carnosol and Inflammation

Inflammation comprises the reaction of the body to injury, in which a series of changes of the terminal vascular bed, blood, and connective tissue tends to eliminate the injurious agent and to repair the damaged tissue. It is a complex process, which involves the release of diverse regulatory mediators. The current anti-inflammatory agents are challenged by multiple side effects and thus, new effective therapies are highly needed. The aim of this review is to summarize the described microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors or transcriptional suppressors from medicinal plants, which could be an ideal approach in the management of inflammatory disorders, but need further clinical trials in order to be ultimately validated.

Topics: Animals; Anti-Inflammatory Agents; Biological Products; Drug Discovery; Enzyme Inhibitors; Humans; Inflammation; Plants, Medicinal; Prostaglandin-E Synthases

Carnosol is a phytopolyphenol (diterpene) found and extracted from plants of Mediterranean diet, which has anti-tumor, anti-inflammatory and antioxidant effects. However, its role in ischemic stroke has not been elucidated.. Primary neurons subjected to oxygen-glucose deprivation (OGD) was used to investigate the effect of carnosol in vitro. A mouse MCAO model was used to evaluate the effect of carnosol on ischemic stroke in vivo. The mRNA level of inflammatory and apoptosis-related genes was determined by RT-PCR. The protein level of total and phosphorylated AMPK was determined by WB. H&E and Immunofluorescent assay was used to investigate the necrosis, inflammation and apoptosis in brain tissue.. Carnosol protected the activity of primary neurons subjected to oxygen-glucose deprivation (OGD) in vitro, as well as inhibited inflammation and apoptosis. Furthermore, carnosol could significantly reduce the infarct and edema volume and protect against neurological deficit in vivo, and had a significant inhibitory effect on brain neuroinflammation and apoptosis. Mechanically, carnosol could activate AMPK, and the effect of carnosol on cerebral ischemia-reperfusion injury cell model could be abolished by AMPK phosphorylation inhibitor.. Carnosol has a protective effect on ischemic stroke, and this effect is achieved through AMPK activation. Our study demonstrates the protective effect of carnosol on cerebral ischemia-reperfusion injury and provides a new perspective for the clinical treatment of ischemic stroke.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Apoptosis; Brain Ischemia; Glucose; Infarction, Middle Cerebral Artery; Inflammation; Ischemic Stroke; Mice; Oxygen; Reperfusion Injury; Stroke

Aberrant activation of inflammasomes, a group of protein complexes, is pathogenic in a variety of metabolic and inflammation-related diseases. Here, we report that carnosol inhibits NLRP3 inflammasome activation by directly targeting heat-shock protein 90 (HSP90), which is essential for NLRP3 inflammasome activity, thereby treating inflammasome-mediated diseases. Our data demonstrate that carnosol inhibits NLRP3 inflammasome activation in primary mouse bone marrow-derived macrophages (BMDMs), THP-1 cells and human peripheral blood mononuclear cells (hPBMCs). Mechanistically, carnosol inhibits inflammasome activation by binding to HSP90 and then inhibiting its ATPase activity. In vivo, our results show that carnosol has remarkable therapeutic effects in mouse models of NLRP3 inflammasome-mediated diseases, including endotoxemia and nonalcoholic steatohepatitis (NASH). Our data also suggest that intraperitoneal administration of carnosol (120 mg/kg) once daily for two weeks is well tolerated in mice. Thus, our study reveals the inhibitory effect of carnosol on inflammasome activation and demonstrates that carnosol is a safe and effective candidate for the treatment of inflammasome-mediated diseases.

Topics: Abietanes; Animals; HSP90 Heat-Shock Proteins; Humans; Inflammasomes; Inflammation; Leukocytes, Mononuclear; Lipopolysaccharides; Macrophages; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein

