OBJECTIVES:To isolate and identify phenolic acid constituents from methanol extract of Inula japonica Thunb. and evaluate their lipid-lowering activity in vitro. METHODS:The methanol extract of Inula japonica Thunb. was purified using silica gel, ODS, and semi-preparative HPLC. The compound structures were determined using physicochemical and spectroscopic analyses, and their hypolipidemic activities were assessed in an AML12 cell model of free fatty acids (FFA)-induced lipid deposition. The active compounds were further assessed for their effects on lipid deposition, reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) of the cell model. RESULTS:A total of 11 phenolic acid compounds were isolated from Inula japonica Thunb., namely dihydrocaffeic acid (1), protocatechualdehyde (2), chlorogenic acid (3), cryptochlorogenic acid (4), 1,3-O-dicaffeoylquinic acid (5), 2,3-dicarboxy-6,7-hydroxy-l-(3',4'-dihydroxy)-phenyl -1,2-dihydronaphthalene-10-methyl ester (6), caffeic acid (7), protocatechuic acid (8), 3-carboxy-6,7-dihydroxy-1-(3',4'-dihydroxyphenyl)-naphthalene (9), p-hydroxybenzoic acid (10), and 4-hydroxyphenylacetic acid (11). Among them, compounds 1 and 9 were isolated for the first time from the genus Inula, and compound 6 was isolated for the first time from this plant. Compounds 6 and 9 showed lipid-lowering effects in FFA-induced AML12 cells, significantly lowered cellular levels of total cholesterol, triglyceride, alanine aminotransferase, and aspartate aminotransferase, reduced lipid accumulation, and alleviated oxidative stress and mitochondrial function. CONCLUSIONS:Inula japonica Thunb. contains diverse phenolic acids, and among them compounds 6 and 9 show hypolipidemic activities via inhibiting lipid accumulation and improving oxidative stress and mitochondrial function and can potentially serve as lead compounds for treatment of metabolic dysfunction-associated steatotic liver disease.

Background Given that metabolic indicators, including obesity and dyslipidemia, are crucial for assessing clinical health, their role in identifying metabolic syndrome is well-established. With China's rapidly aging population leading to a surge in diabetes prevalence among the elderly, analyzing the risk factors for this condition is of great significance for reducing the associated disease burden.To investigate the relationship between various metabolic indices and diabetes in elderly individuals aged 60 and above. Design and Methods A retrospective analysis was conducted using physical examination data from 14,276 elderly subjects in Foshan (2021-2023). Restrictive cubic spline models were used to analyze the dose-response relationships between metabolic indices(Body Mass Index(BMI),Waist Circumference(WC),Total Cholesterol(TC),Triglyceride(TG),High-Density LipoproteinCholesterol(HDL-C), Low-Density Lipoprotein Cholesterol (LDL-C), Uric Acid(UA)) and diabetes. Results Increased BMI, waist circumference, and TG were significantly associated with a higher risk of diabetes, showing nonlinear dose-response relationships. A TC level >5.87 mmol/L and an LDL-C level >3.83 mmol/L were linked to increased diabetes risk (nonlinear relationships). Higher HDL-C was linearly associated with decreased risk. A UA level>278.44μmol/L was related to increased risk (nonlinear relationship). Conclusion Diabetes in the elderly is associated with multiple metabolic indices. Comprehensive monitoring of these indicators is crucial for diabetes prevention and control in this population. Trial registration : not applicable

