Homozygous pathogenic variants in Ig-like domain of LMNA cause severe segmental progeroid syndromes. Unlike typical HGPS, it remains elusive how these pathogenic variants cause segmental progeroid syndromes. We here reported that affected individuals with LMNAR527C/R527C pathogenic variant developed an atypical segmental progeroid syndrome characterized by autoimmune features. Mesenchymal stem cells (MSCs) derived from these affected individuals exhibited significant inflammation and cellular senescence. In mice, LmnaR527C/R527C pathogenic variant triggered chronic interferon signaling, exacerbated aging-related pathologies, and even induced thymic lymphomas following ionizing radiation. In addition, this pathogenic variant increased susceptibility to inflammation induced by a high-fat diet or LCMV infection. R527C pathogenic variant disrupted the interaction between Lamin A and DNA-binding proteins, causing abnormal protein aggregation and hyperactivation of the cGAS-STING. Importantly, blocking DNA sensing pathways suppressed inflammation, rescued senescence in affected individual-derived MSCs, and alleviated premature aging in LmnaR527C/R527C mice. These findings establish a homozygous LMNA pathogenic variant as a key driver of inflammation-driven segmental progeroid syndrome and highlight DNA sensing pathways as promising therapeutic targets.

BackgroundAsthma is a heterogeneous chronic inflammatory airway disease affecting over 300 million people globally. Inhaled corticosteroids remain first-line therapy but cause adverse effects and fail to address core pathologies in 5%–10% of patients—particularly those with Type 2-low endotypes exhibiting glucocorticoid resistance. Natural medicines, with multi-component synergy, offer a promising strategy to bridge this gap.ObjectiveThis review synthesizes advances in botanical extracts and bioactive constituents for asthma management, focusing on pharmacological mechanisms aligned with asthma endotypes.MethodsA literature search across PubMed and Web of Science (2010–2026) included preclinical studies and randomized controlled trials (RCTs). Therapeutic effects were categorized into anti-inflammation, antioxidant modulation, immunoregulation, and anti-remodeling.ResultsBotanical therapeutics concurrently restore epithelial barrier integrity, rebalance Th1/Th2/Th17 immunity, activate Nrf2-mediated antioxidant pathways, and inhibit airway remodeling. RCTs demonstrate adjunctive benefits in mild-to-moderate asthma; however, translational bottlenecks persist, including phytochemical bioavailability issues and insufficient biomarker-stratified data.ConclusionNatural medicines overcome limitations of single-target synthetic drugs via multi-dimensional intervention. Clinical translation necessitates standardized formulations, advanced pulmonary delivery systems, rigorous safety evaluations—including herb-drug interactions—and endotype-stratified RCTs.

UDP-glycosyltransferases (UGTs) contribute to catalyzing the glycosylation of numerous functional natural products and novel derivatives with improved bioactivities. UDP-glucose sterol glucosyltransferase (SGT) is normally involved in the synthesis of sterol glycosides in a variety of organisms. SGT was derived from Salinispora tropica CNB-440 and heterologously expressed in Escherichia coli BL21 (DE3). Novel 12-O-glucosylginsenoside Rh2 was identified using HPLC, high-resolution MS (HR-MS), and NMR analysis. The cell viability assay was performed on 12-O-glucosylginsenoside-treated AGS stomach cancer, HeLa cervical cancer, U87MG glioma, and B16F10 melanoma cell lines. Protein structure modeling, molecular docking, and dynamics simulations were performed using AutoDock 4.2 and GROMACS 2020.1 software. The SGT gene is comprised of 1284 nucleotides and codes for 427 amino acids. The 12-O-glucosylginsenoside Rh2 may be a potential anticancer agent due to its potent viability inhibition of cancer cells. Structural analysis showed critical perspectives into the intermolecular interactions, stability, and binding energetics of the enzyme-ligand complex, with outcomes complementing the experimental data, thereby deepening our understanding of the structural basis of SGT-mediated glycosylation and its functional implications. This report presents a novel ginsenoside, 12-O-glucosylginsenoside Rh2, utilizing reshuffled SGT derived from S. tropica, and provides a promising candidate for anticancer drug research and development.

