caryophyllene and Colitis

Inflammatory bowel diseases (IBD) are the common health concern in populations across the world. Clinical evidence suggests that IBD, characterized by intestinal inflammation, is associated with neuronal manifestations to a greater extent. In this study, we have investigated the protective effects of Viphyllin™, a standardized black pepper (Piper nigrum) seed extract containing 30% β-caryophyllene against dextran sodium sulfate (DSS)-induced colitis in mice. Oral pretreatment of Viphyllin at the 50 mg and 100 mg/kg doses significantly reversed the clinical symptoms of colitis in mice. Viphyllin markedly inhibited NLRP3 inflammasome activation and improved barrier function in colon tissue. Viphyllin further mitigated the DSS-induced anxiety-like behavior in mice. Interestingly, Viphyllin improved brain antioxidant status and promoted neuronal cell survival in colitis model mice. In conclusion, our findings strongly support the health claims of Viphyllin as a functional ingredient to deal with IBD and related neuronal symptoms. PRACTICAL APPLICATIONS: Prevalence of inflammatory bowel diseases is not uncommon in the modern lifestyle. Gut health is associated with neurological disorders that contribute substantially to the deterioration of quality of life and socioeconomic development. In this research work, the protective action of a black pepper seed extract standardized to 30% β-caryophyllene (Viphyllin) is evaluated against Dextran sodium sulfate-induced experimental colitis model. Here we have demonstrated the beneficial role of Viphyllin in mitigating intestinal inflammation as a function of NLRP3 inflammasome inhibition. Further, the extract improves intestinal barrier function. In an important aspect of the study, we have provided the data on the effect of Viphyllin on neurological symptoms and brain health in colitis model mice.

Topics: Animals; Antioxidants; Anxiety; Colitis; Dextran Sulfate; Inflammasomes; Inflammation; Inflammatory Bowel Diseases; Mice; Nigella sativa; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Piper nigrum; Plant Extracts; Polycyclic Sesquiterpenes; Quality of Life; Seeds; Sulfates

Ulcerative colitis is an inflammatory bowel disease characterized by symptoms such as abdominal pain, diarrhea, bleeding, and weight loss. Ulcerative colitis is typically treated with anti-inflammatory drugs; however, these drugs are associated with various side effects, limiting their use. β-Caryophyllene (BCP), a natural compound derived from cloves, has antioxidant, antibacterial, and anti-inflammatory activities. In this study, we aimed to investigate the effects of BCP on colitis in a dextran sulfate sodium (DSS)-induced colitis mouse model. BCP was administered for seven days, followed by 2.5% DSS for additional seven days to induce colitis. Changes in stool weight, recovery of gut motility, colon length, colon histology, myeloperoxidase activity, inflammatory cytokines (TNF-α, IL-1β, IL-6, IgA, and IgG), and the gut microbiota were observed. Administration of BCP increased stool weight, restored gut motility, and considerably increased colon length compared to those in the untreated colitis mouse model. In addition, the amount of mucin and myeloperoxidase activity in the colon increased, whereas the concentrations of IL-1β, IL-6, and TNF-α decreased following the administration of BCP. Furthermore, BCP reduced the abundance of Proteobacteria which can cause intestinal immune imbalance. These results suggest that BCP has a potential to be developed as a preventive agent for colitis.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Inflammation; Interleukin-6; Mice; Peroxidase; Syzygium; Tumor Necrosis Factor-alpha

Macrophage infiltration is one of the main pathological features of ulcerative colitis (UC) and ferroptosis is a type of nonapoptotic cell death, connecting oxidative stress and inflammation. However, whether ferroptosis occurs in the colon macrophages of UC mice and whether targeting macrophage ferroptosis is an effective approach for UC treatment remain unclear. The present study revealed that macrophage lipid peroxidation was observed in the colon of UC mice. Subsequently, we screened several main components of essential oil from Artemisia argyi and found that β-caryophyllene (BCP) had a good inhibitory effect on macrophage lipid peroxidation. Additionally, ferroptotic macrophages were found to increase the mRNA expression of tumor necrosis factor alpha (Tnf-α) and prostaglandin-endoperoxide synthase 2 (Ptgs2), while BCP can reverse the effects of inflammation activated by ferroptosis. Further molecular mechanism studies revealed that BCP activated the type 2 cannabinoid receptor (CB2R) to inhibit macrophage ferroptosis and its induced inflammatory response both in vivo and in vitro. Taken together, BCP potentially ameliorated experimental colitis inflammation by inhibiting macrophage ferroptosis. These results revealed that macrophage ferroptosis is a potential therapeutic target for UC and identified a novel mechanism of BCP in ameliorating experimental colitis.

