kirenol and Inflammation

Kirenol, a potential natural diterpenoid molecule, is mainly found in

Topics: Animals; Anti-Inflammatory Agents; Biological Products; Cytokines; Diterpenes; Drug Design; Drug Development; Humans; Inflammation

Kirenol is a bioactive substance isolated from Herba Siegesbeckiae. Although the anti-inflammatory activity of kirenol has been well documented, its role in autophagy remains unknown. The present study aimed to investigate the protective role of kirenol on inflammation challenged by lipopolysaccharide (LPS) in acute lung injury (ALI) cell and mouse models and unravel the underlying mechanisms, with a particular focus on autophagy. For this purpose, an ALI cell and mouse models were established, and the effects of kirenol on the expression of molecules related to inflammation and autophagy were examined. The present results revealed that kirenol could significantly inhibit inflammatory cytokines secretion in cells and in the mice injured by LPS; this effect may be attributed to enhanced autophagy as evidenced by the up-regulation of LC3-II and the down-regulation of p62 both in vitro and in vivo. Phosphorylated AMPK and ULK1 increased, while phosphorylated mTOR decreased in the kirenol-treated ALI cell model. Moreover, inhibition of autophagy using AMPK inhibitor or 3-MA or chloroquine (CQ) reversed the anti-inflammatory and autophagy-enhancement effects of kirenol exposure in vitro, indicating that kirenol could enhance autophagy by activating the AMPK-mTOR-ULK1 pathway. The results of RNA sequencing suggested that kirenol was strongly related to the biological functions of acute inflammatory response and the AMPK signaling pathway. Further in vivo ALI mouse model studies demonstrated the protective role of kirenol against lung inflammation, such as improved histopathology, decreased lung edema, and leukocyte infiltration were abolished by 3-MA. These findings implicate that kirenol can inhibit LPS-induced inflammation via the AMPK-mTOR-ULK1 autophagy pathway.

Topics: Acute Lung Injury; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Autophagy; Autophagy-Related Protein-1 Homolog; Inflammation; Lipopolysaccharides; Mice; TOR Serine-Threonine Kinases

This present findings hypothesized the modulatory effects of kirenol on expression pattern of cell proliferative and inflammatory markers during DMBA induced HBP carcinogenesis. The machinery pathways for chemomodulatory effect of kirenol was investigated by analyzing the levels of antioxidants histological changes, lipid peroxidation and molecular expression pathway of PCNA, NF-κB in the DMBA only painted HBPC. Oral cancer was developed in the HBP model by DMBA (0.5%) three times a week for 14th weeks. We analyzed body weight with deregulated molecular expressions pattern of PCNA and NF-κB was noticed in the DMBA induced hamsters compared to control hamsters. Oral administration of kirenol 30 mg/kg bw, to DMBA induced hamster models reverted the activity of the biochemical markers in Group 4. Besides, tumor tissues of hamsters receive antioxidant capability from kirenol exclaimed significant modifications in DMBA induced causes: inhibits cell proliferation (inhibits PCNA expression) and suppresses inflammation (decreased NF-κB expression) of markers. Taken together, the protective effect of that kirenol an augmenting inflammation of the started cells and exhibited antiproliferative, anti-inflammatory, antilipid peroxidative and restores the xenobiotic enzymes levels (phase I and II) system and enhances antioxidant properties in oral carcinoma hamsters, in which turn, is reflected diminished tumor burden, volume, and multiplicity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antioxidants; Biomarkers; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell; Cell Proliferation; Cricetinae; Diterpenes; Epithelial Cells; Inflammation; Lipid Peroxidation; Male; Mesocricetus; Mouth Neoplasms; NF-kappa B

Diabetic cardiomyopathy is characterized by diabetes-induced myocardial abnormalities, accompanied by inflammatory response and alterations in inflammation-related signalling pathways. Kirenol, isolated from Herba Siegesbeckiae, has potent anti-inflammatory properties. In this study, we aimed to investigate the cardioprotective effect of kirenol against DCM and underlying the potential mechanisms in a type 2 diabetes mellitus model. Kirenol treatment significantly decreased high glucose-induced cardiofibroblasts proliferation and increased the cardiomyocytes viability, prevented the loss of mitochondrial membrane potential and further attenuated cardiomyocytes apoptosis, accompanied by a reduction in apoptosis-related protein expression. Kirenol gavage could affect the expression of pro-inflammatory cytokines in a dose-dependent manner but not lower lipid profiles, and only decrease fasting plasma glucose, fasting plasma insulin and mean HbA1c levels in high-dose kirenol-treated group at some time-points. Left ventricular dysfunction, hypertrophy, fibrosis and cell apoptosis, as structural and functional abnormalities, were ameliorated by kirenol administration. Moreover, in diabetic hearts, oral kirenol significantly attenuated activation of mitogen-activated protein kinase subfamily and nuclear translocation of NF-κB and Smad2/3 and decreased phosphorylation of IκBα and both fibrosis-related and apoptosis-related proteins. In an Electrophoretic mobility shift assay, the binding activities of NF-κB, Smad3/4, SP1 and AP-1 in the nucleus of diabetic myocardium were significantly down-regulated by kirenol treatment. Additionally, high dose significantly enhanced myocardial Akt phosphorylation without intraperitoneal injection of insulin. Kirenol may have potent cardioprotective effects on treating for the established diabetic cardiomyopathy, which involves the inhibition of inflammation and fibrosis-related signalling pathways and is independent of lowering hyperglycaemia, hyperinsulinemia and lipid profiles.

