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Myrrh mediates haem oxygenase-1 expression to suppress the lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages
Abstract
To elucidate a novel anti-inflammatory mechanism of myrrh against lipopolysaccharide (LPS)-induced inflammation.
RAW264.7 macrophages were cultured in DMEM and then cells were treated with LPS or LPS plus a myrrh methanol extract (MME) for 24h. The culture medium was collected for determination of nitric oxide (NO), prostaglandin (PG)E(2) , interleukin (IL)-1β, and tumour necrosis factor (TNF)-α, and cells were harvested by lysis buffer for Western blot analysis.
Our data showed that treatment with the MME (1∼100µg/ml) did not cause cytotoxicity or activate haem oxygenase-1 (HO-1) protein synthesis in RAW264.7 macrophages. Furthermore, the MME inhibited LPS-stimulated NO, PGE(2) , IL-1β and TNF-α release and inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 protein expression. Zn(II) protoporphyrin IX, a specific inhibitor of HO-1, blocked the inhibition of iNOS and COX-2 expression by the MME.
These results suggest that among mechanisms of the anti-inflammatory response, the MME inhibited the production of NO, PGE(2) , IL-1β and TNF-α by downregulating iNOS and COX-2 gene expression in macrophages and worked through the action of HO-1.
... NO is one of the pathologically elevated factors in UC patients [24]. First, the evidence suggests that myrrh suppresses the inflammatory response in the in vitro model used by mediating haem oxygenase-1 expression [25]. In addition, myrrh suppressed the inflammation by influencing the MAPK signalling pathway in another cell model [11]. ...
... Thus, 37 sesquiterpenes, 1 triterpene, 4 phytosterols, and 1 lignan were identified, including 21 new natural products (1-17, 38-40, and 43) and 12 compounds that have not yet been described for the genus Commiphora. Known compounds that have not been described for Commiphora so far were elucidated by their NMR data to be serralactone A (18) [26], 1β,8β-dihydroxyeudesman-3,7(11)-dien-8α,12-olide (19) [27], neolitacumone B (20) [28], neolitacumone A (21) [27], 3-oxo-5αH,8βH-eudesma-1,4(15),7(11)-trien-8,12-olide (22) [29], (+)-eudebeiolide B (23) [30], linderolide I (24) [31], 1β,8β-dihydroxyeudesma-4,7(11)-dien-8α,12-olide (25) [32], istanbulin B and A (26 and 27) [33], chloraniolide A (28) [34], and 7-ketostigmasterol (42) [35]. For compounds 24 [31] and 28 [34], the additional literature data could be corrected. ...
... For a conclusive statement, however, more experiments are needed due to the structural heterogeneity of the active substances. Initial evidence suggests that myrrh mediates the expression of haem oxygenase-1 and thus suppresses the inflammatory response in the in vitro model used [25]. However, there is likely more than one target in the inflammatory cascade from the stimulation by LPS to the final NO synthesis. ...
Myrrh has a long tradition in the treatment of inflammatory diseases. However, many of its (active) constituents are still unknown. In the present study, secondary metabolites were isolated from an ethanolic extract by various separation methods (liquid–liquid partition, silica and RP18 flash chromatography, CPC, and preparative HPLC), their structures were elucidated with NMR spectroscopy and mass spectrometry, and the selected compounds were tested for their effect on LPS-induced NO production by RAW 264.7 murine macrophages. Among the isolated substances are 17 sesquiterpenes (1–17) including the first 4,8-cycloeudesmane (1), a triterpene (38), two phytosterols (39, 40) and one lignan (43), which were previously unknown as natural products. Numerous compounds are described for the first time for the genus Commiphora. Eight of the eleven compounds tested (1, 29, 31, 32, 34–37) showed a statistically significant, concentration-dependent weak to moderate anti-inflammatory effect on NO production in the LPS-stimulated RAW 264.7 macrophages in vitro. For the reference substance, furanoeudesma-1,3-diene, an IC50 of 46.0 µM was determined. These sesquiterpenes might therefore be part of the multi-target molecular principles behind the efficacy of myrrh in inflammatory diseases.
... resin extract prepared by immersing in methanol on RAW 264.7 macrophages. The extract inhibited NO synthase and cyclooxygenase-2 induction, leading to reduced production of NO, prostaglandin E 2 , interleukin-1beta, and tumor necrosis factor alpha [60]. ...