BACKGROUND:Severe asthma (SA) is characterized by corticosteroid insensitivity, persistent airway inflammation, and excessive oxidative stress, underscoring an urgent unmet therapeutic need. Meroterpenoids derived from Rhododendron capitatum Maxim have demonstrated potent anti-inflammatory properties; however, their therapeutic potential in SA has not been elucidated. METHODS:A meroterpenoid-rich fraction was isolated from R. capitatum Maxim, and cannabichromeorcin (CBCO) was identified as its most abundant constituent. The therapeutic effects of CBCO were evaluated in murine models of SA induced by toluene diisocyanate or by combined house dust mite and lipopolysaccharide exposure. Transcriptomic profiling, TargetNet-based target prediction, molecular docking, and molecular dynamics simulations were employed to identify pharmacological targets. Clinical relevance was examined using transcriptomic datasets from the Unbiased BIOmarkers in Prediction of REspiratory Disease Outcomes project (U-BIOPRED) and validated in an independent clinical cohort. RESULTS:Pretreatment with CBCO ameliorated airway inflammation and oxidative stress in murine models of SA. An integrative approach identified cathepsin L (CTSL) as a redox-sensitive pharmacological target of CBCO. Pretreatment with CBCO inhibited CTSL, thereby reducing the formation of neutrophil extracellular traps containing MMP8, and attenuating the activation of the unfolded protein response (UPR). Pharmacological inhibition of CTSL, MMP8, or the UPR recapitulated the protective effects of CBCO. In vitro, CBCO preserved airway epithelial barrier integrity, reduced reactive oxygen species accumulation, and suppressed alarmin release. Clinically, transcriptomic analyses from the U-BIOPRED cohort revealed elevated MMP8 and DDIT3 expression in sputum and blood samples from patients with SA. In our independent validation cohort, serum MMP8 and DDIT3 levels were increased in SA. Receiver operating characteristic analyses confirmed serum MMP8 and DDIT3 as predictive biomarkers for SA. CONCLUSION:CBCO conferred protection against the development of SA by targeting CTSL to suppress NET formation, UPR activation, and downstream oxidative stress. MMP8 and DDIT3 emerged as promising biomarkers for predicting disease severity.

Dengue has been prevalent in Guangdong Province, China, for more than forty years and has shown an increasing trend over the past decade. A fine-scale analysis of dengue clusters was conducted. The relationship between virus evolution time and spatial distance was analyzed, and a genetic algorithm was used to quantify the effects of environmental, social, and economic factors on the transmission of dengue. A retrospective study analyzed 172 confirmed dengue cases (April 2019 to April 2020) at the Seventh Affiliated Hospital of Southern Medical University. Whole-genome sequencing revealed a unique transmission origin in Lishui town, Guangdong Province (99.64

Abstract Objective: This study aimed to investigate the effects of Wuling San (WLS) on nonalcoholic fatty liver disease (NAFLD) progression and to elucidate its underlying mechanisms, with particular emphasis on mitochondrial dynamics and protein kinase B (AKT)-mediated signaling. Materials and Methods: Ultra-performance liquid chromatography tandem mass spectrometry and network pharmacology were employed to identify the major bioactive components of WLS and predict their potential molecular targets. Both in vivo (db/db mice) and in vitro (free fatty acid-induced alpha mouse liver 12 hepatocyte) models were used to evaluate the effects of WLS. A series of biochemical assays, histological evaluations, metabolomic analyses, mitochondrial function assessments, and molecular docking studies were performed to elucidate the mechanisms of action. Results: WLS significantly reduced hepatic lipid accumulation, improved liver function, and attenuated inflammatory responses. Metabolomic profiling revealed substantial modulation of lipid metabolites, whereas mitochondrial assays confirmed restored dynamics and structural integrity. AKT was identified as a key regulatory target, and inhibition by MK2206 abolished the beneficial effects of WLS and ursolic acid. Conclusions: WLS alleviates NAFLD by enhancing mitochondrial dynamic function through AKT activation, suggesting that it may represent a promising therapeutic strategy for metabolic liver disease.

Rifampicin (RIF), a cornerstone drug in tuberculosis treatment, is associated with hepatotoxicity, which represents a significant adverse effect that frequently causes discontinuation of therapy. However, a comprehensive evaluation of the mechanisms underlying RIF-induced hepatotoxicity remains limited, and the identification of highly effective, low-toxicity therapeutic interventions is urgently needed. In this study, we employed a RIF-induced mouse hepatotoxicity model to systematically investigate the cellular and molecular events associated with RIF-induced liver injury. By integrating single-cell RNA sequencing, bulk RNA-seq, and mass spectrometry-based proteomics and metabolomics, we identified region-specific hepatocyte damage characterized by elevated reactive oxygen species (ROS) levels and activation of the fatty acid oxidation pathway. At the molecular level, RIF treatment resulted in the upregulation of pregnane X receptor (PXR) and Cyp3a11, along with the downregulation of key antioxidant genes. Moreover, decreased mTOR expression and increased expression of fatty acid oxidation-related genes including Acox1 and Acaa1b suggested an enhanced oxidative metabolism. Recruitment of macrophages further exacerbated hepatocyte damage. Importantly, Rosmarinic acid (RA) administration was shown to attenuate RIF-induced hepatotoxicity. These findings provide a comprehensive molecular and cellular perspective on RIF-induced hepatotoxicity and suggest the potential clinical application of RA as a therapeutic agent in the management of RIF-induced liver injury.

