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Phyllanthus emblica L. offers promising therapeutic potential for inflammatory diseases. This study revealed the molecular structure of a homogeneous polysaccharide purified from Phyllanthus emblica L. (PEP-1) and evaluated its anti-inflammatory effects on ulcerative colitis (UC) in mice. In the in vivo experiment, administered in varying dosages to dextran sulfate sodium (DSS)-induced UC models, PEP-1 significantly alleviated colonic symptoms, histological damages and reshaped the gut microbiota. Notably, it adjusted the Firmicutes/Bacteroidetes ratio and reduced pro-inflammatory species, closely aligning with shifts in the fecal metabolites and metabolic pathways such as the metabolism of pyrimidine, beta-alanine, and purine. These findings underscore the potential of PEP-1 as a therapeutic agent for UC, providing insights into the mechanisms through gut microbiota and metabolic modulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cinnamic acids are aromatic acids primarily found in plants and plant-derived food. Phenolic cinnamic acids, with one or more hydroxyl groups in the aromatic ring, often contribute to the biological activities attributed to these compounds. The presence of hydroxyl groups and a carboxyl group makes cinnamic acids very hydrophilic, preventing them from crossing biological membranes and exerting their biological activities. To alleviate this condition, a panel of synthetic modifications have been made leading to a diverse set of phenolic cinnamic structures. In this review, an overview of the natural phenolic cinnamic acid derivatives and their plant sources (more than 200) is described. The synthetic approaches to obtain the referred derivatives (more than 200) namely esters and amides are reviewed. Further, their anti-inflammatory activity (more than 70 compounds) is scrutinized. Finally, future directions will be indicated to translate the research on phenolic cinnamic derivatives into potentially effective anti-inflammatory drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

This study investigated the changes in phytochemical composition and inflammatory response of crude papaya (Carica papaya L.) seed oil (CPO) and its refined forms (degummed, PDG; deacidified, PDA; decolorized, PDC; deodorized, PDO). Oils were analyzed for their phytochemical composition, oil quality parameters, antioxidant activity, and their inflammatory response in LPS-stimulated THP-1 macrophages. At higher refining degrees, particularly after deacidification, the contents of phytochemicals (sterols, tocopherols, and polyphenols) decreased while oxidation products increased. Both CPO (0.1-1.0 mg/mL) and PDG reduced the secretion and mRNA expression of LPS-stimulated inflammatory cytokines and mediators and also blocked the activation of the NF-κB pathway. PDA, PDC, and PDO showed low anti-inflammatory or even pro-inflammatory activity. Correlation analysis showed that 4 polyphenols and 2 phytosterols were responsible for the oil's anti-inflammatory effects. These findings indicated that moderate refining is suggested for papaya seed oil processing for retaining bioactive ingredients and anti-inflammatory ability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The study aimed to isolate and characterize lactic acid bacteria from various traditional fermented fish products from North East India, including Xindol, Hentak, and Ngari, which hold significant dietary importance for the indigenous tribes. Additionally, the study sought to examine their untargeted metabolomic profiles. A total of 43 strains of Bacillus, Priestia, Staphylococcus, Pediococcus, and Lactiplantibacillus were isolated, characterized by 16 S rRNA gene and tested for probiotic properties. Five strains passed pH and bile salt tests with strain dependent antimicrobial activity, which exhibited moderate autoaggregation and hydrophobicity properties. Lactiplantibacillus plantarum MKTJ24 exhibited the highest hydrophobicity (42 %), which was further confirmed by adhesion assay in HT-29 cell lines (100 %). Lactiplantibacillus plantarum MKTJ24 treatment in LPS-stimulated HT-29 cells up-regulated expression of mucin genes compared to LPS-treated cells. Treatment of RAW 264.7 cells with Lactiplantibacillus plantarum MKTJ24 decreased LPS-induced reactive oxygen species (ROS) and nitric oxide (NO) productions. Further, genome analysis of Lactiplantibacillus plantarum MKTJ24 revealed the presence of several probiotic markers and immunomodulatory genes. The genome was found to harbor plantaricin operon involved in bacteriocin production. A pangenome analysis using all the publicly available L. plantarum genomes specifically isolated from fermented fish products identified 120 unique genes in Lactiplantibacillus plantarum MKTJ24. Metabolomic analysis indicated dominance of ascorbic acids, pentafluropropionate, cyclopropaneacetic acid, florobenzylamine, and furanone in Xindol. This study suggests that Lactiplantibacillus plantarum MKTJ24 has potential probiotic and immunomodulatory properties that could be used in processing traditional fermented fish products on an industrial scale to improve their quality and enhance functional properties., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Diabetic heart disease may eventually lead to heart failure, a leading cause of mortality in diabetic individuals. The lack of effective treatments for diabetes-induced heart failure may result from a failure to address the underlying pathological processes, including chronic, low-grade inflammation. Previous studies have reported that lipoxin A 4 (LXA 4 ), known to promote resolution of inflammation, attenuates diabetes-induced atherosclerosis, but its impact on diabetic hearts has not been sought. Thus, we aimed to determine whether LXA 4 therapeutic treatment attenuates diabetes-induced cardiac pathology., Methods: Six-week-old male apolipoprotein E-deficient (ApoE -/- ) mice were followed for 16 weeks after injection of streptozotocin (STZ, 55 mg/kg/day, i.p. for 5 days) to induce type-1 diabetes (T1DM). Treatment with LXA 4 (5 μg/kg, i.p.) or vehicle (0.02% ethanol, i.p.) was administered twice weekly for the final 6 weeks. One week before endpoint, echocardiography was performed within a subset of mice from each group. At the end of the study, mice were euthanized with sodium pentobarbital (100 mg/kg i.p.) and hearts were collected for ex vivo analysis, including histological assessment, gene expression profiling by real-time PCR and protein level measurement by western blot., Results: As expected diabetic mice showed a significant elevation in plasma glycated hemoglobin (HbA 1c ) and glucose levels, along with reduced body weight. Vehicle-treated diabetic mice exhibited increased cardiac inflammation, macrophage content, and an elevated ratio of M1-like to M2-like macrophage markers. In addition, myocardial fibrosis, cardiomyocytes apoptosis and hypertrophy (at the genetic level) were evident, with echocardiography revealing early signs of left ventricular (LV) diastolic dysfunction. Treatment with LXA 4 ameliorated diabetes-induced cardiac inflammation, pro-inflammatory macrophage polarization and cardiac remodeling (especially myocardial fibrosis and cardiomyocytes apoptosis), with ultimate improvement in cardiac function. Of note, this improvement was independent of glucose control., Conclusions: These findings demonstrated that LXA 4 treatment attenuated the extent of cardiac inflammation in diabetic hearts, resulting in limited cardiac remodeling and improved LV diastolic function. This supports further exploration of LXA 4 -based therapy for the management of diabetic heart disease. The recent development of stable LXA 4 mimetics holds potential as a novel strategy to treat cardiac dysfunction in diabetes, paving the way for innovative and more effective therapeutic strategies., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Fructus Choerospondiatis (FC) has been utilized in Mongolian medicine for the treatment of many diseases. This investigation assessed the coloration, five active components, total phenolic and flavonol contents, as well as the antioxidant and antibacterial properties of different parts of FC from eight cultivars, and the optimal cultivar was identified to determine the anti-inflammatory capacity of all parts. The findings revealed that L* and b* values of the dried peel powder were the highest and the a* value of whole fruit powder was the highest. The concentrations of gallic acid, catechin, epicatechin, total phenols, and total flavonoids exhibited a positive correlation with antioxidant activity. A comprehensive analysis revealed that the peel contained a greater abundance of active compounds and exhibited stronger antioxidant and antibacterial properties compared to other parts. RPNO.1 can be used as the source of high-quality FC for clinical application. In vivo anti-inflammatory experiments indicated that both the flesh and peel of RPNO.1 displayed the highest anti-inflammatory effect. This research not only addressed the gap in studies regarding FC ' s anti-inflammatory properties but also proved that the peel of FC, which was often discarded, had utilization value and could be used as a medicinal herb., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and highly fatal disease characterized by excessive accumulation of extracellular matrix (ECM), foci of myofibroblasts, and a usual pattern of interstitial pneumonia. As suggested by international guidelines, the treatment for this disease involves supportive therapies, as there is currently no effective treatment. Plant-derived nanovesicles have emerged as a new treatment for various diseases and have been tested in cellular and murine models., Methods and Results: This research aimed to test the use of Allium sativum nanovesicles (AS-NV) in a murine model of IPF induced by bleomycin. AS-NV reduced the amount of collagen and restored lung architecture in the mouse model. AS-NV was tested on human lung fibroblasts, which do not affect the viability of healthy cells. AS-NV treatment decreases the mRNA levels of genes related to fibrosis, inflammation, and ECM deposition (Mmp2,Timp-2,Vegf,Pcna,Col1a1,Tgf-β,α-Sma,IL-1β,and Hif1a) in bleomycin-induced idiopathic pulmonary fibrosis., Conclusions: This research highlights the anti-inflammatory and antifibrotic activity of AS-NV, which contributes to plant nanovesicle mechanisms in IPF; however, more AS-NV studies are needed to identify alternative treatments for idiopathic pulmonary fibrosis., Competing Interests: Declarations Ethical approval All