... resin extract prepared by immersing in methanol on RAW 264.7 macrophages. The extract inhibited NO synthase and cyclooxygenase-2 induction, leading to reduced production of NO, prostaglandin E2, interleukin-1beta, and tumor necrosis factor alpha [60]. ...
Commiphora myrrha (T.Nees) Engl. resin extracts were prepared via immersion in extraction solvents (hot water, DMSO, hexane, ethanol, and methanol) which have various physical properties, such as different polarity and dielectric constant values. Methanolic C. myrrha (T.Nees) Engl. resin extracts showed broad antibacterial activity against isolated airborne bacteria. All methanolic C. myrrha (T.Nees) Engl. resin extracts were analyzed using GC-MS and Furanoeudesma-1,3-diene and curzerene were found as the main terpenoids. In addition, the methanolic C. myrrha (T.Nees) Engl. resin extracts were found to have antiviral activity (81.2% viral RNA inhibition) against the H1N1 influenza virus. Biochars (wood powder- and rice husk-derived) coated with C. myrrha (T.Nees) Engl. resin extracts also showed antiviral activity (22.6% and 24.3% viral RNA inhibition) due to the adsorption of terpenoids onto biochar. C. myrrha (T.Nees) Engl. resin extract using methanol as the extraction solvent is a promising agent with antibacterial and antiviral efficacy that can be utilized as a novel material via adsorption onto biochar for air filtration processes, cosmetics, fertilizers, drug delivery, and corrosion inhibition.
... All the individual ingredients of the combination exhibit anti-viral activity in addition to anti-inflammatory, antioxidant, and immunomodulatory properties [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Recently, it was also reported that it exhibits antiviral activity against SARS-CoV-2 [5]. ...
... It also exhibits anti-atherosclerotic property due to one of its components, isovitexin [27]. Myrrh mediates antiinflammatory activity by inducing haem oxygenase activity and inhibitory activity against 5lipoxygenase and helps suppress the production of leukotrienes, which are another class of inflammatory cytokines [12]. ...
Background
The coronavirus disease 2019 (COVID-19) pandemic resulted in mortality and morbidity worldwide. Many treatment modalities have been experimented with limited success. Therefore, the traditional system of medicine needs to be explored.
Objective
To evaluate the benefits of Unani regimensTiryaq-e-Arba and Unani Joshanda, as adjuvant therapy, were compared to standard treatment alone among reverse transcription polymerase chain reaction (RT-PCR)-confirmed mild to moderate COVID-19 cases.
Materials and methods
An open-label, double-arm, randomized, controlled interventional clinical study was conducted among 90 RT-PCR-confirmed mild to moderate COVID-19 inpatients admitted to a tertiary care hospital in New Delhi, India. Participants who fulfilled the criteria for inclusion were randomly assigned to two arms, with 43 subjects allocated to the Unani add-on arm and 47 subjects to the control arm receiving standard treatment alone.
Results
Clinical recovery was achieved in all patients of the Unani arm, while in the control arm, three (6.4%) patients deteriorated and had to be shifted to ICU following admission. In the intervention arm, a shorter duration of hospitalization was observed (mean 5.95 days {SD = 1.99}) than in the control arm (mean 7.62 days {SD, 4.06}); which was a statistically significant difference (p-value 0.017). The majority of the patients recovered within 10 days in the Unani add-on arm. The number of days taken for the reduction of symptoms was significantly less in the intervention arm (mean 5.14 days {SD, 2.39}) as compared with standard treatment (mean 6.53 days {SD, 3.06}) (p < 0.02). Renal and liver safety parameters were within the normal limits in both arms and no serious adverse event was reported.
Conclusion
Adding Unani formulations to standard treatment significantly reduced the duration of hospital stay and showed early recovery in COVID-19 patients compared with the control arm. It may be concluded that the synergistic effect of the Unani add-on with standard treatment gave more promising results in mild to moderate COVID-19 patients.