Background/Objectives Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Although microRNAs (miRNAs) are known to play crucial roles in tumor progression, the biological function and mechanistic role of miR-4788 in NSCLC remain undefined. This study investigates the role and mechanism of miR-4788 in NSCLC proliferation and metastasis.Methods miR-4788 expression and its prognostic significance were analyzed using The Cancer Genome Atlas (TCGA) data. In vitro assays were conducted in NSCLC cell lines transfected with miR-4788 mimics, DLG5 siRNA, or a 3 '-UTR-truncated DLG5 overexpression plasmid. In vivo functional validation was performed in zebrafish and murine xenograft models. Functional assays included assessments of cell viability (CCK-8), proliferation (EdU incorporation, colony formation), cell cycle distribution, migration/invasion (wound healing, Transwell), and mitochondrial function (ATP, MMP, ROS, mitophagy markers). A dual-luciferase reporter assay was used to confirm DLG5 as a direct miR-4788 target, and rescue experiments were conducted to validate its downstream role.Results miR-4788 was significantly upregulated in NSCLC tissues and was associated with a lower disease-specific survival rate. Its overexpression in vitro and in vivo promoted the proliferation, migration, and invasion of non-small cell lung cancer cells. This oncogenic effect was accompanied by enhanced mitochondrial function, evidenced by increased mitochondrial membrane potential, ATP production, and reactive oxygen species (ROS) levels, along with suppression of mitophagy (reduced Pink1/Parkin expression). Mechanistically, miR-4788 directly targets the 3 '-UTR of DLG5, downregulating its expression, and restoring the function of DLG5 could alleviate the carcinogenic phenotype caused by miR-4788.Conclusions miR-4788 functions as an oncogenic regulator in NSCLC, promoting tumor development by targeting DLG5 and promoting mitochondrial metabolic reprogramming. These findings provide new insights into the miR-4788-DLG5 axis in NSCLC and suggest its potential role in tumor metabolism and immune microenvironment remodeling.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide and has become a recognized global health problem. Therefore, the search for new anti-CRC agents or the exploration of new effective drug targets for CRC therapy is urgent. Chloroquine (CQ) is a widely-used antimalarial drug and has shown anti-proliferative effects in CRC. However, the underlying mechanisms are not well understood, particularly as the direct targets of CQ have not been identified. In this study, choline kinase alpha (CHKA) and ATP-dependent 6-phosphofructokinase, muscle type (PFKM) were identified and verified as the binding targets of CQ. CQ specifically binds to CHKA, inhibits its expression and enzymatic activity, and downregulates the downstream phosphorylation of PI3K and AKT, thereby suppressing tumor cell proliferation and inducing apoptosis. CQ also binds to PFKM and inhibits its expression and activity, thereby blocking the Warburg effect. In addition, the downregulation of CHKA can decrease the expression of PFKM and inhibit its activity, thereby blocking the Warburg effect. These observations shed new light on the antitumor mechanisms of CQ and provide new evidence for the close relationship between the PI3K/AKT signaling pathway and the Warburg effect, providing new therapeutic targets for treating CRC.