Polyphenols are important immunonutrients which have been investigated in the context of inflammatory and autoimmune disease due to their significant immunosuppressive properties. However, the mechanism of action of many polyphenols is unclear, particularly in human immune cells. The emerging field of immunometabolism has highlighted the significance of metabolic function in the regulation of immune cell activity, yet the effects of polyphenols on immune cell metabolic signaling and function has not been explored. We have investigated the effects of two plant-derived polyphenols, carnosol and curcumin, on the metabolism of primary human dendritic cells (DC). We report that human DC display an increase in glycolysis and spare respiratory capacity in response to LPS stimulation, which was attenuated by both carnosol and curcumin treatment. The regulation of DC metabolism by these polyphenols appeared to be mediated by their activation of the cellular energy sensor, AMP-activated Protein Kinase (AMPK), which resulted in the inhibition of mTOR signaling in LPS-stimulated DC. Previously we have reported that both carnosol and curcumin can regulate the maturation and function of human DC through upregulation of the immunomodulatory enzyme, Heme Oxygenase-1 (HO-1). Here we also demonstrate that the induction of HO-1 by polyphenols in human DC is dependent on their activation of AMPK. Moreover, pharmacological inhibition of AMPK was found to reverse the observed reduction of DC maturation by carnosol and curcumin. This study therefore describes a novel relationship between metabolic signaling via AMPK and HO-1 induction by carnosol and curcumin in human DC, and characterizes the effects of these polyphenols on DC immunometabolism for the first time. These results expand our understanding of the mechanism of action of carnosol and curcumin in human immune cells, and suggest that polyphenol supplementation may be useful to regulate the metabolism and function of immune cells in inflammatory and metabolic disease.

Topics: Abietanes; AMP-Activated Protein Kinases; Cells, Cultured; Curcumin; Dendritic Cells; Heme Oxygenase-1; Humans; Immune System Phenomena; Inflammation; Metabolic Diseases; Polyphenols; Signal Transduction; TOR Serine-Threonine Kinases; Up-Regulation

Interactive relationships among metabolism, mitochondrial dysfunction and inflammation at skeletal muscle level play a key role in the pathogenesis of disorders related to oxidative stress. Mitochondrial dysfunction and oxidative stress result in cellular energy deficiency, inflammation and cell death inducing a vicious cycle that promotes muscle wasting. The histidine-containing dipeptides, carnosine and anserine, are carbonyl scavengers whose cytoprotective contributions extend beyond the antioxidant defence, but the physiological meaning of these capacities is actually limited. In the present study, we compared and investigated the potential protective effects of three different histidine-containing dipeptides: carnosine, anserine and carnosinol, a carnosine-mimetic new compound, against oxidative stress induction in rat L6 skeletal muscle cells. The hydrogen peroxide induced-oxidative stress significantly altered cell morphology, induced apoptosis, oxidative stress and inflammation, decreased mitochondrial peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)/sirtuin3 pathway and the antioxidant system. Notably, all three investigated dipeptides in the present study, with a different extent and in a concentration-dependent manner, reduced myotube oxidative stress, apoptosis and inflammation. The present study underlined that carnosinol, maintaining the safety condition of carnosine and anserine, was the more efficient studied dipeptide in the preservation of mitochondrial environment mediated by PGC-1α and sirtuin3 expression and thereby in the reduction of oxidative stress-related alterations in this in vitro skeletal muscle model. Furthermore, we observed that carnosinol's antioxidant effects are not blocked inhibiting sirtuin3, but are maintained with almost the same extend, indicating its multiple capacities of reactive carbonyl species-scavenging and of mitochondrial modulation through PGC-1α. In conclusion, carnosinol retained and surpassed the efficacy of the well-known investigated histidine-containing dipeptides improving oxidative stress, inflammation and also cell metabolism and so becoming a greatly promising therapeutic carnosine derivate.

Topics: Abietanes; Animals; Anserine; Antioxidants; Apoptosis; Carnosine; Cell Line; Cell Survival; Inflammation; Metabolic Diseases; Microscopy, Electron, Scanning; Models, Biological; Muscle Fibers, Skeletal; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Sirtuins; Superoxide Dismutase

Psoriasis is a chronic autoimmune disease mediated by dysregulated immune responses in dendritic cells (DC) and T cells. The stress-response enzyme heme oxygenase-1 (HO-1) has been described as protective in animal models of psoriasis, however, implementation of HO-1-based therapies is hindered by the lack of clinically-suitable HO-1 inducers. The plant-derived polyphenols, carnosol and curcumin, have been identified as candidate HO-1 inducers however there has been little investigation into their effects on human immune cells. We demonstrate that treatment of human DC with these polyphenols limits DC maturation, reduces pro-inflammatory cytokine production, and prevents induction of allospecific T cell responses, in a manner partially dependent on carbon monoxide (CO). We also characterised their effects in ex-vivo psoriasis PBMC and report that curcumin, but not carnosol, strongly reduces T cell proliferation and cytokine poly-functionality, with reduced expression of psoriatic cytokines IFNγ, IL-17, GM-CSF and IL-22. This study therefore supports reports highlighting the therapeutic potential of curcumin in psoriasis by providing insight into its immunological effects on healthy human DC and psoriasis PBMC. We also demonstrate, for the first time, the anti-inflammatory effects of carnosol in human immune cells.