the experimental animal studies were performed with the approval of the Ethics Committee of the Faculty of Medicine and Surgery – Autonomous University “Benito Juarez” of Oaxaca with registration number 0047-CEI-2022. Informed consent Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Acetaminophen (APAP) overdose is still a leading cause of drug-induced liver injury (DILI), accompanied with severe inflammatory response. However, the therapy for APAP-induced DILI is rather limited. The combined application of natural products to treat DILI induced by APAP may be a new direction of the research. This study was conducted to evaluate the dual anti-inflammatory activity of curcumin (CUR) combined with berberine (BBR) against APAP-mediated DILI. Network pharmacology found that PI3K-Akt and PPAR signaling pathways were primarily involved in anti-DILI of the combination of CUR and BBR. APAP injection enhanced the levels of ALT, AST, IL-1β, IL-6, and TNF-α in mice, while such phenomenon was significantly reversed by the cotreatment of CUR and BBR, which was more effective than either single treatment. The increase of p-NF-κB and p-IKKα/β protein expression and the decrease of p-PI3K, p-AKT, and PPARγ protein expression in APAP-treated mice were markedly inhibited by the coadministration of CUR and BBR. Molecular docking further demonstrated that both CUR and BBR could stably bind to PI3K, AKT, and PPARγ protein. In conclusion, the combination of CUR and BBR more effectively protected liver from APAP-triggered DILI than individual treatment. The mechanism is to alleviate hepatic inflammation by inhibiting NF-κB activation, which is possibly mediated by PI3K/Akt and PPARγ signaling pathways., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Psoriasis is a prevalent, inflammatory skin disease without cure. Further research is required to unravel dysregulated processes and develop new therapeutic interventions. The lack of suitable in vivo and in vitro preclinical models is an impediment in the psoriasis research. Recently, the development of 3D skin models has progressed including replicas with disease-like features. To investigate the use of in vitro models as preclinical test tools, the study focused on treatment responses of 3D skin replicas. Cytokine-priming of skin organoids induced psoriatic features like inflammation, antimicrobial peptides (AMP), hyperproliferation and impaired differentiation. Topical application of dexamethasone (DEX) or celastrol (CEL), a natural anti-inflammatory compound reduced the secretion of pro-inflammatory cytokines. DEX and CEL decreased the gene expression of inflammatory mediators. DEX barely affected the psoriatic AMP transcription but CEL downregulated psoriasis-driven AMP genes. Subcutaneous application of adalimumab (ADM) or bimekizumab (BMM) showed anti-psoriatic effects via protein induction of the differentiation marker keratin-10. Dual blockage of TNF-α and IL-17A repressed the inflammatory psoriasis phenotype. BMM inhibited the psoriatic expression of AMP genes and induced KRT10 and cell-cell contact genes. The present in vitro model provides a 3D environment with in vivo-like cutaneous responses and represents a promising tool for preclinical investigations., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs) expressed orally and extraorally, elicit signaling in response to a large set of tastants. Among 25 functional TAS2Rs encoded in the human genome, TAS2R14 is the most promiscuous, and responds to hundreds of chemically diverse ligands. Here we present the cryo-electron microscopy (cryo-EM) structure of the human TAS2R14 in complex with its signaling partner gustducin, and bound to flufenamic acid (FFA), a clinically approved nonsteroidal anti-inflammatory drug. The structure reveals an unusual binding mode, where two copies of FFA are bound at distinct pockets: one at the canonical receptor site within the trans-membrane bundle, and the other in the intracellular facet, bridging the receptor with gustducin. Together with a pocket-specific BRET-based ligand binding assay, these results illuminate bitter taste signaling and provide tools for a site-targeted compound design., Competing Interests: Competing interests The authors declare no competing interests, (© 2024. The Author(s).)

Background: The global demographic shift towards an aging population is generating a rise in neurodegenerative conditions, with Alzheimer's disease (AD) as the most prominent problem. In this landscape, the use of natural supplements has garnered attention for their potential in dementia prevention. Curcumin (Cur), derived from Curcuma longa, has demonstrated promising pharmacological effects against AD by reducing the levels of inflammatory mediators. However, its clinical efficacy is hindered by poor solubility and bioavailability. Our study introduces the use of H-Ferritin nanocages (HFn) as a nanoformulation vehicle for Cur, aiming to enhance its therapeutic potential for AD. In this work, we characterized a nanoformulation of Cur in HFn (HFn-CUR) by evaluating its safety, stability, and its transport across the blood-brain barrier (BBB) in vitro. Moreover, we evaluated the efficacy of HFn-CUR by transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from both AD patients and healthy controls (HC), and by using the well-established 5xFAD mouse model of AD., Results: Our data show that HFn-CUR exhibits improved water dispersibility, is non-toxic, and can traverse the BBB. Regarding its activity on PBMCs from AD patients, HFn-CUR enhances cellular responses to inflammation and reduces RAGE-mediated stress. Studies on an AD mouse model demonstrate that HFn-CUR exhibits mild beneficial effects on cognitive performance. Moreover, it effectively reduces microgliosis and astrogliosis and in vivo in mouse, suggesting potential neuroprotective benefits., Conclusions: Our data suggest that HFn-CUR is safe and effective in reducing inflammation in both in vitro and in vivo models of AD, supporting the need for further experiments to define its optimal use., Competing Interests: Declarations Ethics approval and consent to participate All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki declaration and its later amendments or comparable ethical standards. The study design was examined by the IRBs of the enrolling institutions. The study protocol to obtain blood from patients was approved by the Ethical Committee of the IRCCS Mondino Foundation (Pavia, Italy) (Code: 20170001758). Informed consent was obtained from all subjects involved in the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Herbacetin, a flavonol abundant in traditional medicines, is documented as an anti-inflammatory agent. However, information regarding its attributes on lipopolysaccharide (LPS)-induced inflammatory immunopathies has not been delineated yet. The present study aimed to comprehend herbacetin effects on LPS-induced aspects of unwarranted, non-resolving inflammation, particularly via targeting the vicious circle of oxi-inflammatory stress, autophagy-apoptosis, macrophages polarization, impaired inflammasome activation, and inflammatory cascades., Methods and Results: In-vitro model of LPS-stimulated RAW 264.7 macrophage was recapitulated to investigate different inflammatory anomalies using enzyme-linked immunosorbent assay, qRT-PCR (Real-Time Quantitative Reverse Transcription PCR), immunoblotting. Concanavalin A challenged splenocytes and in silico studies were performed to measure Tregs population and binding affinity, respectively., Results: Herbacetin administration caused remarkable reduction in nitric oxide, reactive oxygen species, mitochondrial membrane potential hyperpolarization, tumor necrosis factor-α, interferon-γ, interleukin-6, inducible nitric oxide synthase and ratio of M1/M2 markers (inducible nitric oxide synthase/arginase-1/macrophage scavenger receptor-1/mannose receptor C type-1) in in vitro model of persistent inflammation. Suppression of interleukins-5,17 and matrix metalloproteinases-2,3,9,13 and proliferating cell nuclear antigen, signifies its anti-inflammatory attributes. Noticeable decline in monodansylcadaverine-Lysotracker staining, caspase-6, and enhanced p62, B-cell lymphoma-2 expression indicates apoptosis-autophagosome accumulation inhibition and lysosomal destabilization. These were accompanied by reduced NLRP3 activation, caspase-1, AIM-2 expression, and interleukin-1β release. Subsequently, up-regulated activation of TLR-4, NF-κB, PI3K, Akt, ERK1/2, and JNK was decisively thwarted by herbacetin. In silico investigation signified the interaction of herbacetin with these targets. Decreased cytokines and enhanced Tregs conferred its role in extenuating inflammation facilitated by T-cells depletion., Conclusion: Collectively, these findings comprehend attributes of herbacetin as an alternative therapeutic strategy in relieving LPS-associated chronic inflammatory disorders., Competing Interests: Declarations Research involving human participants and/or animals All animal experiment procedures were approved by Institutional Animal Ethics Committee (IAEC) of CSIR-IHBT Palampur with Approval no. IAEC/IHBT/P-5/April 2021. Informed consent All authors confirm their contribution to the manuscript. Human participants were not involved in the study; thus patient informed consent was not required. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

