Gigantol ameliorates DSS-induced colitis via suppressing ß2 integrin mediated adhesion and chemotaxis of macrophage.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium, recognized as "Shihu" in traditional Chinese medicine, holds a rich history of medicinal utilization documented in the Chinese Pharmacopoeia. Ancient texts like "Shen Nong Ben Cao Jing" extol Dendrobium's virtues as a superior herbal medicine fortifying "Yin" and invigorating the five viscera. Dendrobium is extensively employed for the treatment of gastrointestinal inflammatory disorders, showcasing significant therapeutic efficacy, particularly against ulcerative colitis (UC), within the realm of Chinese ethnopharmacology. Dendrobium plays crucial pharmacological roles due to its rich content of polysaccharides, alkaloids, phenanthrenes, and bibenzyls. Gigantol, a prominent bibenzyl compound, stands out as one of the most vital active constituents within Dendrobium, the gigantol content of Dendrobium leaves can reach approximately 4.79 µg/g. Its significance lies in being recognized as a noteworthy anti-inflammatory compound derived from Dendrobium. AIM OF THE STUDY: Given the pivotal role of gigantol as a primary active substance in Dendrobium, the therapeutic potential of gigantol for gastrointestinal diseases remains enigmatic. Our present investigation aimed to evaluate the therapeutic effects of gigantol on dextran sulfate sodium (DSS)-induced colitis and reveal its potential mechanism in countering UC activity. MATERIALS AND METHODS: The protective efficacy of gigantol against colitis was assessed by examining the histopathological changes and conducting biochemical analyses of colon from DSS-challenged mice. Assessments focused on gigantol's impact on improving the intestinal epithelial barrier and its anti-inflammatory effects in colonic tissues of colitis mice. Investigative techniques included the exploration of the macrophage inflammatory signaling pathway via qPCR and Western blot analyses. In vitro studies scrutinized macrophage adhesion, migration, and chemotaxis utilizing transwell and Zigmond chambers. Furthermore, F-actin and Rac1 activation assays detailed cellular cytoskeletal remodeling. The potential therapeutic target of gigantol was identified and validated through protein binding analysis, competitive enzyme-linked immunosorbent assay (ELISA), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assay. The binding sites between gigantol and its target were predicted via molecular docking. RESULTS: Gigantol ameliorated symptoms of DSS-induced colitis, rectified damage to the intestinal barrier, and suppressed the production of pro-inflammatory cytokines in colonic tissues. Intriguingly, gigantol significantly curtailed NF-κB signaling activation in the colons of DSS-induced colitis mice. Notably, gigantol impaired the ß2 integrin-dependent adhesion and migratory capacity of RAW264.7 cells. Moreover, gigantol notably influenced the cytoskeleton remodeling of RAW264.7 cells by suppressing Vav1 phosphorylation and Rac1 activation. Mechanistically, gigantol interacted with ß2 integrin, subsequently diminishing binding affinity with intercellular adhesion molecule-1 (ICAM-1). CONCLUSIONS: In conclusion, these findings elucidate that gigantol ameliorates DSS-induced colitis by antagonizing ß2 integrin-mediated macrophage adhesion, migration, and chemotaxis, thus it may impede macrophage recruitment and infiltration into colonic tissues. This study suggests that gigantol shows promise as a viable candidate for clinical colitis therapy.

Effects of ß2 Integrins on Osteoclasts, Macrophages, Chondrocytes, and Synovial Fibroblasts in Osteoarthritis.

ß2 integrins are transmembrane receptors that exist widely in human immune cells and participate in pathological processes such as chronic inflammation, thrombosis, and malignant tumor formation. They mainly mediate intercellular adhesion, coordinate the ingestion of extracellular matrix components, and regulate cytoskeleton formation, thereby regulating cell signaling. Osteoarthritis (OA) is a chronic joint disease that causes joint pain and increases disease burden; it has a high prevalence among populations worldwide. Previous studies have reported that ß2 integrins are overexpressed in OA and may play an essential role in the occurrence of OA. The important roles of ß2 integrins in the maturation and differentiation of osteoclasts, the regulation of bone homeostasis, and the polarization and migration of macrophages have also been reported. The present review aims to highlight the role of ß2 integrins in OA pathogenesis and outline their potential for serving as therapeutic targets.

Prophylactic uses of integrin CD18-betaA peptide in a murine polymicrobial peritonitis model.

AIM: To evaluate the prophylactic properties of integrin CD18-betaA peptide in a murine model of abdominal polymicrobial peritonitis and sepsis. METHODS: Bacterial sepsis was induced in Institute of Cancer Research (ICR) mice by cecal ligation and puncture (CLP) surgery. Inflicted mice were then injected with either sterile saline or CD18-betaA peptide intraperitoneally at 2 h after surgery, and were sacrificed at 12 and 24 h after surgery. Blood samples were immediately collected, and analyzed for endotoxin activity and tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. Lungs and liver were studied for CD45+ leukocyte and CD3 mRNA content. Pulmonary expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM) and E-selectin was also determined. RESULTS: Intraperitoneal injection of CD18-betaA peptide significantly suppressed circulating endotoxin activity (P < 0.01) at 24 h, as well as serum levels of TNF-alpha (P < 0.05 at 12 and 24 h) and IL-6 (P < 0.01 at 12 h, P < 0.05 at 24 h) in CLP-inflicted mice. CD18-betaA peptide also abrogated leukocyte infiltration into liver and lungs as unveiled by reduced CD45+ leukocyte and CD3 mRNA contents. Furthermore, the peptide significantly reduced pulmonary expression of VCAM (P < 0.01 at 12 h, P < 0.001 at 24 h), E-selectin (P < 0.01 at 12 and 24 h), and ICAM-1 (P < 0.01 at 12 h, P < 0.001 at 24 h). These actions of CD18-betaA peptide collectively protected septic mice against lethality (P < 0.01). CONCLUSION: CD18-betaA peptide is a potent endotoxin antagonist that can protect surgical patients against sepsis-associated lethality.

Endotoxin-neutralizing peptides as gram-negative sepsis therapeutics.

Bacterial endotoxin [e.g. lipopolysaccharide (LPS)] can trigger systemic hyper-inflammatory that subsequently leads to multiple organ failure and lethality (gram-negative sepsis). This paper describes the development of endotoxin-neutralizing peptides that potentially treat sepsis. These peptides have been derived from bactericidal/permeability-increasing protein (BPIP), anti-microbial peptides, and leukocyte CD18 antigen and some of these peptides have been tested in clinical studies.

Mechanisms and pharmacological manipulation of eosinophil accumulation in vivo.

The presence of eosinophils and their products in tissues is frequently associated with the pathogenesis of allergic inflammation. A better understanding of how these cells are recruited from the microcirculation will help in the development of therapies targeted at allergic disorders. Here, Mauro Teixeira, Timothy Williams and Paul Hellewell describe the current concepts of eosinophil accumulation, examine the potential ways of modulating this process, and discuss whether antagonists of eosinophil-specific mediators or functional antagonists would be the preferred therapies.