Topics: Abietanes; Anti-Inflammatory Agents, Non-Steroidal; Carbon Monoxide; Cell Differentiation; Cell Proliferation; Curcumin; Dendritic Cells; Enzyme Activation; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Humans; Inflammation; Leukocytes, Mononuclear; Lymphocyte Activation; Psoriasis; T-Lymphocytes

The diterpenoids carnosol (CS) and carnosic acid (CA) from Salvia spp. exert prominent anti-inflammatory activities but their molecular mechanisms remained unclear. Here we investigated the effectiveness of CS and CA in inflammatory pain and the cellular interference with their putative molecular targets.. The effects of CS and CA in different models of inflammatory pain were investigated. The inhibition of key enzymes in eicosanoid biosynthesis, namely microsomal prostaglandin E. CS and CA displayed significant and dose-dependent anti-inflammatory and anti-nociceptive effects in carrageenan-induced mouse hyperalgesia 4 h post injection of the stimuli, and also inhibited the analgesic response in the late phase of the formalin test. Moreover, both compounds potently inhibited cell-free mPGES-1 and 5-LO activity and preferentially suppressed the formation of mPGES-1 and 5-LO-derived products in cellular studies. Our in silico analysis for mPGES-1 and 5-LO supports that CS and CA are dual 5-LO/mPGES-1 inhibitors.. In summary, we propose that the combined inhibition of mPGES-1 and 5-LO by CS and CA essentially contributes to the bioactivity of these diterpenoids. Our findings pave the way for a rational use of Salvia spp., traditionally used as anti-inflammatory remedy, in the continuous expanding context of nutraceuticals.. This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.

Topics: Abietanes; Analgesics; Animals; Anti-Inflammatory Agents; Computer Simulation; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Inflammation; Lipoxygenase Inhibitors; Male; Mice; Molecular Docking Simulation; Monocytes; Neutrophils; Pain; Prostaglandin-E Synthases; Salvia

Carnosol (CS) is an ortho-diphenolic diterpene in rosemary with great antioxidant potential. This study was designed to investigate the hypolipidemic, anti-oxidant, and anti-diabetic activities of CS.. In our experiment, the rats were divided into the following groups of 8 animals each: control, untreated diabetic, three CS (1, 5, 10 mg/kg/day)-treated diabetic groups. On the first day of the study, the diabetic groups were given streptozotocin (STZ) in a single intraperitoneal (i.p.) injection at a dose of 60 mg/kg for induction of diabetes. CS was injected (i.p.) to the treatment groups from 3 days after STZ administration during a period of 4 weeks. At the end of the experimental period, we assessed the serum levels of glucose, IL-6, TNF-α, malondialdehyde (MDA), glutathione-s transferase (GST), superoxide dismutase (SOD), catalase (CAT) activities, triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL-C), and high density lipoprotein (HDL-C).. The results indicated that STZ caused an elevation of serum glucose, IL-6, TNF-α, MDA, TG, TC, LDL-C, and it also made a reduction of serum GST, SOD, CAT, and HDL-C (p<0.001). The findings showed amelioration in the serum glucose, IL-6, TNF-α, MDA, TG, TC, LDL-C, GST, SOD, CAT, and HDL-C in the CS-treated diabetic groups versus the untreated group, in a dose dependent manner (p < 0.001).. In conclusion, the present investigation proposes that CS may be improved diabetes and its complications by modulation of oxidative stress and inflammatory responses.