We synthesized QM-AgNPs (Dianthus superbus L.-AgNPs, Qu Mai-AgNPs) by an economical and environmentally friendly method using Dianthus superbus L. extract as a reducing and stabilizing agent. The resulting QM-AgNPs were comprehensively characterized and evaluated for their antioxidant, cytotoxic, and antibacterial activities. Herein, TEM analysis revealed that the QM-AgNPs were predominantly spherical, polydisperse, and exhibited a core particle size ranging from 11 to 18 nm. In contrast, DLS analysis showed a larger hydrodynamic diameter (primarily 60–87 nm), reflecting the hydrated shell and surface biomolecular corona. The crystalline nature of QM-AgNPs was confirmed by XRD and SAED spectra while FTIR spectroscopy indicated the presence of functional groups from the plant extract that may contribute to nanoparticle stabilization. Functional assessments demonstrated that QM-AgNPs exhibited strong antioxidant activity, with efficient DPPH radical scavenging, and selective cytotoxicity against A549 cancer cells while sparing normal cells. Moreover, QM-AgNPs showed significant antibacterial activity against both Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative), likely due to membrane disruption and the leakage of intracellular contents. To explore practical applications, we developed a GEL@AgNPs coating system for the postharvest preservation of grapes. As a result, the reduced weight loss and decay rate suggest a potential role for QM-AgNPs in extending fruit freshness. Comprehensive shelf-life studies are planned to further substantiate the potential of QM-AgNPs as an effective material for active food packaging applications.

Ginseng polysaccharides (GPs) are known to have beneficial effects on the gut epithelium and age-related systemic-inflammation through regulation of gut microbiota. However, the underlying pathways and key members of the microbial community involved in this process are poorly understood. In this study, administration of ginseng neutral polysaccharide (GPN) is found to alleviate gut leak and low-grade inflammation, concomitantly with improving the physiological function aged mice. Fecal microbiota transplantation and fecal conditioned medium are used to assess the specific involvement of gut bacterial metabolites in the effects of GPNs. Comprehensive multi-omics analyses showed that GPN significantly enriched the abundance of Alistipes senegalensis, an indole-producing commensal bacterium. Increased expression of tight junction-associated proteins, as well as activation of gut stem cells, are found to be mediated by the AhR pathway, indicating the causal mechanism by which GPN reduced increases in gut permeability. The results are verified in Caco-2/THP-1 cells, Caenorhabditis elegans, and enteroids. To the knowledge, this is the first identification of an integral functional axis through which GPN and functional metabolites of A. senegalensis influence the gut barrier and reduce systemic inflammation, providing clues for the potential development of innovative plant polysaccharide treatment strategies to promote healthy aging.

Excessive fructose intake drives intestinal aging and impairs intestinal stem cell (ISC) function, yet effective therapeutic interventions remain elusive. Astragaloside IV (AS-IV), a natural saponin from Astragalus membranaceus, has been widely recognized for its antiaging, anti-inflammatory, and gut-protective properties. Here, we revealed that AS-IV alleviates fructose-induced intestinal metabolic senescence via direct inhibition of ketohexokinase (KHK), the key rate-limiting enzyme in fructose metabolism. Molecular docking and site-directed mutagenesis identified Asn261 and Ala226 as distinct binding sites for AS-IV on KHK, with Asn261 also serving as a critical catalytic residue that is essential for KHK activity. Mutation at Asn261 abolished KHK enzymatic function, reduced the accumulation of fructose-derived metabolites such as palmitic acid and ceramide, and thereby prevented fructose-induced ISC cycle arrest. AS-IV's therapeutic efficacy was validated across Drosophila, murine intestinal organoids, and mice, where treatment consistently reversed high-fructose-induced intestinal metabolic senescence phenotypes, restored ISC proliferation, and preserved ISC homeostasis. These findings indicate that KHK is a previously unrecognized molecular target of AS-IV and reveal a conserved mechanism by which AS-IV modulates fructose metabolism to interfere with gut aging. Our results highlight its therapeutic potential in treating fructose-driven intestinal aging and associated metabolic disorders.