CNS Drug discovery has been challenging due to the lack of clarity on CNS diseases' basic biological and pathological mechanisms. Despite the difficulty, some CNS drugs have been developed based on phenotypic effects. Herein, we propose a phenotype-structure relationship model, which predicts an anti-neuroinflammatory potency based on 3D molecular structures of the phenotype-active or inactive compounds without specifying targets. For this chemo-centric study, a predictive model of the nitric oxide (NO) inhibitory potency in hyper-activated microglia is built from the 548 agents, which were collected from 95 research articles (28 substructures consisting of natural products and synthetic scaffolds) and doubly externally validated by the agents of 9 research articles as third set. 3D Structures (multi-conformer ensemble) of every agent were encoded into the E3FP molecular fingerprint of the Keiser group as a 3D molecular representation. The location information of the molecular fingerprints could be learned and validated to classify the inhibitory potency of compounds (IC 50 cut-off between the active and inactive: 37.1 µM): (1) multi-layer perceptron (MLP) (AUC- CV : 0.997, AUC- Test : 0.992), (2) recurrent neural network (RNN) (AUC- CV : 0.999, AUC- Test : 0.995), and (3) convolutional neural network (CNN) (AUC- CV : 0.998, AUC- Test : 0.994). The high performance of these models was compared with that of four classical machine classification models (Logistic, Ridge, Lasso, and Naïve Bayes). We named the binary classification models NO-Classifier. Independent test set validation and decision region analysis of the independent test set doubly demonstrated NO-Classifier effectively discerned the anti-inflammatory potency of testing compounds in inflammatory cell phenotype with the webserver in https://no-classifier.onrender.com., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Oxyresveratrol is the main constituent of mulberries and has many bioactive properties beneficial to human health. The purpose of this study was to assess the anti-inflammatory effects of oxyresveratrol on in vitro periodontitis model., Methods: Human periodontal ligament cells were treated with oxyresveratrol (0, 10, and 20 µg/mL) for 72 h. Cell viability and flow cytometry assays were performed. To investigate anti-inflammatory effect of oxyresveratrol on periodontal inflammation, nitric oxide production under lipopolysaccharide stimulation was assessed. Next, expression of biomarkers associated periodontal inflammation was evaluated. Scratch wound assay was performed to evaluate cell migration/proliferation potential of oxyresveratrol under lipopolysaccharide stimulation., Results: Periodontal ligament cell toxicity was not observed in oxyresveratrol treatment. Oxyresveratrol treatment significantly inhibited nitric oxide production and reduced MMP-2, MMP-9, TNF-α, IL-6, and IL-8 expressions after lipopolysaccharide stimulation. Regarding cell migration/proliferation, open wound area in oxyresveratrol (33.28 ± 6.80%) was the lowest (p < 0.05)., Conclusions: Within the limits of this study, oxyresveratrol inhibited lipopolysaccharide-induced inflammation in periodontal ligament cells and promoted periodontal ligament cell migration/proliferation. These findings suggest that oxyresveratrol could be valuable for the management of periodontal diseases., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Inflammation is the physiological response of the immune system to injury or infection, typically manifested by local tissue congestion, swelling, heat, and pain. Prolonged or excessive inflammation can lead to tissue damage and the development of many diseases. The anti-inflammatory effects of natural ingredients have been extensively researched and confirmed. This study investigated the effects of Chlorogenic acid (CGA) isomers -- 3-Caffeolyquninic acid (3-CQA), 4-Caffeolyquninic acid (4-CQA), and 5-Caffeolyquninic acid (5-CQA) -- on the inflammatory response and oxidative stress reaction induced by LPS in RAW264.7 cells. Overall, 3-CQA exhibited the most significant reduction in levels of TNF-α, IL-6, NO, and ROS. 4-CQA showed superior inhibition of TNF-α compared to 5-CQA (p < 0.05), while no significant difference in other parameters. We further used DARTS and CETSA to demonstrate that CGA isomers have stable affinity with AKR1B1. As a positive control, the AKR1B1 antagonist epalrestat exhibited similar effects to the CGA isomers. 3-CQA having the smallest half-inhibitory concentration (IC50) for AKR1B1, while 4-CQA and 5-CQA have similar values. AutoDock simulations of the docking conformations revealed minimal differences in the average binding energies of the CGA isomers. The main differences were that VAL47 formed a hydrogen bond with 3-CQA, whereas GLN49 formed hydrogen bonds with 4-CQA and 5-CQA. Additionally, the number of hydrophobic bonds involving PHE122 and LEU300 varies. Our conclusion is that differences in non-covalent interactions result in the varying inhibitory abilities of CGA isomers on AKR1B1, which further affect the anti-inflammatory and antioxidant effects of CGA isomers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The effective treatment of inflammatory diseases, particularly their chronic forms, is a key task of modern medicine. Herein, we report the synthesis and evaluation of biocompatible polymer conjugates based on N-2-(hydroxypropyl)methacrylamide copolymers enabling the controlled release of acetylsalicylic acid (ASA)-based anti-inflammatory drugs under specific stimuli. All polymer nanotherapeutics were proposed as water-soluble drug delivery systems with a hydrodynamic size below 10 nm ensuring suitability for the parenteral application and preventing opsonization by the reticuloendothelial system. The nanotherapeutics bearing an ester-bound ASA exhibited long-term release of the ASA/salicylic acid mixture, while the nanotherapeutics carrying salicylic acid hydrazide (SAH) ensured the selective release of SAH in the acidic inflammatory environment thanks to the pH-sensitive hydrazone bond between the polymer carrier and SAH. The ASA- and SAH-containing nanotherapeutics inhibited both cyclooxygenase isoforms and/or the production of pro-inflammatory mediators. Thanks to their favorable design, they can preferentially accumulate in the inflamed tissue, resulting in reduced side effects and lower dosage, and thus more effective and safer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hypertension is the key leading risk factor for death globally, affecting ∼1.3 billion adults, particularly in low- and middle-income countries. Most people living with hypertension have uncontrolled high blood pressure, increasing their likelihood of cardiovascular events. Significant issues preventing blood pressure control include lack of diagnosis, treatment, and response to existing therapy. For example, monotherapy and combination therapy are often unable to lower blood pressure to target levels. New therapies are urgently required to tackle this issue, particularly those that target the mechanisms behind hypertension instead of treating its symptoms. Acting via an increase in systemic and tissue-specific inflammation, the immune system is a critical contributor to blood pressure regulation and is considered an early mechanism leading to hypertension development. Here, we review the immune system's role in hypertension, evaluate clinical trials that target inflammation, and discuss knowledge gaps in pre-clinical and clinical data. We examine the effects of anti-inflammatory drugs colchicine and methotrexate on hypertension and evaluate the blockade of pro-inflammatory cytokines IL-1β and TNF-α on blood pressure in clinical trials. Lastly, we highlight how we can move forward to target specific components of the immune system to lower blood pressure. This includes targeting isolevuglandins, which accumulate in dendritic cells to promote T cell activation and cytokine production in salt-induced hypertension. We discuss the potential of the dietary fibre-derived metabolites short-chain fatty acids, which have anti-inflammatory and blood pressure-lowering effects via the gut microbiome. This would limit adverse events, leading to improved medication adherence and better blood pressure control., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Huperzine A (Hup A), an extract from Huperzia serrata, exerted its anti-inflammation and anti-oxidation effect to protect against neurodegenerative disorders and organ injury. Ferroptosis was indicated to involve in the development of acute lung injury (ALI) accompanying by lipid reactive oxygen species (ROS) overexpressed. However, there is little research focused on the protective effect of Hup A on ALI, and the underlying molecular mechanism remains elusive. This study aims to determine the therapeutic effect of Hup A on ALI in vivo and in vitro. Hup A attenuated lung injury and cellular damage in lipopolysaccharide-induced ALI (LPS-ALI) models, both in vivo and in vitro, accompanied by the upregulation of ferroptosis-associated proteins (SLC7A11 and GPX4). Furthermore, the pretreatment with Hup A decreased the abundance of inflammation factors (IL-6, TNF-α), MDA, lipid ROS, and Fe 2+ in the LPS-ALI model, while it also promoted the secretion of SOD and GSH to antagonize peroxidation. Mechanistically, RNA sequencing and network pharmacological analysis synergistically revealed the PI3K/Akt signaling pathway as a potential target of Hup A. In vitro experiments demonstrated that Hup A effectively activated GPX4 through the PI3K/Akt signaling pathway, which was subsequently reversed by LY294002, an inhibitor of the PI3K/Akt signaling pathway. Consequently, our results revealed that Hup A inhibited ferroptosis in LPS-ALI by activating the PI3K-Akt signaling pathway which indicated the potential therapeutical effect of Hup A and further emphasized the pivotal role of ferroptosis in ALI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Toll-like receptors (TLRs) play a pivotal role in initiating immune responses, particularly in the context of inflammation. However, an excessive inflammation can detrimentally affect the immune homeostasis Thus, it is important to regulate TLR signaling pathways appropriately. Gingerenone A (GIA), a bioactive compound derived from ginger, has garnered significant attention due to its potential anti-inflammatory properties. In this study, we investigate modulatory effects of GIA on TLR signaling pathways. Results showed that GIA effectively suppressed TLR-mediated inflammatory responses by modulating key signaling molecules such as nuclear factor kappa B and interferon regulatory factor 3. These results indicate that GIA is a novel regulator of TLR signaling, offering promising avenues for the development of new anti-inflammatory agents., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Bacterial keratitis is a common cause of blindness. Antibiotic treatment leads to the rapid release of lipopolysaccharide (LPS), which can activate corneal fibroblasts and cause persistent and excessive inflammatory responses. The anti-inflammatory drugs currently used to treat keratitis have serious side effects. Therefore, the ability of sodium butyrate (NaB), which can suppress the production of proinflammatory cytokines and promote the production of anti-inflammatory cytokines, to ameliorate keratitis was assessed in the present study., Methods: The effect of NaB on the viability of primary human corneal fibroblasts was assayed with a CCK-8 kit. Cell migration was assessed by an in vitro scratch assay. Cell phenotypes were assessed by Western blotting and immunofluorescence staining. An antibody array was used to measure the production of proinflammatory cytokines and chemokines., Results: At 0-1 mM, NaB had no significant effect on cell viability, promoted