This study aims to explore biomarkers linked to the progression from non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) and their therapeutic potential. Using bioinformatics, we identified key differentially expressed genes from various databases, focusing on genes related to NAFLD, non-alcoholic steatohepatitis, liver cirrhosis, and HCC. Among the upregulated genes, baculoviral IAP repeat containing 5 (BIRC5), cyclin B1 (CCNB1), cyclin-dependent kinase 1 (CDK1), and DNA topoisomerase II alpha (TOP2A) were found to be significant. In vivo and in vitro models of NAFLD and clinical HCC samples validated BIRC5 as a critical regulator in the disease progression. Functional assays revealed that knocking down BIRC5 alleviated fatty acid-induced liver damage and mitochondrial dysfunction in NAFLD models, while also inhibiting HCC cells proliferation and migration, further leading to mitochondrial dysfunction. YM155 (a specific BIRC5 inhibitor) also confirmed the previous experimental results. Then we performed experiments using BIRC5 overexpression plasmid. BIRC5 overexpression exacerbated hepatic steatosis and mitochondrial function in free fatty acid (FFA) -induced AML12 hepatocytes, and enhanced HCC cells proliferation, migration, and invasion. These findings highlight BIRC5 as a pivotal driver in the NAFLD-HCC transition, mediating metabolic dysfunction and malignant transformation. This study proposes BIRC5 as a therapeutic target and diagnostic biomarker, offering perspectives for HCC diagnosis and treatment of HCC. These results underscore the importance of BIRC5 in halting NAFLD-HCC progression and provide valuable insights for future clinical applications.

背景 胰岛素抵抗（IR）的发病率逐年升高，与肥胖、血脂异常和高尿酸血症的共患病率较高，目前IR、肥胖/血脂异常和血尿酸（SUA）水平之间的关系尚不清楚。目的 探讨稳态模型胰岛素抵抗指数（HOMA-IR）与SUA水平之间的剂量反应关系，并评估HOMA-IR在肥胖/血脂四项与SUA水平间的中介效应。方法 回顾性分析2021年11月—2022年12月在南方医科大学第七附属医院进行健康体检的3 928名成年人的临床数据。根据性别及IR分组，比较组间SUA水平、IR指标、肥胖和血脂指标的差异，采用限制性立方样条（RCS）分析HOMA-IR与SUA之间的剂量反应关系。分析HOMA-IR在肥胖、总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）与SUA间的中介作用。采用线性回归模型分析SUA与HOMA-IR、空腹血胰岛素（FINS）、空腹血糖（FBG）的相关性。结果 3 928名体检者中男3 026名，女902名。3 026名男性体检人群中IR者757名，非IR者2 269名；IR者收缩压（SBP）、舒张压（DBP）、SUA、HOMA-IR、FINS、FBG、BMI、腰臀比（WHR）、TG、TC、LDL-C水平均高于非IR者，年龄、HDL-C水平低于非IR者（P<0.05）。902名女性体检人群中IR者226名，非IR者676名；IR者SBP、DBP、SUA、HOMA-IR、FINS、FBG、BMI、WHR、TG、LDL-C水平均高于非IR者，HDL-C水平低于非IR者（P<0.05）。RCS结果显示，在调整协变量后，HOMA-IR与SUA呈非线性剂量反应关系，该关联存在性别差异；随着HOMA-IR增加，男性SUA呈近似“∩”型改变趋势(P 非线性 =0.002)，女性SUA先增加后不变(P 非线性 =0.002)；而随着SUA升高，男性HOMA-IR呈先下降后不变的趋势(P 非线性 =0.002)，而女性HOMA-IR呈近似“U”型的改变趋势(P 非线性 =0.002)。中介分析结果显示，HOMA-IR部分介导了肥胖、中心性肥胖、TG与SUA间的关联，中介效应占比在男性中分别为9.5%、7.9%、5.3%，在女性中分别为36.1%、19.9%、6.5%;HOMA-IR完全介导了HDL-C与SUA间的关联，中介效应占比在男性和女性中分别为20.0%、22.0%。分别对男性、女性人群以SUA=7.28 mg/dL和4.70 mg/dL分层，调整协变量后，线性回归模型分析结果显示，男性中，SUA与FBG始终呈负相关（P<0.05），当SUA≥7.28 mg/dL时，SUA与FINS呈正相关（P<0.05）；女性中，当SUA≥4.70mg/dL时，SUA与HOMA-IR、FINS均呈正相关（P<0.05）。结论 HOMA-IR与SUA具有非线性剂量反应关系。HOMA-IR在肥胖、TG与SUA存在部分中介作用，而在HDL-C与SUA存在完全中介作用。男性人群FBG与SUA显著负相关。

