{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:23:08Z","timestamp":1785424988484,"version":"3.56.0"},"reference-count":51,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2025-24523909"],"award-info":[{"award-number":["RS-2025-24523909"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"award":["RS-2025-24523909"],"award-info":[{"award-number":["RS-2025-24523909"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Palmatine chloride (berbericinine, C21H22ClNO4) is a protoberberine alkaloid found in several plants, including Rhizoma Coptidis, Cortex Phellodendri, Rhizoma Corydalis, Guduchi (Tinospora cordifolia), and Tinospora sagittata roots. Palmatine chloride (PA) is known as an inhibitor of dopamine generation. However, its effect on endoplasmic reticulum (ER) stress-related macrophage activation caused by endotoxin (lipopolysaccharide) is not yet well known. In this study, the effects of PA on pyroptotic responses of mouse macrophages (RAW 264.7) activated by endotoxin were investigated using Griess reagent assay for nitric oxide (NO) production, fluo-4 assay for cytosolic calcium release, dihydrorhodamine 123 assay for hydrogen peroxide production, multiple cytokine assay for cytokine production, real-time PCR for inflammatory gene transcriptions, and flow cytometry assay for p38 MAPK activation. Preliminary experiments using THP-1 human monocytic cells demonstrated that PA was not cytotoxic and significantly reduced basal NO production. Results revealed that PA significantly reduced excessive production levels of NO, hydrogen peroxide, pro-inflammatory cytokines (such as interleukin (IL)-6, CCL3 (MIP-1\u03b1), and CSF2 (GM-CSF)), and cytosolic calcium release in endotoxin-stimulated RAW 264.7, but significantly increased the production of anti-inflammatory cytokine IL-10. PA inhibited endotoxin-induced transcripts of Chop, Stat1, Fas, and c-Fos in activated RAW 264.7. It also decreased p38 MAPK phosphorylation and level of Fas in RAW 264.7 stimulated by endotoxin. To further interpret these findings, a network pharmacology-informed analysis based on large-scale literature mining was performed, supporting the multi-target regulatory role of PA in ER stress-related pathways. Briefly, PA exerts anti-inflammatory effects on endotoxin-stimulated RAW 264.7 via the calcium-CHOP pathway, consequently reducing endotoxin-induced production of pro-inflammatory mediators (NO, cytokines, etc.) and relieving ER stress-related pyroptotic cascade.<\/jats:p>","DOI":"10.3390\/ijms27135704","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T05:48:16Z","timestamp":1782366496000},"page":"5704","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anti-Inflammatory Effect of Palmatine Chloride on Lipopolysaccharide-Stimulated RAW 264.7 Mouse Macrophages via Calcium-CHOP Pathway"],"prefix":"10.3390","volume":"27","author":[{"given":"Young-Jin","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Pathology, College of Korean Medicine, Gachon University, Seongnam 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8752-4365","authenticated-orcid":false,"given":"Wansu","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Korean Medicine, Gachon University, Seongnam 13120, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"541340","DOI":"10.1155\/2014\/541340","article-title":"Multidrug Resistance: An Emerging Crisis","volume":"2014","author":"Tanwar","year":"2014","journal-title":"Interdiscip. Perspect. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"197","DOI":"10.3390\/jox11040013","article-title":"Review on Multiple Facets of Drug Resistance: A Rising Challenge in the 21st Century","volume":"11","author":"Saha","year":"2021","journal-title":"J. Xenobiot."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6928","DOI":"10.3390\/molecules27206928","article-title":"Natural Compounds in the Battle Against Microorganisms-Linalool","volume":"27","author":"Maczka","year":"2022","journal-title":"Molecules"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Feitosa, B.F., de Alcantara, C.M., de Lima, A.B.S., Silva, A.S., Araujo, A.D.S., Cavalcanti, M.T., Mori, E., Araujo, I.M., de Farias, P.A.M., and Wilairatana, P. (2022). Bioactive Natural Products for Chemical Control of Microorganisms: Scientific Prospecting (2001\u20132021) and Systematic Review. Molecules, 27.","DOI":"10.3390\/molecules27185917"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3577","DOI":"10.3390\/nu12113577","article-title":"Rubi Fructus Water Extract Alleviates LPS-Stimulated Macrophage Activation Via an ER Stress-Induced Calcium\/CHOP Signaling Pathway","volume":"12","author":"Kim","year":"2020","journal-title":"Nutrients"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kim, Y.J., Lee, J.Y., Kim, H.J., Kim, D.H., Lee, T.H., Kang, M.S., and Park, W. (2018). Anti-Inflammatory Effects of Angelica Sinensis (Oliv.) Diels Water Extract on RAW 264.7 Induced with Lipopolysaccharide. Nutrients, 10.","DOI":"10.3390\/nu10050647"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"An, H., Lee, J., and Park, W. (2022). Baicalin Modulates Inflammatory Response of Macrophages Activated by LPS Via Calcium-CHOP Pathway. Cells, 11.","DOI":"10.3390\/cells11193076"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1096\/fasebj.8.2.8119492","article-title":"Bacterial Endotoxin: Molecular Relationships of Structure to Activity and Function","volume":"8","author":"Rietschel","year":"1994","journal-title":"FASEB J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1574-695X.1996.tb00127.x","article-title":"Molecular