the expression of the keratocyte marker keratocan and inhibited the fibroblast marker vimentin. Inhibition of cell migration was observed in the wound healing assay. By targeting the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway, NaB decreased the levels of inflammation-related cytokines and chemokines whose expression was induced by LPS., Conclusions: NaB maintained the keratocyte phenotype, inhibited cell migration, and relieved LPS-induced inflammatory responses through the JAK/STAT signalling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Inflammatory bowel diseases (IBDs) are chronic, relapsing, and inflammatory disorders of the gastrointestinal tract characterized by abnormal immune responses. Recently, STING has emerged as a promising therapeutic target for various autoinflammatory diseases. However, few STING-selective small molecules have been investigated as novel strategies for IBD. In this study, we sought to examine the effects of PROTAC-based STING degrader SP23 on acute colitis and explore its underlying mechanism. SP23 treatment notably alleviates dextran sulfate sodium (DSS)-induced colitis. Pharmacological degradation of STING significantly reduced the production of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, and inhibited macrophage polarization towards the M1 type. Furthermore, SP23 administration decreased the loss of tight junction proteins, including ZO-1, occludin, and claudin-1, and downregulated STING and NLRP3 signaling pathways in intestinal inflammation. In vitro, STING activated NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, which could be abrogated by SP23 and STING siRNA intervention. In conclusion, these findings provide new evidence for STING as a novel therapeutic target for IBD, and reveal that hyperactivation of STING could exaggerate colitis by inducing NLRP3/Caspase-1/GSDMD axis mediated intestinal epithelial cells pyroptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Depression is a complex neurological disease that holds many theories on its aetiology and pathophysiology. The monoamine strategy of treating depression with medications to increase levels of monoamines in the (extra)synapse, primarily through the inhibition of monoamine transporters, does not always work, as seen in patients that lack a response to multiple anti-depressant exposures, as well as a lack of depressive symptoms in healthy volunteers exposed to monoamine reduction. Depression is increasingly being understood not as a single condition, but as a complex interplay of adaptations in various systems, including inflammatory responses and neurotransmission pathways in the brain. This understanding has led to the development of the neurodegenerative hypothesis of depression. This hypothesis, which is gaining widespread acceptance posits that both oxidative stress and inflammation play significant roles in the pathophysiology of depression. This article is a review of the literature focused on neuroinflammation in depression, as well as summarised studies of anti-inflammatory and antioxidant effects of antidepressants., Competing Interests: Declaration of competing interest We confirm that the paper has been seen and reviewed by co-authors, approved the submission to the journal. We confirm that there are no conflicts of interest in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Turmeric (Curcuma longa L.) extract (CLE) has been shown to elicit several pharmacological properties and is widely used in Asian traditional medicine. Herein, we assessed the impact of CLE on airway inflammation in BALB/c mice and A549 cells to clarify the underlying mechanism. An asthmatic mouse model was established by administering ovalbumin (OVA). CLE (100 or 300 mg/kg/day) was orally administered daily from days 18 to 23, with dexamethasone (3 mg/kg/day) used as the positive control. Human airway epithelial cells, A549, were stimulated using recombinant tumor necrosis factor-α. The CLE100 and CLE400 groups exhibited a significant downregulation in eosinophil counts, cytokine levels, and immunoglobulin-E levels. Moreover, CLE administration dose-dependently suppressed oxidative stress and airway inflammation in the lung tissue. CLE administration inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) and the expression and activity of matrix metalloproteinase (MMP)-9. In vitro, CLE treatment reduced mRNA levels of proinflammatory cytokines, MAPK phosphorylation, and the expression and activity of MMP-2 and MMP-9. Additionally, 50 µg/mL CLE and 2.5 µg/mL curcumin showed similar anti-inflammatory effects. Collectively, our findings revealed that CLE could suppress airway inflammation in asthmatic mice and A549 cells via oxidative stress-driven MAPK/MMPs signaling, suggesting that CLE could be developed as a potential treatment option for patients with asthma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lung inflammation as a result of exposure to toxicants is a major pathological problem. Autophagy (AP) is a process of cell self-digestion and can be disrupted by environmental toxicants, leading to oxidative stress, inflammation and cellular damage. Bryophyllum pinnatum (Lam.) Oken has been used in folklore medicine to manage pathological abnormalities, including inflammation, but mechanisms remain unclear. This work investigated the effects of Bryophyllum pinnatum ethanol leaf extract (BP) on dysfunctional AP in the lungs of Wistar rats exposed to zinc oxide nanoparticles (ZONPs). The experimental rats were orally administered ZONPs for seven days (10 mg/kg). Some exposed rats were post-treated with BP (62.5 and 125 mg/kg) through oral gavage. Oxidative stress, inflammation, and apoptotic and autophagic parameters were assessed using biochemical assay and gene expression methods. Several indices of pulmonary damage were also evaluated. PCR analysis suggested that ZONP downregulated the expression of pro-autophagy-related genes (Beclin 2, ATG5, DAPK, and FOXP3) and upregulated the expression of the TNF-alpha, NF-Kb, LC3 and Bcl2 genes. In contrast, BP significantly (p < 0.0001) reversed ZONP-induced pulmonary toxicity and oxidative stress. It reduced MDA levels and increased SOD, CAT, GSH and GPxD activities. BP significantly (p < 0.0001) downregulated the expressions of proinflammatory genes (IL-6 and JNK) and upregulated the expressions of IL-10, CAT and SOD genes in ZONP-exposed rats. BP restored the lung's histoarchitectural structure after ZNOP-induced distortion. The results suggested that BP has antioxidant and anti-inflammatory properties, and could effectively restore ZNOP-induced dysfunctional AP in the lungs of Wistar rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease (IBD). There is a growing prevalence of UC, but current conventional drugs lack efficacy. Carthamin yellow (CY) is a flavonoid compound extracted from safflower that is widely used and has various pharmacological effects. In the present study, we established colitis models in mice via DSS and in Caco-2 cells via lipopolysaccharide (LPS). Our results showed that CY treatment attenuated the symptoms of colitis by decreasing colonic pathological damage and improving disease activity index (DAI) scores. Notably, we observed that CY treatment decreased the levels of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) by inhibiting the NLRP3/Caspase-1/IL-1β and MAPK/NF-κB signaling pathways. Moreover, we verified that treatment with CY obviously improved intestinal barrier function in both DSS-induced mice and LPS-stimulated Caco-2 cells. Ferroptosis-related markers were assessed. CY attenuated DSS-induced colitis by inhibiting ferroptosis, as assessed by Fe 2+ accumulation, total antioxidant capacity (T-AOC), and reactive oxygen species (ROS), 4-hydroxynonenal (4-HNE), and glutathione (GSH) levels. Additionally, there was an increase in superoxide dismutase (SOD) and catalase (CAT) activity, as well as alterations in ferroptosis-related protein and gene expression (ACSL4, GPX4, SLC7A11, TfR1, and FTH1). Further analyses revealed that CY could inhibit ferroptosis via the Nrf2/GPX4 axis in both in vivo and RSL3-induced Caco-2 cell models. Importantly, the antiferroptotic and protective effects of CY were nullified by Nrf2 knockout in vivo and by the use of ML385 in vitro. In conclusion, the effects of CY on UC are strongly associated with the Nrf2 pathway. CY might be a potential candidate for the treatment of UC. Therefore, our results provide an important reference for investigating the mechanisms of flavonoid compounds involved in preventing inflammatory diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acute kidney injury (AKI) is a severe medical condition that can lead to illness and death. A disintegrin and metalloprotease (ADAM) protein family is a potential treatment target for AKI due to its involvement in inflammation, growth, and differentiation. While ADAM10 and ADAM17 have been identified as significant contributors to inflammation, it is unclear whether they play a critical role in AKI. In this study, we induced AKI in male and female mice using lipopolysaccharide, a bacterial endotoxin that causes inflammation and oxidative stress. The role of kaempferol, which is found in many natural products and known to have antioxidant and anti-inflammatory activity in many pre-clinical studies, was investigated through ADAM10/17 enzymes in AKI. We also investigated the efficacy of a selective synthetic inhibitor named GW280264X for ADAM10/17 inhibition in AKI. Blood urea nitrogen and creatinine levels were measured in serum, while tumor necrosis factor-α, vascular adhesion molecule, interleukin (IL)-1β, glucose regulatory protein-78, IL-10, nuclear factor κ-B, thiobarbituric acid reactive substances, total thiol, ADAM10, and ADAM17 levels were measured in kidney tissue. We also evaluated kidney tissue histologically using hematoxylin and eosin, periodic acid-schiff, and caspase-3 staining. This research demonstrates that GW280264X and kaempferol reduces inflammation and oxidative stress, as evidenced by biochemical and histopathological results in AKI through ADAM10/17 inhibition. These findings suggest that inhibiting ADAM10/17 may be a promising therapeutic approach for treating acute kidney injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Uterine inflammation affects 8% of women in the United States and 32% in developing nations, often caused by uncontrolled inflammation and oxidative stress. This condition significantly impacts women's health, productivity, and quality of life, and increases the risk of related morbidities leading to higher healthcare