Non‑alcoholic fatty liver disease (NAFLD), characterized by excessive lipid accumulation in hepatocytes, has emerged as the leading cause of chronic liver disorders globally. As the central metabolic organ, the liver critically depends on mitochondrial integrity. Mitophagy, a selective form of autophagy, plays a pivotal role in sustaining mitochondrial homeostasis by eliminating dysfunctional mitochondria. Dysregulated mitophagy contributes to the progression of NAFLD, while its restoration mitigates disease severity. The present review outlines the tripartite axis of mitophagy, namely, the PTEN‑induced putative kinase 1/Parkin, PI3K/AKT/mTOR and AMP‑activated protein kinase pathways, in NAFLD pathogenesis across the various stages of disease development, including steatosis, nonalcoholic steatohepatitis and fibrosis, and explores their therapeutic potential. Additionally, emerging regulators, including FUN14 domain‑containing protein 1, prohibitin 2, ceramide signaling and non‑coding RNAs, which fine‑tune mitophagy in NAFLD are highlighted. By integrating evidence from pharmacological and natural agents, including traditional Chinese medicines, mitophagy‑centric strategies to promote hepatic lipid metabolism, mitigate disease progression and inform novel NAFLD therapeutics are discussed. This exploration of the mechanisms that govern mitochondrial‑autophagic crosstalk not only advances mechanistic insights but also opens new avenues for precision medicine in the treatment of metabolic liver diseases.

Programmed death-ligand 1 (PD-L1), a prominent immune checkpoint, interacts with programmed death protein-1 (PD-1) on cytotoxic T cells within tumors and promotes immune evasion. Emodin, which is known to destabilize PD-L1 in breast cancer, has great potential for enhancing anti-tumor immunity. However, whether emodin can modulate PD-L1 levels in hepatocellular carcinoma (HCC) and enhance anti-tumor immune response remains unclear. PD-L1 levels were assessed by western blot and RT-qPCR, the degradation mechanism was analyzed using specific inhibitors. Network pharmacology, molecular docking, and glycogen synthase kinase-3 beta (GSK-3β) modulation analyzes were performed to validate emodin’s target. In vivo anti-tumor effects were evaluated in H22 subcutaneous tumor model, and CD8+ T cells and RNA-seq data were analyzed. The synergistic effects of emodin and an anti-PD-L1 antibody were assessed. Emodin effectively reduced PD-L1 levels in H22 cells and increased anti-tumor activity in an H22 subcutaneous tumor model by promoting CD8+ T cells infiltration and TNF-α, IFN-γ, and granzyme B secretion. Mechanistically, emodin accelerated PD-L1 degradation through the proteasome pathway in both mouse and human HCC cell lines, as confirmed by the use of proteasome, lysosome and autophagy inhibitors. Network pharmacology analysis and molecular docking revealed that GSK-3β, a key regulator of PD-L1 degradation, is a target of emodin. Selective inhibitor-mediated suppression of GSK-3β largely reversed the regulatory effect of emodin on PD-L1. In contrast, overexpression of GSK-3β with a plasmid decreased PD-L1 protein levels and augmented emodin’s effect on PD-L1. Additionally, RNA-sequencing revealed the role of emodin in improving the immune responses in the tumor microenvironment. Finally, we observed a synergistic effect when the H22 cell subcutaneous tumor model was treated with emodin and anti-PD-L1 antibody. Emodin exerts anti-tumor effects by promoting GSK-3β-mediated PD-L1 proteasomal degradation and enhancing the anti-tumor effects of CD8+ T cells, indicating that emodin may be a promising therapeutic option for HCC.

[This corrects the article DOI: 10.3389/fpubh.2024.1425387.].