... The intestinal histological sections exhibited a documented improvement, evidenced by the presence of reduced Cryptosporidium oocysts inside the intestinal epithelium, accompanied by modest inflammatory cellular infiltration in mice treated with a combination of NTZ-artesunate delivered by polymeric nano-fibre and NTZ-loaded Chitosan nanoparticles (Abdelhamed et al., 2019;Moawad et al., 2021). Cheng et al. (2011) and Hemphill et al. (2019) stated that the enhancement in the clinical presentation, seen by the restoration of the brush border to its normal architecture, can be ascribed to the diminished quantity of oocysts and/ or a decrease in cytokine and inflammatory cell production. ...
Background: Cryptosporidiosis poses several health risks, particularly due to its potential severity and the populations it can affect. Comprehending these hazards is crucial for efficient prevention and treatment. This study was to investigate the efficiency of cellulose nanocrystals (CNC), nitazoxanide (NTZ) and nitazoxanide-cellulose nanocrystals (NTZ-CNC) in treating experimental infected mice of cryptosporidiosis. Methods: A total of 75 male swiss albino mice were allocated into eight groups (5 mice/ group) with triplicates of each group. Infection with cryptosporidiosis was conducted with 3000 Cryptosporidium parvum oocysts. All treatments commenced on the initial day of oocyst emergence and persisted for five succeeding days across all groups, except for the negative control group. Oocysts shedding was estimated daily from 1st till 20 days post treatment. Hematological and blood biochemical analysis, immunoglobulins levels as well as histopathological studies were performed. Result: It was detected that NTZ-CNC group had the lowest Cryptosporidium oocysts shedding. Also, these treatments induced significant improvements in hematological, blood biochemical, immunoglobulins levels including immunoglobulin G and immunoglobulin M with best improvements recorded in NTZ-CNC treated groups. A remarkable amelioration of the intestinal histopathological lesions was observed, especially in NTZ-CNC treated group. In conclusion, this study reported that CNC could significantly enhance the therapeutic effects of NTZ, making it a promising treatment for cryptosporidiosis due to its potent anti-parasitic and anti-inflammatory capabilities.
... Cheng et al. reported the anti-inflammatory effects of a myrrh resin extract prepared by immersing in methanol on RAW 264.7 macrophages. The extract inhibited NO synthase and cyclooxygenase-2 induction, leading to reduced production of NO, prostaglandin E2, interleukin-1beta, and tumor necrosis factor-alpha [64]. ...
Commiphora molmol myrrh resin extracts, which have different physical properties such as polarity and dielectric constant, were prepared by immersion in extraction solvents (hot water, DMSO, hexane, ethanol, and methanol). Methanolic myrrh resin extracts showed broad antibacterial activity against isolated airborne bacteria. Furanoeudesma-1,3-diene and curzerene, as the main terpenoids in the methanolic myrrh resin extract, were analyzed using GC-MS, and the methanolic myrrh resin extracts were found to have antiviral activity (81.2% viral RNA inhibition) against H1N1 influenza virus. Biochars (wood powder-and rice husk-derived) coated with myrrh resin extracts also showed antiviral activity (22.6% and 24.3% viral RNA inhibition), due to the adsorption of terpenoids onto biochar. Myrrh resin extract using methanol as the extraction solvent is a promising agent with antibacterial and antiviral efficacy, and it can be utilized as a novel material via adsorption onto biochar for air filtration processes, cosmetics, fertilizers, drug delivery, and corrosion inhibition.
... A significant inhibition of NO formation by methanol resin extract of C. mukul in lipopolysaccharide (LPS) activated murine macrophages was exhibited using IC50 = 15 mg/ mL (Meselhy 2003;Matsuda et al. 2004a). Also, MeOH extract demonstrated an anti-inflammatory property against LPS-induced inflammation (Cheng et al. 2011). Isolated compounds, polypodane triterpenoids, cembrane diterpenoids, lignans, and steroids have been studied for COX inhibitory activity and NO production. ...