costs. Research now focuses on natural antioxidants and anti-inflammatory, particularly berberine (BBR), an isoquinoline alkaloid known for its antioxidant, anti-inflammatory, and antiapoptotic activities. The present study sought to examine the potential therapeutic efficacy of BBR against uterine inflammation induced by the intrauterine infusion of an iodine (I 2 ) mixture in an experimental setting. Female Sprague Dawley rats (n = 6) were divided into five groups, control, sham, I 2 , I 2 and BBR 10 mg/kg, and I 2 and BBR 25 mg/kg-treated groups. Compared to I 2 infusion, BBR treatment effectively restored normal uterine histopathology and reduced inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nuclear factor- kappa B (NF-κB), monocyte chemoattractant protein 1 (MCP1), and myeloperoxidase (MPO). It lowered oxidative markers like malondialdehyde (MDA), and increased antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). It balanced apoptotic genes by upregulating B-cell lymphoma 2 (Bcl-2) and downregulating Bcl-2-associated X protein (Bax). Furthermore, BBR reduced the expression of Toll-like receptor 2 (TLR-2), phosphorylated phosphatidylinositol 3‑kinase (p-PI3K), and phosphorylated protein kinase B (p-AKT) in the rats treated with intrauterine I 2 . Ultimately, the therapeutic benefits of BBR can be attributed, to some extent, to its antioxidant, anti-inflammatory, and antiapoptotic properties, in addition to its ability to modulate the TLR-2/p-PI3K/p-AKT axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is an autoimmune disorder primarily targeting peripheral joints. The global prevalence of RA is increasing, posing a significant challenge in patient care management. Despite therapeutic advancements, their inherent limitations highlight the need for further research on safer treatment interventions. Among potential candidates, sesquiterpenes, a subclass of plant secondary metabolites composed of three isoprene units, have exhibited remarkable efficacy in treating various inflammatory disorders, including RA. In this systematic review, we summarized the treatment evidence of sesquiterpenes and their derivatives on RA. Specific major sesquiterpenoids have been discussed in detail, as well as the possible mechanisms by which cells and chemical messengers are involved in treating RA. Our review indicated that sesquiterpenes are potential novel, bioactive compounds for RA prevention and treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Inflammation is a protective mechanism against endogenous and exogenous pathogens. It is a typical feature of numerous chronic diseases and their complications. Keap1 is an essential target in oxidative stress and inflammatory diseases. Among them, the Keap1-Nrf2-ARE pathway (including Keap1-Nrf2-HO-1) is the most significant pathway of Keap1 targets, which participates in the control of inflammation in multiple organs (including renal inflammation, lung inflammation, liver inflammation, neuroinflammation, etc.). Identifying new Keap1 inhibitors is crucial for new drug discovery. However, most drugs have specificity issues as they covalently bind to cysteine residues of Keap1, causing off-target effects. Therefore, direct inhibition of Keap1-Nrf2 PPIs is a new research idea. Through non-electrophilic and non-covalent binding, its inhibitors have better specificity and ability to activate Nrf2, and targeting therapy against Keap1-Nrf2 PPIs has become a new method for drug development in chronic diseases. This review summarizes the members and downstream genes of the Keap1-related pathway and their roles in inflammatory disease models. In addition, we summarize all the research progress of anti-inflammatory drugs targeting Keap1 from 2010 to 2024, mainly describing their biological functions, molecular mechanisms of action, and therapeutic roles in inflammatory diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Constant efforts have been made to move towards maintaining the positive anti-inflammatory functions of glucocorticoids (GCs) while minimizing side effects. The anti-inflammatory effect of GCs is mainly attributed to the inhibition of major inflammatory pathways such as NF-κB through GR transrepression, while its side effects are mainly mediated by transactivation. Here, we investigated the selective glucocorticoid receptor modulator (SGRM)-like properties of a plant-derived compound. In this study, glucocorticoid receptor (GR)-mediated alleviation of inflammation by SP-8 was investigated by a combination of in vitro, in silico, and in vivo approaches. Molecular docking and cellular thermal shift assay suggested that SP-8 bound stably to the active site of GR via hydrogen bonding and hydrophobic interactions. SP-8 activated GR, induced GR nuclear translocation, and inhibited NF-κB pathway activation. Furthermore, SP-8 did not up-regulate the gene and protein expression of PEPCK and TAT in HepG2 cells, and it did not induce fat deposition like GC and has little effect on bone metabolism. Interestingly, SP-8 upregulated GR protein expression and did not cause GR phosphorylation at Ser211 in RAW264.7 cells. This work proved that SP-8 dissociated characteristics of transrepression and transactivation can be separated. In addition, the in vitro and in vivo anti-inflammatory effects of SP-8 were confirmed in LPS-induced RAW 264.7 cells and in a mouse model of DSS-induced ulcerative colitis, respectively. In conclusion, SP-8 might serve as a potential SGRM and might hold great potential for therapeutic use in inflammatory diseases., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We the undersigned declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We understand that the Corresponding Author is the sole contact for the Editorial process. She is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs., (Copyright © 2024. Published by Elsevier B.V.)

Gelidium sesquipedale is valued in the Spanish agar industry, but its production generates substantial waste, often discarded despite its nutritional and bioactive content. Subcritical water extraction (SWE) at 175 °C and 50 bar for 130 min was performed on this waste after agar extraction, comparing it to conventional ethanol extraction. The SWE extract exhibited superior nutritional profile, including proteins (170.6 ± 1.0 mg/g freeze-dried-extract ), essential amino acids (18.1%), carbohydrates (148.1 ± 0.3 mg/g freeze-dried-extract ), total phenolic content (57 ± 7 mg-EqGA/g freeze-dried-extract ), and also containing Maillard reaction compounds, such as 5-hydroxymethylfurfural, furfural, 2-furanmethanol, 1-(2-furanyl)-ethanone, and 5-methyl-2-furfural, influencing color, aroma and flavor. This extract showed better antioxidant and anti-inflammatory properties than the conventional extract, and higher xanthine oxidase, tyrosinase, and acetylcholinesterase inhibition activities. Toxicological assessment on human cells indicated the safety of the SWE extract. Therefore, SWE technology offers a promising method to valorize G. sesquipedale residue, yielding a bioactive and nutrient-rich extract suitable for food and nutraceutical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ectodermal mesenchymal stem cells-derived conditioned medium (EMSCs-CM) has been reported to protect against ulcerative colitis (UC) in mice, but its underlying mechanism in alleviating UC need to be further elucidated. Here, it is reported that EMSCs-CM could attenuate pro-inflammatory response of LPS-induced IEC-6 cells and regulate the polarization of macrophages towards anti-inflammatory type in vitro. Furthermore, PLGA microspheres prepared by the double emulsion method were constructed for oral delivery of EMSCs-CM (EMSCs-CM-PLGA), which are beneficial for colon-targeted adhesion of EMSCs-CM to the damaged colon mucosa. The results showed that orally-administered of EMSCs-CM-PLGA microspheres reduced inflammatory cells infiltration and maintained the intestinal mucosal barrier. Further investigation found that EMSCs-CM-PLGA microspheres treatment gradually inhibited the activation of NF-κB pathway to regulate M1/M2 polarization balance in colon tissue macrophages, thereby alleviating DSS-induced UC. These results of this study will provide a theoretical basis for clinical application of EMSCs-CM in UC repair., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Increasing evidence has demonstrated that coenzyme Q10 (CoQ10) exhibits a range of biological properties. Herein, we explored the protective effect and potential molecular mechanism of CoQ10 on lipopolysaccharide (LPS)-induced acute lung injury (ALI). We found that medium (10 mg/kg) and high (50 mg/kg) doses of CoQ10 ameliorated LPS (50 µg/µL)-induced ALI to varying degrees, as demonstrated by reduced lung coefficient, lower wet/dry weight lung tissue ratio, decreased bronchoalveolar lavage fluid protein concentration, less anatomical and histopathological damage to the lung, and increased expression of proteins related to lung epithelial barrier structure. CoQ10 also alleviated LPS-induced oxidative stress and inflammation mediated by NOD-like receptor protein 3 (NLRP3) by reducing the reactive oxygen species (ROS), malondialdehyde, and mitochondrial ROS concentrations, increasing superoxide dismutase, glutathione, and catalase activity, and decreasing NLRP3 expression at the protein and mRNA levels. Moreover, CoQ10 alleviated structural and functional damage to the mitochondria, inhibited mitochondrial fission, and promoted mitochondrial fusion, mainly by inhibiting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and Ser637. Correlation analysis revealed that mitochondrial fission (especially Drp1) was positively correlated with oxidative stress, NLRP3-mediated inflammation, and structural damage to the lung epithelial barrier. Molecular docking analysis showed that CoQ10 binds stably to Drp1, with a binding energy of -5.9 kcal/mol. Furthermore, the use of schaftoside (a Drp1 inhibitor) has further elucidated the mechanism of action of CoQ10. Together, these results suggest that CoQ10 alleviates LPS-induced ALI by regulating mitochondrial dynamics, attenuating oxidative stress, and decreasing NLRP3-medated inflammation, thereby promoting lung epithelial barrier structural remodeling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Cerebral ischemia-reperfusion injury (CI/RI) is a leading cause of disability and mortality worldwide, with limited therapeutic options available. Erianin, a natural compound derived from traditional Chinese medicine, has been reported to possess anti-inflammatory and neuroprotective properties. This study aimed to