Cognitive impairment, hypertension and diabetes are prevalent chronic conditions in populations of older ages. Previous studies have shown that hypertension and diabetes are risk factors for the development of cognitive impairment. However, the impact of hypertension combined with diabetes (HD) and their cumulative effects on cognitive impairment remain unclear. We aimed to investigate whether HD influences development of cognitive impairment and whether the effect is cumulative. A case–control study was conducted. From 40,103 subjects aged 60 years or older, enrolled from 28 representative communities of 9 provinces of China between January 2015 and December 2021 into the Prevention and Intervention on Neurodegenerative Disease for Elderly in China program using multi-stage stratified random sampling, individuals not meeting our propensity score matching criteria were excluded, and 13,252 individuals were finally selected for the study. Exposure factors included hypertension, diabetes and their comorbidity. Odds ratios (ORs) of exposure factors on cognitive impairment were measured using multiple logistic regression. We found significant impacts of hypertension, diabetes and their comorbidity on cognitive impairment occurrence. The OR values for dementia were 1.18 for individuals with hypertension only, 1.26 for those with diabetes only, and 1.53 for those with HD. Compared to participants without hypertension and diabetes, the OR values for mild cognitive impairment (MCI) were 1.11 for individuals with hypertension only, 1.32 for those with diabetes only, and 1.27 for those with HD. For subjects with HD longer than 5 years, the comorbidity significantly impacted on MCI and dementia, and the degree of impact increased with the duration of comorbidity. For hypertension, the influence of hypertension on dementia were most influential in middle-aged (45–64 years old) people. By contrast, the influence of diabetes on people younger than 45-year-old was most significant, with the middle-age group being the second most impacted subjects. The elderly with HD have a heightened risk of developing cognitive impairment, particularly dementia, compared to those with either hypertension or diabetes alone. The study revealed a significant cumulative impact of HD on cognitive impairment.

The lack of targetable antigens poses a significant challenge in developing effective cancer-targeted therapies. Cell surface translocation of endoplasmic reticulum (ER) chaperones, such as glucose-regulated protein 78 (GRP78), during malignancy, drug resistance, and ER stress induced by therapies, offers a promising pan-cancer target. To target GRP78, nanobody C5, identified from a phage library and exhibiting high affinity for human and mouse GRP78, is utilized to develop the Pseudomonas exotoxin (PE) immunotoxin C5-PE38. C5-PE38 induced ER stress, apoptosis and immunogenic cell death in targeted cells and showed antitumor efficacy against colorectal cancer and melanoma models without obvious toxicity. Mechanistically, transcriptome profiling showed that C5-PE38 reshaped the tumor immune microenvironment with enhanced innate and adaptive immune response and response to interferon beta. Moreover, C5-PE38-induced cell death could trans-activate STING pathway in dendritic cells and macrophages, promoting CD8+ T cell infiltration. It also sensitizes both primary and metastatic melanomas to anti-PD1 therapy, partly through STING activation. Overall, this study unveils a feasible GRP78 nanobody-directed therapy strategy for single or combinatorial cancer intervention. This work finds that C5-PE38-induced cell death stimulates STING-dependent cytosolic DNA release to promote antitumor immunity, a mechanism not previously reported for PE38, providing valuable insights for its clinical use.

Acute pneumonia is a kind of widespread inflammatory pathological process. Dihydrocaffeic acid (DA), metabolite of chlorogenic acid, possesses potent pharmacologic activity for the therapy of a wide range of disorders and various biological properties, such as anti-inflammation. Nevertheless, the specific protein targets and potential molecular mechanisms of DA in acute pneumonia are still poorly understood. To investigate the anti-inflammation effects of DA and its target and its specific mechanisms. Here, we conducted lipopolysaccharides (LPS)-induced acute pneumonia model mice. Besides, the activity-based protein profiling (ABPP) was performed to explore the potential targets of DA. Furthermore, cellular thermal shift assay (CETSA) and pulldown-western blot assays were used to validate the conclusion. In this study, we indicated that DA alleviated acute pneumonia in mice and displayed excellent anti-inflammatory efficacy in vivo and in vitro. Besides, we discovered DA binds directly to transaldolase 1(TALDO1) and influenced its enzymatic activity, and identified the specific cysteine sites Cys250. Also we demonstrated that DA reveals anti-inflammation effect through TALDO1 mediated PERK-IκBα-NF-κB pathway in RAW 264.7 cells. This study provide support for the potential advancement of DA for use as a therapeutic agent for the treatment of acute pneumonia and inflammation-associated diseases.