Medicinal plants have a long track record of use in history, and one of them is Commiphora myrrh which is commonly found in the southern part of Arabia, the northeastern part of Africa, in Somalia, and Kenya. Relevant literatures were accessed via Google Scholar, PubMed, Scopus, and Web of Science to give updated information on the phytochemical constituents and pharmacological action of Commiphora myrrh . It has been used traditionally for treating wounds, mouth ulcers, aches, fractures, stomach disorders, microbial infections, and inflammatory diseases. It is used as an antiseptic, astringent, anthelmintic, carminative, emmenagogue, and as an expectorant. Phytochemical studies have shown that it contains terpenoids (monoterpenoids, sesquiterpenoids, and volatile/essential oil), diterpenoids, triterpenoids, and steroids. Its essential oil has applications in cosmetics, aromatherapy, and perfumery. Research has shown that it exerts various biological activities such as anti-inflammatory, antioxidant, anti-microbial, neuroprotective, anti-diabetic, anti-cancer, analgesic, anti-parasitic, and recently, it was found to work against respiratory infections like COVID-19. With the advancement in drug development, hopefully, its rich phytochemical components can be explored for drug development as an insecticide due to its great anti-parasitic activity. Also, its interactions with drugs can be fully elucidated.
This review highlights an updated information on the history, distribution, traditional uses, phytochemical components, pharmacology, and various biological activities of Commiphora myrrh .
Graphical abstract
Graphical summary of the phytochemical and pharmacological update of Commiphora myrrh
... Additionally, myrrh resin has been found to induce antibacterial activity by acting on specific pathways. Researchers asserted that myrrh resin acts by inducing haem oxygenase activity, which stops the degradation of IKB alpha as a response to the activation of inflammatory receptors [19]. Such activation plays a crucial role in preventing the translocation of nuclear factor kappaB. ...
This paper reviews the therapeutic effects of Commiphora myrrh in different diseases. It is organized by sub-themed sections: nature and history of myrrh, its use in different cultures, its chemical action, and effect on virus or/and bacteria, benefits of its utilization for respiratory problems and oral diseases. A literature research for the Myrrh or C. myrrh was performed using Cochrane Library databases and Medline. Forty two papers, including abstracts and full articles published from 2007 to 2020, in the area of interest were reviewed. It was found that Myrrh or C. myrrh is one of the medicinal plants believed to have therapeutic effects in various diseases. It has medicinal properties, such as immunomodulatory, anti-inflammatory, cytotoxic, antioxidant, antimicrobial, hepatoprotective, anti-tumor, anti-ulcer, and analgesic activities. Besides, Myrrh has also shown to have antiviral properties that help in preventing different types of viral diseases. It noticed in the State of Qatar, sales of herbs and Myrrh has escalade since the surgency of COVID-19 cases, so is there a belief in Myrrh's effectiveness to be used during COVID-19? Studying the effectiveness of Myrrh mouthwashes to combat COVID-19 can emerge as a promising avenue in the field of research.
... The improvement in the pathological picture was indicated by the recuperation of the brush border to regular structure in response to treatment with NTZ and Cm-CsNFs (100 mg/kg). This can be attributed to the decreased number of oocysts (Tables 1 and 2) and trophozoites (Tables 3 and 4), and/or reduction of of cytokines and inflammatory cells production [51,54] . ...
... The guggul gum-resins of myrrh tree (Commiphora wightii and Commiphora mukul) have showed the potent anti-inflammatory activity [8,9]. A significant improvement in osteoarthritis has been observed when guggul's methanolic extract 500 mg per day administrated for one month [41]. In vivo study revealed that mansumbinoic acid (48) HPLC E-and Z-isomers of guggulsterone (bulk drug and in formulations). ...
Background: In the herbal drug pharmaceutical industry, guggul is enjoying emergent consumer acceptance around the world. In the Indian market, more than fifty formulations of guggul have been introduced by well-known brands including Himalaya, Patanjali and Baidyanath Pharmaceuticals. Basically, guggul is the gum resin from Commiphora wightii (syn. Commiphora Mukul). It has been used to treat various ailments including obesity, osteoarthritis, arthritis, constipation, liver disorders, inflammation, anemia, diabetes etc. Including medicinal properties, it is used as a good binding agent and mixed in various herbal formulations.
Objectives: To review the major phytochemical, medicinal properties and analytical methods involved in the detection of guggul by using the exhaustive bibliographic research by means of various scientific engines and databases.
Conclusion: Guggul contained approximately 66 phytochemical including gallic acid, quercetin, and guggulsterones E and Z. These phytochemicals have a wide range of pharmacological activities such as antioxidant, antibacterial, antimutagenic, antivenom and antitumor. It has been noticed that the mode of action of guggulsterone has not been fully explored. Pharmacology and toxicological studies are very few. These works have shown huge literature gap, which is to be fulfilled through the detailed in-vivo and in-vitro studies.