Background and Purpose: Polysaccharides from Panax ginseng C. A. Meyer (P. ginseng) are the main active component and exhibit significant intestinal anti-inflammatory activity. However, the unclear therapeutic mechanism of ginseng polysaccharide hinders the application for medicine or functional food. Experimental Approach: In this study, a polysaccharide was isolated from P. ginseng (GP). The primary structure and morphology of GP were studied by HPLC, FT-IR spectra, and scanning electron microscopy (SEM). Further, its intestinal anti-inflammatory activity and its mechanism of function were evaluated in experimental systems using DSS-induced rats, fecal microbiota transplantation (FMT), and LPS-stimulated HT-29 cells. Key Results: Results showed that GP restored mTOR-dependent autophagic dysfunction via modulating the structure of gut microbiota and blocking the TLR4-MyD88 pathway. Consequently, active autophagy suppressed inflammation through the inhibition of NF-κB, oxidative stress, and the release of cytokines. Conclusion and Implications: Therefore, our research provided a rationale for future investigations into the relationship between microbiota and autophagy via TLR4 and revealed the therapeutic potential of GP for inflammatory bowel disease.

Background: Panax ginseng Meyer (P. ginseng) is a traditional natural/herbal medicine. The amelioration on inflammatory bowel disease (IBD) activity rely mainly on its main active ingredients that are referred to as ginsenosides. However, the current literature on gut microbiota, gut microbiota-host co -metabo-lites, and systems pharmacology has no studies investigating the effects of ginsenoside on IBD.Methods: The present study was aimed to investigate the role of ginsenosides and the possible under-lying mechanisms in the treatment of IBD in an acetic acid-induced rat model by integrating meta-genomics, metabolomics, and complex biological networks analysis. In the study ten ginsenosides in the ginsenoside fraction (GS) were identified using Q-Orbitrap LC-MS.Results: The results demonstrated the improvement effect of GS on IBD and the regulation effect of ginsenosides on gut microbiota and its co-metabolites. It was revealed that 7 endogenous metabolites, including acetic acid, butyric acid, citric acid, tryptophan, histidine, alanine, and glutathione, could be utilized as significant biomarkers of GS in the treatment of IBD. Furthermore, the biological network studies revealed EGFR, STAT3, and AKT1, which belong mainly to the glycolysis and pentose phosphate pathways, as the potential targets for GS for intervening in IBD.Conclusion: These findings indicated that the combination of genomics, metabolomics, and biological network analysis could assist in elucidating the possible mechanism underlying the role of ginsenosides in alleviating inflammatory bowel disease and thereby reveal the pathological process of ginsenosides in IBD treatment through the regulation of the disordered host-flora co-metabolism pathway.(c) 2022 The Korean Society of Ginseng. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Hemicelluloses, a major component of plant cell walls, are a non-cellulosic heteropolysaccharide composed of several distinct sugars that is second in abundance to cellulose, which are one of the most abundant and cheapest renewable resources on earth. Hemicelluloses structure is complex and its chemical structure varies greatly among the different plant species. In addition to its wide use in production of feed and other chemical materials, hemicelluloses are known for its remarkable biological activities that remain largely underutilised to date. Therefore, comprehensive investigations of hemicelluloses structural and biological properties would be helpful for achieving rational utilisation and high-value conversion of this underutilised substance into agents with enhanced health benefits for incorporation in drugs and health foods. In this review, details of diverse research initiatives that have enhanced our understanding of hemicelluloses properties are summarised, including hemicelluloses sources, extraction and purification methods, structural characteristics and biological activities. Furthermore, hemicelluloses structure-activity relationships and new directions for future hemicelluloses research studies are discussed.