Topics: Abietanes; Animals; Antioxidants; Blood Glucose; Diabetes Mellitus, Experimental; Hypoglycemic Agents; Inflammation; Male; Oxidative Stress; Rats; Rats, Wistar; Rosmarinus

Propionibacterium acnes is a key pathogen involved in the progression of acne inflammation. The development of a new agent possessing antimicrobial and anti-inflammatory activity against P. acnes is therefore of interest. In this study, we investigated the inhibitory effect of rosemary (Rosmarinus officinalis) extract on P. acnes-induced inflammation in vitro and in vivo. The results showed that ethanolic rosemary extract (ERE) significantly suppressed the secretion and mRNA expression of proinflammatory cytokines, including interleukin (IL)-8, IL-1β, and tumor necrosis factor-α in P. acnes-stimulated monocytic THP-1 cells. In an in vivo mouse model, concomitant intradermal injection of ERE attenuated the P. acnes-induced ear swelling and granulomatous inflammation. Since ERE suppressed the P. acnes-induced nuclear factor kappa-B (NF-κB) activation and mRNA expression of Toll-like receptor (TLR) 2, the suppressive effect of ERE might be due, at least partially, to diminished NF-κB activation and TLR2-mediated signaling pathways. Furthermore, three major constituents of ERE, carnosol, carnosic acid, and rosmarinic acid, exerted different immumodulatory activities in vitro. In brief, rosmarinic acid significantly suppressed IL-8 production, while the other two compounds inhibited IL-1β production. Further study is needed to explore the role of bioactive compounds of rosemary in mitigation of P. acnes-induced inflammation.

Topics: Abietanes; Acne Vulgaris; Animals; Anti-Inflammatory Agents; Cinnamates; Cytokines; Depsides; Humans; Inflammation; Inflammation Mediators; Male; Mice; Mice, Inbred ICR; Phytotherapy; Plant Extracts; Propionibacterium acnes; RNA, Messenger; Rosmarinic Acid; Rosmarinus; Signal Transduction

Rosmarinus officinalis, also named rosemary, is a native plant from the Mediterranean region that is useful for the treatment of inflammatory diseases. Studies using experimental models and/or in vitro tests have shown the important biological effects of rosemary. In this context, the mechanism of the anti-inflammatory activity of rosemary must be investigated to support the discovery of new substances with anti-inflammatory effects. The aim of the present study was to investigate the anti-inflammatory effects of crude extract oil free obtained from the leaves of rosemary in an animal model of inflammation, thus evaluating its medicinal use for the treatment of inflammatory conditions. Also its ethanol, hexane, and ethyl acetate fractions, as well as its isolated compounds carnosol and rosmarinic acid were analyzed. Swiss mice were used for the in vivo experiments. The effect of this herb on the inhibition of the leukocytes, exudation, myeloperoxidase, and adenosine-deaminase activities, nitrite/nitrate, interleukin 17A, and interleukin 10 levels and mRNA expression was determined. The crude extract and its derived fractions, in addition to its isolated compounds, inhibited leukocytes and decreased exudation and myeloperoxidase and adenosine-deaminase activities, as well as nitrite/nitrate and interleukin 17A levels and mRNA expression, besides increasing interleukin 10 levels and mRNA expression. Rosemary showed important anti-inflammatory activity by inhibiting leukocytes and decreasing exudation. These effects were associated with a decrease in the proinflammatory parameters (myeloperoxidase, adenosine-deaminase, nitrite/nitrate, and interleukin 17A) and an increase in the anti-inflammatory cytokine (interleukin 10). This study confirms the anti-inflammatory properties of rosemary and validates its use in folk medicine to treat inflammatory diseases such as rheumatism and asthma.

Topics: Abietanes; Adenosine Deaminase; Animals; Anti-Inflammatory Agents; Carrageenan; Cinnamates; Cytokines; Depsides; Disease Models, Animal; Inflammation; Inflammation Mediators; Leukocytes; Mice; Mice, Inbred Strains; Nitrates; Nitrites; Peroxidase; Phytotherapy; Plant Extracts; Plant Leaves; Pleurisy; RNA, Messenger; Rosmarinic Acid; Rosmarinus