... Recently, numerous studies of oleo gum resin collected from Commiphora species have been published which showing their medicinal activities against many types of diseases such as antimicrobial activities [4] and anti-inflammatory activity [5] as well as its role as an inhibitor for tumor cell proliferation [6]. Although, more than 300 molecules have been identified from Myrrh, wide potential applications of Myrrh extract are attributed to the presence of a combination of terpenoids [7]. ...
This study describes the formulation of new buccoadhesive films containing Myrrh extract as a natural and safe antimicrobial agent to give a long local medication. Buccoadhesive films of Myrrh extract were developed using solvent evaporation technique. The fabricated Myrrh extract films were evaluated for their palatability, weight, surface pH, and their content uniformity. In addition, tensile strength and the percentage of elongation of the films as well as in vitro mucoadhesive time were determined. Also, the films were tested for their antimicrobial activities. Obtained results showed that the tested films are elegant in appearance and have neutral pH, palatable by volunteers and have good tensile strength and elasticity. They also exhibited antibacterial activities against different types of bacterial strains as well as antifungal activity against Candida albicans.
... The oleo-gum-resin obtained from this plant is called myrrh and is traditionally used as a remedy in asthmatic patients. Methanol extract of C. myrrha gum resin inhibited the production of PGE2, IL-1β, TNF-α and NO via down-regulating iNOS and COX-2 gene expression in RAW264.7 macrophages; an effect that was mediated by alteration in the HO-1 expression [84]. Z-guggulsterone, Eguggulsterone, myrrhanone A, and myrrhanol A, isolated from the resins of Commiphora species, inhibited the induction of iNOS in LPS-activated mouse peritoneal macrophages [85,86]. ...
Objective:
To search major Traditional Persian Medicine (TPM) textbooks for medicinal plants used to treat asthma. The conformity of the TPM findings on the anti-asthmatic efficacy of plants with the findings of pharmacological studies was also explored.
Methods:
Major TPM textbooks were hand searched to find medicinal plants used for the treatment of asthma. Scientific names of TPM-suggested plants were determined using botanical databases and were used for a multi-database electronic search in PubMed, Scopus, ScienceDirect and Google Scholar databases. Then, the anti-asthmatic effectiveness of TPM-recommended plants was verified in view of the findings from modern pharmacological investigations.
Results:
According to the main TPM texts, Adianthum capillus-veneris, Boswellia oleogumresin, Crocus sativus, Glycyrrhiza glabra, Hyssopus officinalis and Ruta graveolens were the most efficacious medicinal plants for the treatment of asthma. This finding was confirmed by pharmacological studies which showed counterbalancing effects of the above-mentioned plants on inflammation, oxidative stress, allergic response, tracheal smooth muscle cell constriction and airway remodeling.
Conclusions:
The strong ethnobotanical background of plants used in TPM could be a valuable tool to find new anti-asthmatic medications. In this review, TPM-suggested anti-asthmatic plants were found to possess several mechanisms relevant to the treatment of respiratory diseases according to the information retrieved from modern pharmacological studies. This high degree of conformity suggested further proof-of-concept trials to ascertain the role of these plants in the routine management of asthmatic patients.
... 89 The methanol and EtOAc fraction of C. wightii has been shown to inhibit the NO formation by down regulation of iNOS and COX-2 gene expression. 90 Guggulipid prevented the production of NO and ROS generation 91 in rat astrocytoma cell line. Nishaa et al. 92 ROS production and cell death was also reduced by SZS. ...