Background and objective: The ginsenoside compound K (C-K) (which is a de-glycosylated derivative of major ginsenosides) is effective in the treatment of cancer, diabetes, inflammation, allergy, angiogenesis, aging, and has neuroprotective, and hepatoprotective than other minor ginsenosides. Thus, a lot of studies have been focused on the conversion of major ginsenosides to minor ginsenosides using glycoside hydrolases but there is no study yet published for the bioconversion of minor ginsenosides into another high pharmacological active compound. Therefore, the objective of this study to identify a new gene (besides the glycoside hydrolases) for the conversion of minor ginsenosides C-K into another highly pharmacological active compound. Methods and Results: Lactobacillus brevis which was isolated from Kimchi has showed the ginsenoside C-K altering capabilities. From this strain, a novel potent decarboxylation gene, named HSDLb1, was isolated and expressed in Escherichia coli BL21 (DE3) using the pMAL-c5X vector system. Recombinant HSDLb1 was also characterized. The HSDLb1 consists of 774 bp (258 amino acids residues) with a predicted molecular mass of 28.64 kDa. The optimum enzyme activity was recorded at pH 6.0–8.0 and temperature 30 °C. Recombinant HSDLb1 effectively transformed the ginsenoside C-K to 12-β-hydroxydammar-3-one-20(S)-O-β-D-glucopyranoside (3-oxo-C-K). The experimental data proved that recombinant HSDLb1 strongly ketonized the hydroxyl (-O-H) group at C-3 of C-K via the following pathway: C-K → 3-oxo-C-K. In vitro study, 3-oxo-C-K showed higher solubility than C-K, and no cytotoxicity to fibroblast cells. In addition, 3-oxo-C-K induced the inhibitory activity of ultraviolet A (UVA) against matrix metalloproteinase-1 (MMP-1) and promoted procollagen type I synthesis. Based on these expectations, we hypothesized that 3-oxo-C-K can be used in cosmetic products to block UV radiations and anti-ageing agent. Furthermore, we expect that 3-oxo-C-K will show higher efficacy than C-K for the treatment of cancer, ageing and other related diseases, for which more studies are needed.

A rapid induction of antiviral genes is critical for eliminating viruses, which requires activated transcription factors and opened chromatins to initiate transcription. However, it remains elusive how the accessibility of specific chromatin is regulated during infection. Here, we found that XAF1 functioned as an epigenetic regulator that liberated repressed chromatin after infection. Upon RNA virus infection, MAVS recruited XAF1 and TBK1. TBK1 phosphorylated XAF1 at serine-252 and promoted its nuclear translocation. XAF1 then interacted with TRIM28 with the guidance of IRF1 to the specific locus of antiviral genes. XAF1 de-SUMOylated TRIM28 through its PHD domain, which led to increased accessibility of the chromatin and robust induction of antiviral genes. XAF1-deficient mice were susceptible to RNA virus due to impaired induction of antiviral genes. Together, XAF1 acts as an epigenetic regulator that promotes the opening of chromatin and activation of antiviral immunity by targeting TRIM28 during infection.

TANK-binding kinase 1 (TBK1) is a nodal protein involved in multiple signal transduction pathways. In RNA virus-mediated innate immunity, TBK1 is recruited to the prion-like platform formed by MAVS and subsequently activates the transcription factors IRF3/7 and NF-κB to produce type I interferon (IFN) and proinflammatory cytokines for the signaling cascade. In this study, TRAF7 was identified as a negative regulator of innate immune signaling. TRAF7 interacts with TBK1 and promotes K48-linked polyubiquitination and degradation of TBK1 through its RING domain, impairing the activation of IRF3 and the production of IFN-β. In addition, we found that the conserved cysteine residues at position 131 of TRAF7 are necessary for its function toward TBK1. Knockout of TRAF7 could facilitate the activation of IRF3 and increase the transcript levels of downstream antiviral genes. These data suggest that TRAF7 negatively regulates innate antiviral immunity by promoting the K48-linked ubiquitination of TBK1.