Topics: Animals; Colitis; Colitis, Ulcerative; Dextran Sulfate; Ferroptosis; Inflammation; Mice; Polycyclic Sesquiterpenes

Cannabinoid receptor 2 (CB2) activation is suggested to trigger the peroxisome proliferator-activated receptor-γ (PPARγ) pathway, and agonists of both receptors improve colitis. Recently, the plant metabolite (E)-β-caryophyllene (BCP) was shown to bind to and activate CB2. In this study, we examined the anti-inflammatory effect of BCP in dextran sulfate sodium (DSS)-induced colitis and analyzed whether this effect was mediated by CB2 and PPARγ. Oral treatment with BCP reduced disease activity, colonic macro- and microscopic damage, myeloperoxidase and N-acetylglucosaminidase activities, and levels and mRNA expression of colonic tumor necrosis factor-α, IL-1β, interferon-γ, and keratinocyte-derived chemokine. BCP treatment also inhibited the activation of extracellular signal-regulated kinase 1/2, nuclear factor κB, IκB-kinase α/β, cAMP response element binding and the expression of caspase-3 and Ki-67. Moreover, BCP enhanced IL-4 levels and forkhead box P3 mRNA expression in the mouse colon and reduced cytokine levels (tumor necrosis factor-α, keratinocyte-derived chemokine, and macrophage-inflammatory protein-2) in a culture of macrophages stimulated with lipopolysaccharide. The use of the CB2 antagonist AM630 or the PPARγ antagonist GW9662 significantly reversed the protective effect of BCP. Confirming our results, AM630 reversed the beneficial effect of BCP on pro-inflammatory cytokine expression in IEC-6 cells. These results demonstrate that the anti-inflammatory effect of BCP involves CB2 and the PPARγ pathway and suggest BCP as a possible therapy for the treatment of inflammatory bowel disease.

Topics: Animals; Caspase 3; Caspase Inhibitors; Claudin-4; Colitis; Colon; Cyclic AMP Response Element-Binding Protein; Cytokines; Dextran Sulfate; Extracellular Signal-Regulated MAP Kinases; I-kappa B Kinase; Inflammation Mediators; Ki-67 Antigen; Lipopolysaccharides; Macrophage Activation; Macrophages; Membrane Proteins; Mice; NF-kappa B; Oxazolone; Polycyclic Sesquiterpenes; PPAR gamma; Receptor, Cannabinoid, CB2; Sesquiterpenes; Signal Transduction

beta-Caryophyllene (BCP), a naturally occurring plant sesquiterpene, was examined for anti-inflammatory activity in a mouse model of experimental colitis induced by dextran sulfate sodium (DSS). Colitis was induced by exposing male BALB/c mice to 5% DSS in drinking water for 7 days. BCP in doses of 30 and 300 mg/kg was administered orally once a day, beginning concurrently with exposure to DSS. The body weight and colon length were measured, and histological damage and myeloperoxidase (MPO) activity as well as inflammatory cytokines were assessed in both serum and colonic tissue after 7 days of treatment with DSS. The DSS treatment damaged the colonic tissue, increased MPO activity and inflammatory cytokines, lowered the body weight, and shortened the length of the colon. Oral administration of BCP at 300 mg/kg significantly suppressed the shortening of colon length and slightly offset the loss of body weight. BCP treatment (300 mg/kg) also significantly reduced the inflammation of colon and reversed the increase in MPO activity that had been induced by exposure to DSS. Further, BCP significantly suppressed the serum level of IL-6 protein (a 55% reduction) as well as the level of IL-6 mRNA in the tissue. These results demonstrate that BCP ameliorates DSS-induced experimental colitis, and may be useful in the prevention and treatment of colitis.

Topics: Animals; Body Weight; Colitis; Cytokines; Dextran Sulfate; Enzyme-Linked Immunosorbent Assay; Indicators and Reagents; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; Organ Size; Peroxidase; Polycyclic Sesquiterpenes; Reverse Transcriptase Polymerase Chain Reaction; Sesquiterpenes