The anti-inflammatory and anti-nociceptive properties of Rosmarinus officinalis L. (ROL) extract and its major constituent, carnosol in male NMRI mice (W:25-30 g) have been evaluated in the present study. Formalin (2%, 20 microL) was injected into the plantar portion of the hind paw and resulting pain and inflammation was studied for 60 min. The plant extract, carnosol and other drugs were administered intraperitoneally or subcutaneously 30 min before formalin injection. In a separate experiment, the effects of the extract and carnosol on plasma corticosterone levels and activity of the enzymes cyclooxygenase type 1 and 2 (COX1 and COX2) were investigated. Injection of different doses of ROL and carnosol reduced pain in the phase 2 of the formalin test, which was not inhibited by naloxone and/or memantine. In addition, pretreatment of the animals with ROL and/or carnosol reduces the formalin-induced inflammation. Furthermore, the extract and carnosol did not affect plasma corticosterone levels compared with the control group. Interestingly, both the extract and carnosol inhibited COX1 and COX2 activity. It could be concluded that ROL extract and carnosol suppressed pain and inflammation induced by formalin injection, which may be due to inhibition of COX1 and COX2 enzymes activity.

Topics: Abietanes; Alcohols; Analgesics; Animals; Anti-Inflammatory Agents; Corticosterone; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Inflammation; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Membrane Proteins; Mice; Pain; Phytotherapy; Plant Extracts; Plants, Medicinal; Rosmarinus; Solvents

Salvia officinalis L. has been used as a traditional herbal medicine for gastric disturbances and inflammatory processes. This study investigated the toxicological, antinociceptive and anti-inflammatory effects of the hydroalcoholic extract (HE) from leaves of Salvia officinalis and its isolated compounds in mice.. Mice were treated with HE before the induction of nociceptive response by chemical agents (acetic-acid, formalin, glutamate, capsaicin and cinnamaldehyde). Total leukocytes and plasma extravasation induced by acetic acid and paw oedema induced by glutamate, capsaicin and cinnamaldehyde were also measured. The antinociceptive effect of carnosol and ursolic acid/oleanolic acid were evaluated on formalin and cinnamaldehyde models.. In the acute toxicity test the value of estimated LD50 for HE was 44.7579 g/kg. Oral administration of HE (10, 30 and 100 mg/kg) inhibited the number of writhings, total leukocytes and plasma extravasation induced by acetic acid. In the formalin test, HE reduced both neurogenic and inflammatory phases, effect that was affected by naloxone. The glutamate-, capsaicin- and cinnamaldehyde-induced nociception and paw oedema were reduced by HE at doses that did not affect the locomotor activity of mice in the open field test. Carnosol (10mg/kg) and ursolic acid/oleanolic acid (30 mg/kg) inhibited the inflammatory phase of formalin and the nociception and mechanical allodynia induced by cinnamaldehyde.. These results demonstrate that HE presents significant anti-inflammatory and also antinociceptive effects on chemical behavioral models of nociception that involves an opioid mechanism. In addition, carnosol and ursolic acid/oleanolic acid contained in this plant appears to contribute for the antinociceptive property of the extract, possibly through a modulatory influence on TRPA1-receptors. However, further studies regarding the precise site and the mechanism of action of HE and carnosol and ursolic acid/oleanolic acid merited exploring further.

Topics: Abietanes; Administration, Oral; Analgesics; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Inflammation; Lethal Dose 50; Mice; Motor Activity; Narcotic Antagonists; Oleanolic Acid; Pain; Pain Measurement; Plant Extracts; Plant Leaves; Plants, Medicinal; Salvia officinalis; Time Factors; Triterpenes; Ursolic Acid

In chronic inflammation, cytokines induce the production of nitric oxide (NO.) that is converted to DNA damaging and carcinogenic peroxynitrite and nitrite. The compounds epigallocatechin gallate (EGCG), carnosol, and curcumin are non-vitamin phytochemicals contained in commonly consumed dietary plants. They are known to be anti-inflammatory and cancer preventive. Therefore, we studied their effect on the generation of peroxynitrite radicals and nitrite. They inhibited lipopolysaccharide (LPS) and interferon-gamma (IFN gamma) induced nitrite production by mouse peritoneal cells by more than 50% at 2.5-10 microM. Cell viability assays verified that the inhibition was not due to general cellular toxicity.

Topics: Abietanes; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Catechin; Cell Survival; Curcumin; Inflammation; Interferon-gamma; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Mice, Inbred BALB C; Nitrites; Phenanthrenes; Recombinant Proteins; Spices; Tea; Tumor Necrosis Factor-alpha