Mimicry of Host Structures by Bacterial Lipopolysaccharides and its Contribution to Disease","volume":"16","author":"Moran","year":"1996","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1089\/ars.2009.2469","article-title":"Macrophage Apoptosis in Atherosclerosis: Consequences on Plaque Progression and the Role of Endoplasmic Reticulum Stress","volume":"11","author":"Tabas","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1161\/CIRCRESAHA.110.224766","article-title":"The Role of Endoplasmic Reticulum Stress in the Progression of Atherosclerosis","volume":"107","author":"Tabas","year":"2010","journal-title":"Circ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1007\/s00109-019-01787-9","article-title":"Regulation and Role of the ER Stress Transcription Factor CHOP in Alveolar Epithelial Type-II Cells","volume":"97","author":"Klymenko","year":"2019","journal-title":"J. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"175352","DOI":"10.1016\/j.ejphar.2022.175352","article-title":"Quercetin Protects Against LPS-Induced Lung Injury in Mice Via SIRT1-Mediated Suppression of PKM2 Nuclear Accumulation","volume":"936","author":"Chen","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10124","DOI":"10.3390\/ijms231710124","article-title":"Anti-Inflammation and Anti-Pyroptosis Activities of Mangiferin Via Suppressing NF-kappaB\/NLRP3\/GSDMD Signaling Cascades","volume":"23","author":"Feng","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1083\/jcb.200904060","article-title":"Role of ERO1-Alpha-Mediated Stimulation of Inositol 1,4,5-Triphosphate Receptor Activity in Endoplasmic Reticulum Stress-Induced Apoptosis","volume":"186","author":"Li","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"E40","DOI":"10.1111\/j.1749-6632.2009.04957.x","article-title":"Macrophage Apoptosis in Advanced Atherosclerosis","volume":"1173","author":"Tabas","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1172\/JCI38857","article-title":"Calcium\/calmodulin-Dependent Protein Kinase II Links ER Stress with Fas and Mitochondrial Apoptosis Pathways","volume":"119","author":"Timmins","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_18","first-page":"4399","article-title":"Regulation of the NLRP3 Inflammasome and Macrophage Pyroptosis by the p38 MAPK Signaling Pathway in a Mouse Model of Acute Lung Injury","volume":"18","author":"Li","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1126\/science.272.5266.1347","article-title":"Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase","volume":"272","author":"Wang","year":"1996","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6245","DOI":"10.4049\/jimmunol.176.10.6245","article-title":"C\/EBP Homologous Protein (CHOP) is Crucial for the Induction of Caspase-11 and the Pathogenesis of Lipopolysaccharide-Induced Inflammation","volume":"176","author":"Endo","year":"2006","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Krupkova, O., Sadowska, A., Kameda, T., Hitzl, W., Hausmann, O.N., Klasen, J., and Wuertz-Kozak, K. (2018). P38 MAPK Facilitates Crosstalk between Endoplasmic Reticulum Stress and IL-6 Release in the Intervertebral Disc. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01706"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"753","DOI":"10.2174\/1566524043359944","article-title":"Inflammatory Modulation of Hepatocyte Apoptosis by Nitric Oxide: In Vivo, in Vitro, and in Silico Studies","volume":"4","author":"Vodovotz","year":"2004","journal-title":"Curr. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"L793","DOI":"10.1152\/ajplung.00266.2003","article-title":"Roles of iNOS and nNOS in Sepsis-Induced Pulmonary Apoptosis","volume":"286","author":"Rudkowski","year":"2004","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.freeradbiomed.2006.05.011","article-title":"Nitric Oxide and Reactive Nitrogen Species in Airway Epithelial Signaling and Inflammation","volume":"41","author":"Bove","year":"2006","journal-title":"Free Radic. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1616S","DOI":"10.1093\/jn\/137.6.1616S","article-title":"Regulation of Nitric Oxide Synthesis and Apoptosis by Arginase and Arginine Recycling","volume":"137","author":"Mori","year":"2007","journal-title":"J. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1093\/jb\/mvp189","article-title":"Molecular Mechanisms of the LPS-Induced Non-Apoptotic ER Stress-CHOP Pathway","volume":"147","author":"Nakayama","year":"2010","journal-title":"J. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1161\/01.ATV.0000223900.67024.15","article-title":"Nitric Oxide and Endoplasmic Reticulum Stress","volume":"26","author":"Gotoh","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12343","DOI":"10.1074\/jbc.M107988200","article-title":"Nitric Oxide-Induced Apoptosis in RAW 264.7 Macrophages is Mediated by Endoplasmic Reticulum Stress Pathway Involving ATF6 and CHOP","volume":"277","author":"Gotoh","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zeeshan, H.M.A., Lee, G.H., Kim, H., and Chae, H. (2016). Endoplasmic Reticulum Stress and Associated ROS. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17030327"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.molcel.2004.08.025","article-title":"Degradation of Misfolded Proteins Prevents ER-Derived Oxidative Stress and Cell Death","volume":"15","author":"Haynes","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18525","DOI":"10.1073\/pnas.0809677105","article-title":"Antioxidants Reduce Endoplasmic Reticulum Stress and Improve Protein Secretion","volume":"105","author":"Malhotra","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"19794","DOI":"10.1073\/pnas.0609671104","article-title":"Combinatorial Pattern Recognition Receptor Signaling Alters the Balance of Life and Death in Macrophages","volume":"103","author":"Seimon","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0966-842X(00)01936-3","article-title":"Pro-Inflammatory Programmed Cell Death","volume":"9","author":"Cookson","year":"2001","journal-title":"Trends Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1111\/imr.12287","article-title":"Pyroptotic Cell Death Defends Against Intracellular Pathogens","volume":"265","author":"Jorgensen","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"151884","DOI":"10.1016\/j.imbio.2019.11.019","article-title":"Research Progresses of Molecular Mechanism of Pyroptosis and its Related Diseases","volume":"225","author":"Gong","year":"2020","journal-title":"Immunobiology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s10787-012-0141-9","article-title":"Involvement of p38 MAPK-Dependent Activator Protein (AP-1) Activation in Modulation of Gastric Mucosal Inflammatory Responses to Helicobacter Pylori by Ghrelin","volume":"21","author":"Slomiany","year":"2013","journal-title":"Inflammopharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.jhep.2009.03.007","article-title":"Signalling Pathways in Alcohol-Induced Liver Inflammation","volume":"50","author":"Mandrekar","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1038\/sj.onc.1204381","article-title":"The Mammalian Jun Proteins: Redundancy and Specificity","volume":"20","author":"Gerald","year":"2001","journal-title":"Oncogene"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"11298","DOI":"10.1038\/s41598-021-90752-z","article-title":"Berberine Modulates Hyper-Inflammation in Mouse Macrophages Stimulated with Polyinosinic-Polycytidylic Acid Via Calcium-CHOP\/STAT Pathway","volume":"11","author":"Kim","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.biochi.2019.04.008","article-title":"Palmatine: A Review of its Pharmacology, Toxicity and Pharmacokinetics","volume":"162","author":"Long","year":"2019","journal-title":"Biochimie"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/ptr.6504","article-title":"Palmatine: A Review of Pharmacological Properties and Pharmacokinetics","volume":"34","author":"Tarabasz","year":"2020","journal-title":"Phytother. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4963","DOI":"10.2147\/DDDT.S280520","article-title":"Palmatine as an Agent Against Metabolic Syndrome and its Related Complications: A Review","volume":"14","author":"Ekeuku","year":"2020","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ativui, S., Danquah, C.A., Ossei, P.P.S., and Ofori, M. (2022). Palmatine Attenuates Metastatic Lung Colonization of Triple Negative Breast Cancer Cells. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.853230"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s11418-016-1057-2","article-title":"Gastroprotective Effect of Palmatine Against Acetic Acid-Induced Gastric Ulcers in Rats","volume":"71","author":"Wang","year":"2017","journal-title":"J. Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.phrs.2018.09.010","article-title":"Palmatine Ameliorated Murine Colitis by Suppressing Tryptophan Metabolism and Regulating Gut Microbiota","volume":"137","author":"Zhang","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"491","DOI":"10.3892\/mmr.2016.5285","article-title":"Palmatine from Mahonia Bealei Attenuates Gut Tumorigenesis in ApcMin\/+ Mice Via Inhibition of Inflammatory Cytokines","volume":"14","author":"Ma","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1080\/13880209.2019.1577466","article-title":"Coptidis Rhizoma: A Comprehensive Review of its Traditional Uses, Botany, Phytochemistry, Pharmacology and Toxicology","volume":"57","author":"Wang","year":"2019","journal-title":"Pharm. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7621929","DOI":"10.1155\/2019\/7621929","article-title":"Phellodendri Cortex: A Phytochemical, Pharmacological, and Pharmacokinetic Review","volume":"2019","author":"Sun","year":"2019","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.intimp.2016.02.029","article-title":"Chondroprotective effects of palmatine on osteoarthritis in vivo and in vitro: A possible mechanism of inhibiting the Wnt\/\u03b2-catenin and Hedgehog signaling pathways","volume":"34","author":"Zhou","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1211\/jpp.61.05.0014","article-title":"Identification of in-vivo and in-vitro metabolites of palmatine by liquid chromatography-tandem mass spectrometry","volume":"61","author":"Yang","year":"2009","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1007\/s10753-013-9703-2","article-title":"Anti-inflammatory activity of baicalein in LPS-stimulated RAW264.7 macrophages via estrogen receptor and NF-\u03baB-dependent pathways","volume":"36","author":"Fan","year":"2013","journal-title":"Inflammation"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5704\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T04:10:44Z","timestamp":1782965444000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5704"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,24]]},"references-count":51,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135704"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135704","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,24]]}}}