investigate the therapeutic potential of Erianin in CI/RI and elucidate its underlying mechanisms. Network pharmacology analysis predicted that Erianin could target the PI3K/AKT pathway, which are closely associated with CI/RI. In vivo experiments using a rat model of CI/RI demonstrated that Erianin treatment significantly alleviated neurological deficits, reduced infarct volume, and attenuated neuronal damage. Mechanistically, Erianin inhibited microglial cell polarization towards the pro-inflammatory M1 phenotype, as evidenced by the modulation of specific markers. Furthermore, Erianin suppressed the expression of pro-inflammatory cytokines and mediators, such as TNF-α, IL-6, and COX-2, while enhancing the production of anti-inflammatory factors, including Arg1, CD206, IL-4 and IL-10. In vitro studies using oxygen-glucose deprivation/reoxygenation (OGD/R)-stimulated microglial cells corroborated the anti-inflammatory and anti-apoptotic effects of Erianin. Notably, Erianin inhibited the NF-κB signaling pathway by inhibiting p65 phosphorylation and preventing the nuclear translocation of the p65 subunit. Collectively, these findings suggest that Erianin represents a promising therapeutic candidate for CI/RI by targeting microglial cell polarization and inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Liver inflammatory diseases are marked by serious complications. Notably, nicardipine (NCD) has demonstrated anti-inflammatory properties, but its benefits in liver inflammation have not been studied yet. However, the therapeutic efficacy of NCD is limited by its short half-life and low bioavailability. Therefore, we aimed to evaluate the potential of NCD-loaded chitosan nanoparticles (ChNPs) to improve its pharmacokinetic profile and hepatic accumulation. Four formulations of NCD-ChNPs were synthesized and characterized. The optimal formulation (NP2) exhibited a mean particle diameter of 172.6 ± 1.94 nm, a surface charge of +25.66 ± 0.93 mV, and an encapsulation efficiency of 88.86 ± 1.17 %. NP2 showed good physical stability as a lyophilized powder over three months. It displayed pH-sensitive release characteristics, releasing 77.15 ± 5.09 % of NCD at pH 6 (mimicking the inflammatory microenvironment) and 52.15 ± 3.65 % at pH 7.4, indicating targeted release in inflamed liver tissues. Pharmacokinetic and biodistribution studies revealed that NCD-ChNPs significantly prolonged NCD circulation time and enhanced its concentration in liver tissues compared to plain NCD. Additionally, the study investigated the protective effects of NCD-ChNPs in thioacetamide-induced liver injury in rats by modulating the NFκB/NLRP3/IL-1β signaling axis. NCD-ChNPs effectively inhibited NFκB activation, reduced NLRP3 inflammasome activation, and subsequent release of IL-1β, which correlated with improved hepatic function and reduced inflammation and oxidative stress. These findings highlight the potential of NCD-ChNPs as a promising nanomedicine strategy for the treatment of liver inflammatory diseases, warranting further investigation into their clinical applications, particularly in hypertensive patients with liver inflammatory conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Despite the high mortality associated with sepsis, effective and targeted treatments remain scarce. The use of conventional antibiotics such as TIENAM (imipenem and cilastatin sodium for injection, TIE) is challenging because of the increasing bacterial resistance, which diminishes their efficacy and leads to adverse effects. Our previous studies demonstrated that ulinastatin (UTI) exerts a therapeutic impact on sepsis by reducing systemic inflammation and modulating immune responses. In this study, we examined the possibility of administering UTI and TIE after inducing sepsis in a mouse model using cecal ligation and puncture (CLP). We assessed the rates of survival, levels of inflammatory cytokines, the extent of tissue damage, populations of immune cells, microbiota in ascites, and important signaling pathways. The combination of UTI and TIE significantly improved survival rates and reduced inflammation and bacterial load in septic mice, indicating potent antimicrobial properties. Notably, the survival rates of UTI+TIE-treated mice increased from 10 % to 75 % within 168 h compared to those of mice that were subjected to CLP. The dual treatment successfully regulated the levels of inflammatory indicators (interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]-α) and immune cell numbers by reducing B cells, natural killer cells, and TNFR2 + T reg cells and increasing CD8 + T cells. Additionally, the combination of UTI and TIE alleviated tissue damage, reduced bacterial load in the peritoneal cavity, and suppressed the NF-κB signaling pathway. Our findings indicate that UTI and TIE combination therapy can significantly enhance sepsis outcomes by reducing inflammation and boosting the immune system. The results offer a promising therapeutic approach for future sepsis treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Jingqian Su reports financial support was provided by National Natural Science Foundation of China. Jingqian Su reports financial support was provided by Natural Science Foundation of Fujian Province. Jingqian Su reports financial support was provided by Fujian Provincial Regional Development Project]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sepsis, characterized by high mortality rates, causes over 50 % of acute lung injury (ALI) cases, primarily due to the heightened susceptibility of the lungs during this condition. Suppression of the excessive inflammatory response is critical for improving the survival of patients with sepsis; nevertheless, no specific anti-sepsis drugs exist. Huperzine A (HupA) exhibits neuroprotective and anti-inflammatory properties; however, its underlying mechanisms and effects on sepsis-induced ALI have yet to be elucidated. In this study, we demonstrated the potential of HupA for treating sepsis and explored its mechanism of action. To investigate the in vivo impacts of HupA, a murine model of sepsis was induced through cecal ligation and puncture (CLP) in both wild-type (WT) and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice. Our results showed that HupA ameliorates sepsis-induced acute lung injury by activating the α7nAChR. We used the CLP sepsis model in wild-type and α7nAChR -/- mice and found that HupA significantly increased the survival rate through α7nAChR, reduced the pro-inflammatory cytokine levels and oxidative stress, ameliorated histopathological lung injury, altered the circulating immune cell composition, regulated gut microbiota, and promoted short-chain fatty acid production through α7nAChR in vivo. Additionally, HupA inhibited Toll-like receptor NF-κB signaling by upregulating the α7nAChR/protein kinase B/glycogen synthase kinase-3 pathways. Our data elucidate HupA's mechanism of action and support a "new use for an old drug" in treating sepsis. Our findings serve as a basis for further in vivo studies of this drug, followed by application to humans. Therefore, the findings have the potential to benefit patients with sepsis., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Despite the high mortality rate, sepsis lacks specific and effective treatment options. Conventional antibiotics, such as TIENAM (TIE; imipenem and cilastatin sodium for injection), face challenges owing to the emergence of bacterial resistance, which reduces their effectiveness and causes adverse effects. Addressing resistance and judicious drug use is crucial. Our research revealed that aloin (Alo) significantly boosts survival rates and reduces inflammation and bacterial load in mice with sepsis, demonstrating strong antimicrobial activity. Using a synergistic Alo + TIE regimen in a cecal ligation and puncture (CLP)-induced sepsis model, we observed a remarkable increase in survival rates from 10 % to 75 % within 72 h compared with the CLP group alone. This combination therapy also modulated inflammatory markers interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α, mitigated tissue damage, regulated immune cells by lowering NK, activated CD8 + and CD4 + T cells while increasing peritoneal macrophages, and decreased the bacterial load in the peritoneal cavity. We noted a significant shift in the abdominal cavity microbiota composition post-treatment, with a decrease in harmful bacteria, such as Lachnospiraceae&#95;NK4A136&#95;group, Klebsiella, Bacillus, and Escherichia, and an increase in beneficial bacteria, such as Lactobacillus and Mucispirillum. Our study emphasizes the efficacy of combining Alo with TIE to combat sepsis, and paves the way for further investigations and potential clinical applications aiming to overcome the limitations of TIE and enhance the therapeutic prospects of Alo., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jingqian Su reports financial support was provided by National Natural Science Foundation of China. Jingqian Su reports financial support was provided by Natural Science Foundation of Fujian Province. Jingqian Su reports financial support was provided by Fujian Provincial Regional Development Project., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ulcerative colitis (UC) is a chronic inflammatory disease that is increasing in prevalence globally. Senescence is characterized by a specific chronic, low-grade, "sterile" inflammatory state known as inflammaging, suggesting that senescence may exacerbate the severity of UC. However, the link between UC and senescence remains unclear. Valnemulin (VAL) is a semi-synthetic derivative of a naturally occurring diterpenoid antibiotic (pleuromutilin), which can inhibit peptidyl transferase. Studies investigating the potential of valnemulin to inhibit senescence and alleviate colitis are currently limited. In this study, we revealed that dextran sulfate sodium (DSS), an inducer of UC, induces senescence in both colon epithelial NCM460 cells and colon tissues. Additionally, VAL, identified from a compound library, exhibited robust anti-senescence activity in DSS-treated NCM460 cells. Identified in our study as an anti-senescence agent, VAL effectively mitigated DSS-induced UC and colonic senescence in mice. Through network pharmacology analysis and experimental validation, the potential signaling pathway (AMPK/NF-κB) for VAL in treating UC was identified. We discovered that DSS significantly inhibited the AMPK signaling pathway and activated the NF-κB signaling pathway. However, supplementation with VAL remarkably restored AMPK activity and inhibited the NF-κB signaling pathway, which led to