astragaloside IV (AST-IV) is a saponin isolated from Astragalus membranaceus (AM). This study aimed to explore the underlying mechanisms of action of AST-IV in ALD by integrating metabolomics and network pharmacology. Methods Sprague-Dawley (SD) rats were used to establish a rat model of ALD. AST-IV and polyene phosphatidyl choline (PPC; a positive control drug) were administered to rats with ALD for 4 weeks. We measured the body weight, liver index, ALT, AST, TC, TG, inflammatory markers (IL-1β, IL-6, and TNF-α), and oxidative stress markers (SOD, MDA) and used H&E and ORO staining to evaluate the hepatoprotective effect of both AST-IV and PPC on ALD. Subsequently, we performed untargeted metabolomics to predict the influence of AST-IV on lipid metabolism in rats with ALD. We then used a network pharmacology approach to identify the core targets through which AST-IV corrected lipid metabolism disorders and validated these targets through molecular docking, qRT-PCR and western blot analyses. Finally, we calculated the relationships between ALD-related biochemical markers, differential liver metabolites, and core targets using Spearman's correlation analysis. Results AST-IV improved pathological damage and reduced lipid accumulation in the hepatocytes of rats with ALD. Furthermore, AST-IV inhibited oxidative stress and inflammatory responses in rats with ALD. The metabolomic results showed that AST-IV corrected hepatic lipid metabolism disorders by targeting linoleic acid, necrosis, sphingolipid, and glycerophospholipid metabolism. The Network pharmacology analysis revealed that the core targets of AST-IV exerting the above effects were p-RIPK3, p-MLKL, CYP1A2, CYP2C19, PPARα, PCSK9. Spearman's correlation analysis showed a strong correlation between ALD-related serum biochemical indices, core targets, and liver differential metabolites. Conclusion AST-IV corrects the metabolic disorders of linoleic acid, sphingolipid, and glycerophospholipid, and alleviates necrosis in rats with ALD through the core targets p-RIPK3, p-MLKL, CYP1A2, CYP2C19, PPARα, and PCSK9. This study is the first to reveal the mechanism of ALD protection through AST-IV from the perspective of metabolomics and network pharmacology. Therefore, a novel target has been identified to exert protection against ALD. This study provides a reference for ALD treatment.

Pancreatic cancer (PC) is a lethal disease and associated with metabolism dysregulation. Nogo-B is related to multiple metabolic related diseases and types of cancers. However, the role of Nogo-B in PC remains unknown. In vitro , we showed that cell viability and migration was largely reduced in Nogo-B knockout or knockdown cells, while enhanced by Nogo-B overexpression. Consistently, orthotopic tumor and metastasis was reduced in global Nogo knockout mice. Furthermore, we indicated that glucose enhanced cell proliferation was associated to the elevation expression of Nogo-B and nuclear factor K B (NF - K B). While, NF - K B, glucose transporter type 1 (GLUT1) and sterol regulatory element -binding protein 1 (SREBP1) expression was reduced in Nogo-B deficiency cells. In addition, we showed that GLUT1 and SREBP1 was downstream target of NF - K B. Therefore, we demonstrated that Nogo deficiency inhibited PC progression is regulated by the NF- K B/GLUT1 and SREBP1 pathways, and suggested that Nogo-B may be a target for PC therapy.

Lycopene (LYC) is a natural phytonutrient with various bioactivities, such as anti-oxidative stress and anti-inflammation. In this study, human endothelial cells (HUVECs), macrophages and human platelets, and carrageenan-induced thrombosis mouse model were used to evaluate the antithrombosis effects of LYC. In vitro, LYC reduced reactive oxygen species (ROS) production by activating antioxidant enzymes and inhibiting cellular inflammatory factors. LYC inhibited platelets activation by enhancing antioxidant enzymes expression through reducing AKT/FoxO3a signaling pathway. In vivo, LYC effectively improved carrageenan-induced thrombosis in mouse tail, liver and lung tissues. Additionally, in mouse liver and lung tissues, LYC reduced inflammation by inhibiting toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway, and inhibited oxidative stress by increasing antioxidant enzymes expression. In conclusion, LYC can inhibit thrombosis in mouse model, which suggesting that LYC could act as a potential functional food for prevention or treatment of thrombus.