Alzheimer's disease (AD) is a neurological condition that progresses with age. Amyloid-β (Aβ) aggregation has been suggested to be a key pathogenic process in Alzheimer's disease. Ginseng polysaccharides (GP), the main biologically active components isolated from Panax ginseng C. A. Meyer (ginseng), may act as neuroprotective agents with potential benefits for AD patients. However, GP effects on Aβ pathology and AD symptoms are still unclear. Here, a 4.7-kDa GP termed GP4 was purified and subjected to basic physicochemical characterization. The biological effects of GP4 to prevent Aβ aggregation were then assessed with cross-species AD models, including Aftin-5-treated SH-SY5Y cells and cerebral organoids, and transgenic C. elegans overexpressing the full-length human Aβ42 peptide. These analyses ultimately demonstrated that GP4 was capable of inhibiting Aβ accumulation both in vivo and vitro, and with early intervention of GP4 being sufficient to alleviate Aβ42-associated aging phenotypes and memory loss in C. elegans model of AD. Furthermore, neuroinflammation was significantly down-regulated in human cells and cerebral organoids. From a mechanistic perspective, the ability of GP4 to inhibit Aβ aggregation was found to be related to its ability to promote neuronal mitophagic activity. This finding offers a robust theoretical foundation for the further development of GP4 as a candidate drugs with the potential to treat AD.

Abstract Homozygous mutations in Ig-like domain of LMNA cause severe progeria. Unlike typical HGPS mediated by progerin due to LMNAWT/G608G mutation, it remains elusive how these homozygous mutations cause progeria. We here found that patients with LMNAR527C/R527C mutation developed an atypical progeria with autoimmune symptoms. Compare to LMNAWT/G608G mutation, this mutation led to more severe inflammation in patients. MSCs from LMNAR527C/R527C patients exhibited overt inflammation and cellular senescence. Mechanistically, LMNAR527C/R527C mutation attenuated its binding to DNA binding protein BAF, which led to aberrant aggregation of Lamin A and activation of DNA sensing pathways. Inhibition of DNA sensors, cGAS or AIM2, can suppress inflammation and rescue the senescence of patient-derived MSCs. LmnaR527C/R527C mice showed enhanced inflammation, and developed accelerated aging and dead at an early age after high-fat diet (HFD) feeding, which could be rescued by deficiency of AIM2 or treatment by a small molecule inhibitor of cGAS-STING. Therefore, we demonstrated that LMNAR527C/R527C mutation damped its interaction with DNA-binding proteins and exposed damaged DNA to the cytosolic DNA sensors, which triggered aberrant inflammatory responses and promoted the onset of accelerated aging. The present study uncovered that an inflammation driven progeria was caused by LMNA mutation and DNA sensing pathways could be potential therapeutic targets for progeria syndromes caused by homozygous mutations in Ig-like domain of LMNA.

Under pathological conditions, human tau (htau) hyperphosphorylation promotes formation of proteotoxic intracellular amyloid aggregates that may underlie neurodegenerative diseases known as tauopathies, prompting researchers to develop treatments that inhibit htau aggregation as a promising therapeutic strategy. Ginsenosides, the main active constituents of Panax ginseng C. A. Meyer (ginseng), appear to inhibit tau aggregation and disassociation in tauopathy models, although their active components and molecular mechanisms are unknown. Here, we used a novel Caenorhabditis elegans (C. elegans) tauopathy model to identify ginsenoside monomers which may repress htau proteotoxicity. Our findings indicated that ginsenoside Rf prevented tau aggregation and reversed abnormal tau aggregation-induced phenotypes and alleviated neurodegeneration in worms. Notably, deep RNA-seq analysis of ginsenoside Rf-treated and untreated worms with tauopathy revealed that ginsenoside Rf altered expression levels of 24 up- and 36 down-regulated lncRNA transcripts, 32 up- and 22 down-regulated miRNAs and 65 up- and 30 down-regulated mRNA transcripts. Based on GO and KEGG pathway annotation analyses, identified mRNAs, miRNAs and lncRNAs-associated gene targets were functionally related to neuron-related terms (e.g., neuron development, axon and motor neuron axon guidance) and longevity regulating pathways. Importantly, RT-qRCR results suggested that 6 miRNAs (miR-786, miR-2208b, miR-34, miR-241, miR-247 and miR-4805), 8 lncRNAs (MSTRG.20812.2, MSTRG.22617.2, MSTRG.28210.13, MSTRG.5728.12, MSTRG.29708.1, MSTRG.3342.25, MSTRG.3342.31 and MSTRG.8841.8) and 7 mRNAs (nas-33, math-28, T14B4.19, col-17, rol-6, sqt-1 and irg-4) were potential targets of ginsenoside Rf inhibition of tauopathy. These results partially explain mechanisms underlying ginsenoside Rf-associated alleviation of htau proteotoxicity and will guide future strategies to discover potential therapeutic targets for preventing and alleviating tauopathies.