the inhibition of senescence. In summary, our study demonstrated that DSS-induced UC stimulates the senescence of colonic tissues, and VAL can effectively alleviate DSS-induced colonic damage and reduce colonic senescence. Our research findings provide a new perspective for targeting anti-senescence in the treatment of UC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Melatonin (MEL) has shown positive effects in anti-inflammatory and anti-oxidative stress research. This study investigates whether MEL can positively impact bone loss induced by valproic acid (VPA) in rats. The study examines changes in MC3T3-E1 cell viability and osteogenic potential, along with osteoclast differentiation in RAW264.7 cells in the presence of VPA using CCK-8, ALP staining, AR staining, and TRAP staining. In vitro experiments reveal that VPA-induced inhibition of osteogenic differentiation and promotion of osteoclastic differentiation are linked to increased inflammation and oxidative stress. Furthermore, MEL has demonstrated the ability to reduce oxidative stress and inflammation, boost osteogenic differentiation, and inhibit osteoclast differentiation. Animal experiments confirm that MEL significantly increases SOD2 expression and decreases TNF-α expression, leading to the restoration of impaired bone metabolism, enhanced bone strength, and higher bone mineral density. The combined experimental results strongly suggest that MEL can enhance osteogenic activity in the presence of VPA by reducing inflammation and oxidative stress, impeding osteoclast differentiation, and alleviating bone loss in VPA-treated rat models., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Vietnamese people use mugwort (Artemisia vulgaris L.) to treat arthritis and gout. Our previous research shows that mugwort contains flavonoids, and its extract possesses antibacterial and anti-inflammatory activities. However, no publications have been on the xanthine oxidase inhibitory activity of mugwort and acute anti-inflammatory activity in vivo., Aim of the Study: The study aimed to verify the antioxidant, xanthine oxidase inhibitory, and anti-inflammatory capabilities of mugwort extract in vitro and in vivo, isolate phyto-compounds from potential bioactive fractions, and then evaluate their potential in inhibiting xanthine oxidase., Methods: According to established methods, the extract and the active flavonoids were obtained using different chromatographic techniques. DPPH, ABTS, reducing power, and H 2 O 2 elimination were used to evaluate antioxidant activity. The model of LPS-induced RAW264.7 cells was used to measure the inhibition of NO production. The carrageenan-induced paw oedema model was used to assess acute inflammation in mice. In vitro, xanthine oxidase inhibition assay was applied to investigate the effects of extract/compounds on uric acid production. Chemical structures were identified by spectral analysis., Results: The assessment of the acute inflammatory model in mice revealed that both the 96% ethanol and the 50% ethanol extracts significantly decreased oedema in the mice's feet following carrageenan-induced inflammation. 96% ethanol extract exhibited a better reduction in oedema at the low dose. The analysis revealed that the ethyl acetate fraction had the highest levels of total polyphenols and flavonoids. Additionally, this fraction demonstrated significant antioxidant activity in various assays, such as DPPH, ABTS, reducing power, and H 2 O 2 removal. Furthermore, it displayed the most potent inhibition of xanthine oxidase, an anti-inflammatory activity. Five phytochemicals were isolated and determined from the active fraction such as luteolin (1), rutin (2), apigenin (3), myricetin (4), and quercetin (5). Except for rutin, the other compounds demonstrated the ability to inhibit effective xanthine oxidase compared to standard (allopurinol). Moreover, quercetin (5) inhibited NO production (IC 50 21.87 μM)., Conclusion: The results indicate that extracts from A. vulgaris effectively suppressed the activity of xanthine oxidase and exhibited antioxidant and anti-inflammatory properties, potentially leading to a reduction in the production of uric acid in the body and eliminating ROS. The study identified mugwort extract and bioactive compounds derived from Artemisia vulgaris, specifically luteolin, apigenin, and quercetin, as promising xanthine oxidase inhibitors. These findings suggest that further development of these compounds is warranted. At the same time, the above results also strengthen the use of mugwort to treat gout disease in Vietnam., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The pathway of Janus-activated kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) (termed as JAK2/STAT3) plays an active role in stroke-related inflammation induced by ischemic stress. Gastrodin, the primary compound in Gastrodia elata Bl, has been identified for its notable neuroprotective effects and demonstrated to ameliorate cerebral ischemia-reperfusion but its exact mechanisms governing this defense are still unclear. This study aims to investigate whether gastrodin can regulate mitochondrial function via the JAK2/STAT3 pathway to limit cerebral ischemia-reperfusion. In vivo, gastrodin significantly reduced infarct volume, improved neurobiological function, attenuated neuronal apoptosis, oxidative stress, mitochondrial impairment, mtDNA leakage, and inflammatory responses. At the cellular level, gastrodin administration rescued OGD/R-induced cell apoptosis, oxidative stress, and mitochondrial dysfunction. Mechanistically, gastrodin notably suppressed Toll-like receptor 9 (TLR9) expression, important for the recognition of disrupted endogenous DNA to produce inflammatory reactions. Furthermore, gastrodin mitigated inflammation by inhibiting JAK2/STAT3 signaling, influencing inflammatory factors to aggravate inflammation. Notably, the effects of gastrodin were abolished by Coumermycin A1 (C-A1), a JAK2 agonist, validating the role of JAK2/STAT3 signaling. In summary, gastrodin enhances the protective effect against mitochondrial damage in ischemic stroke by inhibiting JAK2/STAT3 signaling. Gastrodin is a possible therapy for cerebral ischemia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) not only could cause abnormal lipid metabolism in the liver, but also could cause liver inflammation. Previous studies have shown that Polysaccharide of Atractylodes macrocephala Koidz (PAMK) could alleviate animal liver inflammatory damage and alleviate NAFLD in mice caused by high-fat diet(HFD), but regulation of liver inflammation caused by NAFLD has rarely been reported. In this study, an animal model of non-alcoholic fatty liver inflammation in the liver of mice was established to explore the protective effect of PAMK on the liver of mice. The results showed that PAMK could alleviate the abnormal increase of body weight and liver weight of mice caused by HFD, alleviate the abnormal liver structure of mice, reduce the level of oxidative stress and cytokine secretion in the liver of mice, and downregulate the mRNA expression of TLR4, MyD88, NF-κB and protein expression of P-IκB, P-NF-κB-P65, TLR4, MyD88, NF-κB in the liver. These results indicate that PAMK could alleviate hepatocyte fatty degeneration and damage, oxidative stress and inflammatory response of the liver caused by NAFLD in mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Inflammatory bowel disease (IBD) is a chronic condition characterized by inflammation of the digestive tract, whose exact cause remains unknown, and its prevalence is on the rise. This study investigated the effects of a walnut-derived peptide LPLLR (LP-5) on intestinal inflammation and metabolism in IBD mice. Metabolomics revealed that LP-5 regulated the levels of metabolites, such as thalsimidine, fumagillin, and geniposide, and LP-5 could regulate several signaling pathways, such as protein digestion and absorption, aminoacyl-tRNA biosynthesis, and ABC transporters. Additionally, LP-5 alleviated dextran sulfate sodium (DSS)-induced colitis by modulating autophagy and inflammasome pathways. Western blotting demonstrated that LP-5 reduced the expressions of NLRP3, Caspase-1, ASC and IL-1β, and increased the expressions of Beclin-1 and LC3-II/LC3-I, corresponding to activation of the AMPK/mTOR/ULK1 pathway. These findings suggested that LP-5 activated autophagy in vivo to suppress inflammation and modulate metabolic substances, highlighting potential implications for gut health and the development of functional foods containing LP-5., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Linoleic acid (LA) is an omega-6 polyunsaturated fatty acid. Conjugated linoleic acid (CLA) is a family of LA isomers that includes both a trans fatty acid and a cis fatty acid. Both fatty acids play a nutritional role in maintaining health. Inflammation is critical in the pathogenesis of many diseases, including cancer. This study found that the combination of LA and CLA (LA/CLA), each of which had no effect, had a strong anti-synergistic effect on inflammatory macrophage RAW264.7 cells in vitro. Cells were cultured in a DMEM containing fetal bovine serum with or without either LA, CLA, or a combination of LA/CLA. The composition of LA and CLA at a comparatively lower concentration synergistically suppressed cell growth, resulting in a reduction in cell number. The underlying mechanism of this effect was based on reduced levels of Ras, PI3K, Akt, MAPK, and mTOR and elevated levels of p21, p53, and Rb, which are associated with cell growth. In addition, the combination of LA and CLA at a lower concentration stimulated potential cell death associated with increased caspase-3 and cleaved caspase-3 levels. Notably, this composition synergistically suppressed the production of TNF-α, IL-6, and PGE2, which are a major mediator of inflammation, with lipopolysaccharide stimulation in RAW264.7 cells This effect was associated with decreased levels of COX-1, COX-2, and NF-κB p65. This study may provide a useful tool for treating inflammatory conditions with the composition of LA and CLA., Competing Interests: Declaration of competing interests All authors declare that they have no known competing financial interests or personal relationships that could be perceived as influencing the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Ethnopharmacological Relevance: In Mongolian medicine, Loulu flower (LLF), the dried inflorescence of Rhaponticum uniflorum (L.) DC. from the Compositae family, has been used to clear heat and relieve toxicity for millennia, particularly in the treatment of pneumonia., Aim of This