Renal fibrosis, a terminal manifestation of chronic kidney disease, is characterized by uncontrolled inflammatory responses, increased oxidative stress, tubular cell death, and imbalanced deposition of extracellular matrix. 5,2'-Dibromo-2,4',5'-trihydroxydiphenylmethanone (LM49), a polyphenol derivative synthesized by our group with excellent anti-inflammatory pharmacological properties, has been identified as a small-molecule inducer of extracellular matrix degradation. Nonetheless, the protective effects and mechanisms of LM49 on renal fibrosis remain unknown. Here, we report LM49 could effectively alleviate renal fibrosis and improve filtration function. Furthermore, LM49 significantly inhibited macrophage infiltration, pro-inflammatory cytokine production and oxidative stress. Interestingly, in HK-2 cells induced by tumour necrosis factor alpha under oxygen-glucose-serum deprivation conditions, LM49 treatment similarly yielded a reduced inflammatory response, elevated cellular viability and suppressed cell necrosis and epithelial-to-mesenchymal transition. Notably, LM49 prominently suppressed the high-mobility group box 1 (HMGB1) expression, nucleocytoplasmic translocation and activation. Mechanistically, drug affinity responsive target stability and cellular thermal shift assay confirmed that LM49 could interact with the target heat shock protein 90 alpha family class A member 1 (Hsp90α), disrupting the direct binding of Hsp90α to HMGB1 and inhibiting the nuclear export of HMGB1, thereby suppressing the inflammatory response, cell necrosis and fibrogenesis. Furthermore, molecular docking and molecular dynamic simulation revealed that LM49 occupied the N-terminal ATP pocket of Hsp90α. Collectively, our findings show that LM49 treatment can ameliorate renal fibrosis through inhibition of HMGB1-mediated inflammation and necrosis via binding to Hsp90α, providing strong evidence for its anti-inflammatory and anti-fibrotic actions.

Lung cancer is the most common cause of cancer-related deaths worldwide and is caused by multiple factors, including high-fat diet (HFD). CD36, a fatty acid receptor, is closely associated with metabolism-related diseases, including cardiovascular disease and cancer. However, the role of CD36 in HFD-accelerated non-small-cell lung cancer (NSCLC) is unclear. In vivo , we fed C57BL/6J wild-type (WT) and CD36 knockout (CD36 −/− ) mice normal chow or HFD in the presence or absence of pitavastatin 2 weeks before subcutaneous injection of LLC1 cells. In vitro , A549 and NCI-H520 cells were treated with free fatty acids (FFAs) to mimic HFD situation for exploration the underlying mechanisms. We found that HFD promoted LLC1 tumor growth in vivo and that FFAs increased cell proliferation and migration in A549 and NCI-H520 cells. The enhanced cell or tumor growth was inhibited by the lipid-lowering agent pitavastatin, which reduced lipid accumulation. More importantly, we found that plasma soluble CD36 (sCD36) levels were higher in NSCLC patients than those in healthy ones. Compared to that in WT mice, the proliferation of LLC1 cells in CD36 −/− mice was largely suppressed, which was further repressed by pitavastatin in HFD group. At the molecular level, we found that CD36 inhibition, either with pitavastatin or plasmid, reduced proliferation- and migration-related protein expression through the AKT/mTOR pathway. Taken together, we demonstrate that inhibition of CD36 expression by pitavastatin or other inhibitors may be a viable strategy for NSCLC treatment. Graphical abstract 1) Pitavastatin reduces NSCLC progression by inhibiting CD36. 2) Inhibition of CD36 can improve HFD- or FFA-induced NSCLC. 3) AKT/mTOR pathway is involved in CD36-regulated NSCLC. 4) Inhibition of CD36 by pitavastatin or other inhibitors may be a strategy for NSCLC treatment.