Rheumatoid arthritis (RA), a prevalent and incurable autoimmune disease globally, is characterized by the immune system attacking the body's own tissues, leading to joint inflammation and damage. Capsaicin (CAP), from Capsicum annuum L., is known for its burning sensation-inducing property and has shown various pharmacological effects, yet its specific mechanisms and targets in RA treatment remain largely unclear. This study aimed to investigate the role of CAP in RA by synthesizing CAP probes and using activity-based protein profiling. We found that CAP reduced joint swelling in arthritic mice and exerted anti-inflammatory and antiproliferative effects on fibroblast-like synoviocytes. We identified that CAP binds to PRDX2, inhibiting its antioxidant function and inducing oxidative stress and apoptosis, contributing to the antiarthritic effects. These results suggest that PRDX2 is a potential target for CAP in RA treatment, providing new insights into the molecular mechanisms and potential therapeutic strategies for RA.

The detailed mycochemical exploration of the EtOAc extract of a famous edible mushroom Thelephora ganbajun, resulted in the isolation of six new p-terphenyl derivatives, named theleganbanins A - F (1-6), together with five known ones, namely atromentin (7), fendleryl B (8), 2-O-methylatromentin (9), vialinin B (10), and ganbajunin B (11). Their structures were precisely determined through comprehensive spectroscopic analyses, especially 1D and 2D NMR data and HRMS measurement. Single crystal X-ray diffraction and comparison of calculated and experimental ECD spectra were conducted to further confirm the absolute configurations of compounds 1-6. Theleganbanins A (1) and B (2) featuring a rare α, β-unsaturated-γ-butyrolactone core were proposed to be biosynthesized through aldol condensation for the first time in naturally occurring p-terphenyl derivatives. Theleganbanin C (3) was identified as a pair of p-terphenyl enantiomers with a novel 1', 6'-dyhydro-2', 5'-pyridinedione ring. Theleganbanin D (4) was the first example of p-terphenyl derivatives with a hemiacetal furanone moiety. The anti-neuroinflammatory activities of compounds 1-2 and 4-10 were screened. As a result, these compounds showed inhibitory activity on the production of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Further investigation showed that compound 2 could inhibit the phosphorylation of JAK2/STAT3 signaling pathway. These finding indicated that p-terphenyl derivatives from edible mushroom Thelephora ganbajun Zang would be promising drug candidates in treatment of neuroinflammatory related diseases.

Fungi from the plant rhizosphere microbiome are considered an important source of bioactive novel natural compounds. In this study, three new sesquiterpenes, penisterpenoids A-C (1-3), 1 - 3 ), and three new viridin derivatives, peniviridiols A-C (4-6), 4 - 6 ), along with twenty one known compounds (7-27), 7 - 27 ), were isolated from the rhizosphere fungus Penicillium sp. SMU0102 of medicinal plant Bupleurum chinense DC. Their structures were elucidated by extensive spectroscopic analysis. The absolute configurations of compounds 1 - 6 were determined by experimental and calculated ECD spectra, DP4 + probability analysis, modified Mosher's method, and X-ray crystallography. All new compounds were screened for their cytotoxic and lipid-lowering activities in vitro. . Among them, compound 1 (20 mu M) remarkably alleviated lipid accumulation both in FFA-induced LO2 cells and TAA-induced zebrafish NAFLD models. Furthermore, compound 1 enhanced ATP production and mitochondrial membrane potential (MMP), suppressed reactive oxygen species (ROS) formation, restored mitochondrial structure, and induced autophagosome formation. Moreover, compound 1 significantly upregulated the expression of representative proteins for the mitochondrial homeostasis, including OPA1, DRP1, MFF, and Fis1, as well as mitophagy representative proteins PINK1, Parkin, and P62. Further mechanistic investigations indicated that compound 1 primarily alleviated lipid accumulation through selective activation of the PINK1/Parkin mitophagy signaling pathway.