Study: To reveal the effects of LLF on mice with lipopolysaccharide (LPS)-stimulated acute lung injury (ALI) and elucidate the underlying mechanisms., Materials and Methods: ALI was established in BALB/c mice via nasal drops administration of LPS (5 mg/kg). The mice were then orally administrated with various doses of LLF extracts and the positive drug dexamethasone (DEX, 5 mg/kg), once daily for seven consecutive days. Last day, after being stimulated with LPS for 6h, the mice were closed dislocation of cervical vertebra, the serum, bronchus alveolar lavage fluid (BALF) and lung tissue were put into the EP tube and stored at -80 °C for further analysis. The changes of histopathology were tested by hematoxylin and eosin stain (H&E), the levels of, IL-1β, IL-18, TNF-α and IL-4 in BALF and serum were measured by ELISA. The pathways related to the treatment of ALI were predicted by network pharmacology. The expression levels of TLR4/NF-κB and NLRP3 signaling pathway-associated proteins, COX-2 and ERK were tested by western blotting. The levels of P65 and NLRP3 in lung tissues were determined by immunofluorescence analysis., Results: LLF total extract and the extract parts could alleviate the inflammatory cell infiltration, thicken the alveolar walls in lung tissues, reduce the levels of IL-18, IL-1β in BALF, the TNF-α in both BALF and serum, meantime enhance the level of IL-4 in BALF and serum in mice with LPS-induced ALI. Our network pharmacology and comprehensive gene ontology analyses revealed the active constituents of LLF and the pathways, including TLR4/NF-κB, NLRP3 and MAPK signaling pathways, which play significant roles in ALI. Furthermore, both the total extract and its extraction portions suppressed the expressions of proteins related with the COX-2, p-ERK and TLR4/NF-κB signaling pathway (TLR4, p-IκB, p-p65), as well as the NLRP3 signaling pathway (NLRP3, cleaved caspase-1, caspase-1, IL-1β)., Conclusion: LLF could improve the pathological changes and reducing inflammatory reactions in mice induced by LPS. The mechanism may be related to the modulation of the TLR4/NLRP3 signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is the predominant cause of disability among elderly people worldwide and is characterized by cartilage degeneration and excessive bone formation. Phillyrin, derived from forsythia, is a key extract renowned for its pronounced antibacterial and anti-inflammatory effects. Forsythia, deeply integrated into traditional Oriental medicine, has historically been utilized for its various pharmacological effects, including antibacterial, anti-inflammatory, and hepato-protective properties. Nevertheless, the anti-inflammatory impact of phillyrin on the progression of osteoarthritis remains enigmatic. The objective of this research was to assess the anti-inflammatory and anti-aging properties of phillyrin in mouse chondrocytes induced by IL-1β, as well as to elucidate the fundamental mechanisms underlying the phenomenon at play. Additionally, the investigation extends to observing the impact of phillyrin by establishing a murine osteoarthritic model. The ultimate goal was to identify phillyrin as a potential antiosteoarthritic agent. This investigation employs a multifaceted approach. Initially, key action targets of phillyrin, along with its probable action pathways, were identified by molecular docking and network pharmacological techniques. These findings were subsequently confirmed through both in vivo and in vitro studies. Network pharmacological analysis revealed NFE2L2 (NRF2), NFKB1, TLR4, and SERPING1 as pivotal candidate targets for the treatment of osteoarthritis with phillyrin. Molecular docking revealed hydrogen bond interactions between phillyrin and Arg415, Arg483, Ser508, and Asn387 on the Nrf2 receptor, while electrostatic interactions occurred with residues Arg415 and Arg380. Experiments conducted in vitro indicated that phillyrin preconditioning hindered the IL-1β-induced expression of proinflammatory factors which included TNF-α, COX-2, IL-6, and iNOS. Furthermore, phillyrin counteracts the IL-1β-induced degradation of aggrecan and collagen II within the extracellular matrix (ECM). This protective action is caused by the inhibition of the NF-κB pathway by phillyrin. Additionally, the mitigation of chondrocyte aging by phillyrin was observed. Our investigation revealed that phillyrin mitigates inflammation and counteracts cartilage degeneration in osteoarthritis (OA) patients by suppressing inflammation in chondrocytes and impeding aging through suppression of the NF-κB pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Eleven compounds including caffeic acid (CA), 4 kinds of caffeoylquinic acid (CQA) and 6 kinds of dicaffeoylquinic acid (DCQA), were selected to evaluate the anti-inflammatory effectiveness using mouse primary peritoneal macrophages in the absence or presence of lipopolysaccharide (LPS). The optimal non-cytotoxic doses of each individual compound were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Pro-inflammatory (TNF-α, IL-1β, IL-6) and anti-inflammatory (IL-10) cytokines secreted by treated macrophages were analyzed using the enzyme-linked immunosorbent assay. Cytokine secretion profiles of each individual test sample at optimal non-cytotoxic doses were further analyzed using Principal Component Analysis (PCA). The results showed that CA and all selected CQAs exhibited lower cytotoxicity (IC 50 : >50 μmol/l). Both CA and 5-CQA were found to have the most significant contributions for inhibiting pro-inflammatory cytokines, but increasing anti-inflammatory cytokine secretions, evidencing that CA at 10 μmol/l and 5-CQA at 25 μmol/l can be qualified as potent anti-inflammatory agents for treating inflammation-related diseases., Competing Interests: Declaration of competing interest The authors declare that there is no known competing interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Plant vernacular names can provide clues about the popular use of a species in different regions and are valuable sources of information about the culture or vocabulary of a population. Several medicinal plants in Brazil have received names of medicines and brand-name products., Aim of the Study: The present work aimed to evaluate the chemical composition and pharmacological activity in the central nervous system of three species known popularly by brand names of analgesic, anti-inflammatory, antispasmodic, and digestive drugs., Materials and Methods: Hydroethanolic extracts of Alternanthera dentata (AD), Ocimum carnosum (OC), and Plectranthus barbatus (PB) aerial parts were submitted to phytochemical analysis by HPLC-PAD-ESI-MS/MS and evaluated in animal models at doses of 500 and 1000 mg/kg. Mice were tested on hot plate, acetic acid-induced writing, formalin-induced licking, and intestinal transit tests. Aspirin and morphine were employed as standard drugs., Results: The three extracts did not change the mice's response on the hot plate. Hydroethanolic extracts of AD and PB reduced the number of writhes and licking time, while OC was only effective on the licking test at dose of 1000 mg/kg. In addition, AD and OC reduced intestinal transit, while PB increased gut motility., Conclusions: Pharmacological tests supported some popular uses, suggesting peripheral antinociceptive and anti-inflammatory effects, while the phytochemical analysis showed the presence of several flavonoids in the three hydroethanolic extracts and steroids in PB, with some barbatusterol derivatives described for the first time in the species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Sangju Cold Granule (SJCG) is a classical traditional Chinese medicine (TCM) prescription described in "Item Differentiation of Warm Febrile Diseases". Historically, SJCG was employed to treat respiratory illnesses. Despite its popular usage, the alleviating effect of SJCG on influenza A virus infection and its mechanisms have not been fully elucidated., Aim of the Study: Influenza is a severe respiratory disease that threatens human health. This study aims to assess the therapeutic potential of SJCG and the possible molecular mechanism underlying its activity against influenza A virus in vitro and in vivo., Materials and Methods: Ultrahigh-performance liquid chromatography (UPLC)-Q-Exactive was used to identify the components of SJCG. The 50% cytotoxic concentration of SJCG in MDCK and A549 cells were determined using the CCK-8 assay. The activity of SJCG against influenza A virus H1N1 was evaluated in vitro using plaque reduction and progeny virus titer reduction assays. RT-qPCR was performed to obtain the expression levels of inflammatory mediators and the transcriptional regulation of RIG-I and MDA5 in H1N1-infected A549 cells. Then, the mechanism of SJCG effect on viral replication and inflammation was further explored by measuring the expressions of proteins of the RIG-I/NF-kB/IFN(I/III) signaling pathway by Western blot. The impact of SJCG was explored in vivo in an intranasally H1N1-infected BALB/c mouse pneumonia model treated with varying doses of SJCG. The protective role of SJCG in this model was evaluated by survival, body weight monitoring, lung viral titers, lung index, lung histological changes, lung inflammatory mediators, and peripheral blood leukocyte count., Results: The main SJCG chemical constituents were flavonoids, carbohydrates and glycosides, amino acids, peptides, and derivatives, organic acids and derivatives, alkaloids, fatty acyls, and terpenes. The CC 50 of SJCG were 24.43 mg/mL on MDCK cells and 20.54 mg/mL on A549 cells, respectively. In vitro, SJCG significantly inhibited H1N1 replication and reduced the production of TNF-α, IFN-β, IL-6, IL-8, IL-13, IP-10, RANTES, TRAIL, and SOCS1 in infected A549 cells. Intracellularly, SJCG reduced the expression of RIG-I, MDA5, P-NF-κB P65 (P-P65), P-IκBα, P-STAT1, P-STAT2, and IRF9. In vivo, SJCG enhanced the survival rate and decreased body weight loss in H1N1-infected mice. Mice with H1N1-induced pneumonia treated with SJCG showed a lower lung viral load and lung index than untreated mice. SJCG effectively alleviated lung damage and reduced the levels of TNF-α, IFN-β, IL-6, IP-10, RANTES, and SOCS1 in lung tissue. Moreover, SJCG significantly ameliorated H1N1-induced leukocyte changes in peripheral blood., Conclusions: SJCG significantly reduced influenza A virus and virus-mediated inflammation through inhibiting the RIG-I/NF-kB/IFN(I/III) signaling pathway. Thus, SJCG could provide an effective TCM for influenza treatment., Competing Interests: Declaration of Competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)