Due to their known health-enhancing properties, Laminaria japonica polysaccharides (LJP) may alleviate obesity via unknown mechanisms. This study aimed to investigate beneficial LJP effects and mechanism(s) of action using an animal obesity model (ICR mice fed a high-fat diet). First, LJP were confirmed to consist of sulfated polysaccharides via infrared spectroscopy. Next, LJP administration to mice was found to induce weight loss, reduce liver fat accumulation, and support healthy obesity-related blood serum indicator levels. Notably, LJP treatment significantly reduced TC and LDL levels and significantly increased HDL, LPL, UCP-2, and PPAR-α levels. Furthermore, examinations of tissues of LJP-treated mice revealed significantly reduced intestinal tissue inflammation as compared to corresponding results obtained for untreated obese controls. Additionally, LJP treatment relieved colonic shortening and reduced colonic levels of inflammatory factors TNF-α and IL-6. Further exploration of LJP treatment effects on mouse gut microbiota conducted via fecal 16S rRNA gene sequence-based gut microbiome profiling analysis revealed that LJP treatment increased the Bacteroidetes/Firmicutes ratio and increased gut abundances of probiotics Bacteroides acidifaciens, s_Lactobacillus intestinalis, and s_Lactobacillus murinus. In conclusion, these results collectively suggest that LJP use as a food supplement may alleviate obesity and related gut microbiota dysbiosis and intestinal inflammatory disorders.

QingFei Yin (QFY), a Chinese traditional medicine recipe, is known for its excellent therapeutic pharmacological effects for the treatment of bacterial lung infections, although its molecular mechanism of action remains unknown. Here, QFY chemical composition was determined using a High-Performance Liquid Chromatography-Mass (HPLC-MS/MS)-based method then QFY was evaluated for protective pharmacological effects against pneumonia using two models: a Streptococcus pneumoniae-induced in vivo mouse model and an in vitro pneumolysin (PLY)-induced murine lung alveolar-derived MH-S cell line-based model. Notably, QFY exerted prominent anti-pneumonia effects both in vivo and in vitro. To further explore QFY protective effects, 4D label-free proteomics analysis, pathologic evaluation, and immunohistochemical (IHC) analysis were conducted to identify cellular pathways involved in QFY protection. Notably, our results indicated that NF-κB/NLRP3 and autophagy pathways may contribute to pharmacological effects associated with QFY-based protection. Briefly, QFY triggered autophagy via down-regulation of upstream NLRP3/mTOR signaling pathway events, resulting in the amelioration of inflammatory injury. Collectively, our results revealed molecular mechanisms underlying QFY protection against pneumonia as a foundation for the future development of novel treatments to combat this disease and reduce antibiotic abuse.

Upon recognition of intracytoplasmic viral RNA, activated RIG-I is recruited to the mitochondrion-located adaptor protein VISA (also known as MAVS, CARDIF, and IPS-1). VISA then acts as a central signaling platform for linking RIG-I and downstream signaling components, such as TRAF2, 5, and 6, TBK1, and IKK, leading to activation of the kinases TBK1 and IKK. These activated kinases further phosphorylate the transcription factors IRF3/7 and NF-κB, leading to the induction of downstream antiviral genes. Here, we report a mitochondrial isoform, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), DUT-M, as a positive regulator in RLR-VISA-mediated antiviral signaling. DUT-M interacts with VISA and RIG-I to facilitate the assembly of the VISA-TRAF2 complex and to augment the polyubiquitination of TRAF2, leading to potentiated activation of IRF3 dimerization and phosphorylation of P65, and enhanced VISA-mediated innate immune response. RLR-VISA-mediated IRF3 dimerization and P65 phosphorylation, were inhibited in DUT-knockdown and DUT-deficient 293 cells. Thus, DUT-M is a positive regulator of the RIG-I-VISA-mediated innate immune response to RNA viruses.