Topics: Animals; Biomarkers; Blood Glucose; Body Weight; Cell Death; Cell Proliferation; Cell Survival; Collagen; Cytokines; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diterpenes; Fibroblasts; Fibrosis; Glucose; Inflammation; Male; Mitogen-Activated Protein Kinases; Myocardium; Myocytes, Cardiac; NF-KappaB Inhibitor alpha; Phosphorylation; Protein Binding; Proto-Oncogene Proteins c-akt; Rats; Smad Proteins; Ventricular Remodeling

Rheumatoid arthritis is characterized by the imbalance of T cells, which leads to increased pro-inflammatory and reduced anti-inflammatory cytokines. Modulating the balance among T cells is crucial for the treatment of RA. Kirenol is a major diterpenoid components of Herba Siegesbeckiae, which has been applied for arthritic therapy for centuries. Since prior research showed Kirenol exhibited anti-inflammatory effect in rats, in this study we have evaluated the effect and mechanism of bioactive Kirenol in a rat model of collagen-induced arthritis (CIA) on modulation of T cells. After immunization with bovine type II collagen (CII), Wistar rats were orally administered saline (CIA group), 2 mg/kg Kirenol or 2 mg/kg prednisolone daily for 30 days. The severity of arthritis was clinically and histologically assessed. The numbers of CD4⁺CD25⁺Foxp3⁺ T regulatory cells (Tregs) and IFNγ⁺CD4⁺ and IL4⁺CD4⁺ T cells were determined by flow cytometry, the mRNA expression level of Foxp3 was quantified by RT-PCR, cytokine levels were measured by ELISA and CII-induced cell proliferation was quantified in vitro. Kirenol significantly delayed the occurrence and reduced the disease severity of CIA. Histological analysis confirmed Kirenol suppressed joint inflammation and inhibited cartilage and bone destruction, compared to the CIA group. Kirenol also upregulated the mRNA expression of Foxp3, increased the numbers of CD4⁺CD25⁺Foxp3⁺ and IL4⁺CD4⁺ T cells, and reduced the number of IFNγ⁺CD4⁺ T cells. Kirenol reduced the levels of TNF-α, IL-17A and IL-6 in synovial fluid and TNF-α, IL-17A and IFN-γ in serum, and increased the serum levels of IL-4, IL-10 and TGF-β1. In addition, Kirenol inhibited the ability of CII to induce splenocyte, PBMC and lymph node cell proliferation in vitro, compared to cells from CIA rats. In conclusion, these results suggest that Kirenol may be a potential immunosuppressant for the treatment for rheumatoid arthritis.

Topics: Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Asteraceae; Bone and Bones; Cartilage; Cattle; CD4-Positive T-Lymphocytes; Cell Proliferation; Collagen Type II; Cytokines; Diterpenes; Drugs, Chinese Herbal; Female; Forkhead Transcription Factors; Immunosuppressive Agents; Inflammation; Inflammation Mediators; Interleukin-2 Receptor alpha Subunit; Joint Diseases; Leukocytes, Mononuclear; Lymph Nodes; Phytotherapy; Prednisolone; Rats; Rats, Wistar; RNA, Messenger; Severity of Illness Index; Spleen; Synovial Fluid; T-Lymphocytes, Regulatory

Siegesbeckia orientalis has been traditionally used as a topical anti-inflammatory and analgesic agent.. Current study was designed to explore the topical anti-inflammatory and analgesic effects of a constituent isolated from Siegesbeckia orientalis (Compositae), in order to validate its folk use.. Kirenol was isolated from ethanolic extract of Siegesbeckia orientalis. Several topical formulations containing kirenol were investigated for anti-inflammatory and analgesic activities in rat. The effects were studied using carrageenan-induced rat acute inflammation model, complete Freund's adjuvant (CFA)-induced chronic inflammation and formalin test in rats. Piroxicam gel and methyl salicylate ointment were studied as positive control for anti-inflammatory and analgesic activity, respectively.. The anti-inflammatory effect of kirenol 0.4-0.5% (w/w) was similar to the effect of piroxicam gel 4h after carrageenan injection. The analgesic activity of topical preparation with more than 0.4% (w/w) was observed in the late phase. These effects may be due, at least in part, to the pro-inflammatory cytokine production of IL-1β and TNF-α. The administration of kirenol cream at the dose of 0.3, 0.4 and 0.5% (w/w) significantly inhibited the development of joint swelling induced by CFA, which was auxiliary supported by histopathological studies.. Kirenol has demonstrated its significant potential to be further investigated for its discovery as a new lead compound for management of topical pain and inflammation, although further pharmacological research is necessary to fully understand its mechanism of action. It also supports the potential beneficial effect of topically administered Siegesbeckia orientalis in inflammatory diseases.

Topics: Administration, Topical; Analgesics; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Asteraceae; Carrageenan; Diterpenes; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Ethanol; Formaldehyde; Freund's Adjuvant; Inflammation; Inflammation Mediators; Interleukin-1beta; Pain; Piroxicam; Plant Components, Aerial; Plants, Medicinal; Rats; Salicylates; Solvents; Time Factors; Tumor Necrosis Factor-alpha