Epilepsy is a neuropsychiatric disorder associated with religiosity and spirituality. Nasal drug delivery systems are the best for diseases related to brain. In older times RishiMuni, ancient scholars and physicians used to recommend Hawan for mental peace and well being. Gayatri Mantra also tells that sughandhim (aroma, fragrance) puushtivardhanam (gives rise to good health). Om triambkum yajamahe, sughandhim puushtivardhanam, urvarukmev vandhanaat, mrityu mokshay mamritaat! Hawan is a scientific experiment in which special herbs (Hawan Samagri) are offered in the fire of medicinal woods ignited in a specially designed fire pit called agnikuñda. Hawan seems to be designed by the ancient scholars to fight with the diseases of the brain. Our metadata analysis demonstrates that the components of Hawan are having a number of volatile oils that are specifically useful for epilepsy through one or the other mechanism of action. Due to high temperature of fire the vapors of these oils enter into the central nervous system through nasal route. The routine of performing Hawan might keep the threshold value of the therapeutic components in the body and help in preventing epilepsy. In the present manuscript authors have tried to highlight and integrate the modern and ancient concepts for treatment and prevention of epilepsy.
... Published studies have discussed the various anti-inflammatory effects of the herbal ingredients. For example, Cheng and coworkers demonstrated that a myrrh methanol extract exerts an inhibitory effect on the production of NO, PGE2, IL-1b, and TNF-a by down-regulating inducible nitric oxide synthase and COX-2 gene expression via haem oxygenase-1 protein synthesis induction in LPS-stimulated macrophages [45]. Bhaskaran and co-workers showed that murine macrophages pretreated with chamomile are protected from cell death caused by H 2 O 2 . ...
Background:
We found the first evidence of the efficacy of a herbal treatment with myrrh, dry extract of chamomile flowers, and coffee charcoal for ulcerative colitis (UC). However, the impact of the herbal treatment on the CD4+ T-cell compartment, which is essential for both the induction of UC and the maintenance of tolerance in the gut, is not well understood.
Aim:
To analyze the frequency and functional phenotype of CD4+ T cells and of immune-suppressive CD4+CD25high regulatory T cells (Tregs) in healthy control subjects, patients with UC in remission, and patients with clinical flare of UC.
Methods:
Patients in clinical remission were treated with either mesalazine or the herbal preparation for 12 months. The frequencies of whole CD4+ T cells, CD4+CD25med effector T cells, and Tregs and the expression of Foxp3 within the CD4+CD25hig Tregs were determined by flow cytometry at 6 time points. We determined the suppressive capability of Tregs from healthy control subjects and from patients in remission or clinical flare.
Results:
A total of 79 patients (42 women, 37 men; mean age, 48.5 years; 38 with clinical flare) and 5 healthy control subjects were included in the study. At baseline the frequencies of whole CD4+ T cells, CD4+CD25med effector cells, and Tregs did not differ between the two treatment groups and the healthy control subjects. In addition, patients with UC in sustained clinical remission showed no alteration from baseline after 1, 3, 6, 9, or 12 months of either treatment. In contrast, CD4+ T cells, CD4+CD25med effector T cells, and Tregs demonstrated distinctly different patterns at time points pre-flare and flare. The mesalazine group showed a continuous but not statistically significant increase from baseline to pre-flare and flare (p = ns). In the herbal treatment group, however, the percentage of the CD4+ T cells was lower at pre-flare than at baseline. This decrease was completely reversed after flare, when a significant increase was seen (CD4+CD25med pre-flare/flare p = 0.0461; CD4+CD25high baseline/flare p = 0.0269 and pre-flare/flare p = 0.0032). In contrast, no changes in the expression of Foxp3 cells were detected within the subsets of CD4+CD25high regulatory T cells. Of note, no alterations were detected in the suppressive capability of CD4+CD25high regulatory T cells isolated from the peripheral blood of healthy donors, from patients in remission, or from patients with clinical flare.
Conclusions:
In patients with UC experiencing acute flare, the CD4+ T compartment demonstrates a distinctly different pattern during treatment with myrrh, chamomile extract, and coffee charcoal than during treatment with mesalazine. These findings suggest an active repopulation of regulatory T cells during active disease.
Trial registration:
EU Clinical Trials Register 2007-007928-18/DE.
... Many studies have shown that a number of plant-based extracts (phytopharmaceuticals) induce HO-1, leading to ameliorated oxidative stress and inflammation. The sources of these compounds are several different plant species and plant organs, ranging from seeds to fruits to leaves to roots [238,245,247,[280][281][282][283][284][285][286][287][288][289][290][291][292][293]. Some of these compounds can be Fig. ...
Heme oxygenase-1 (HO-1) is a highly inducible and ubiquitous cellular enzyme that sub-serves cytoprotective responses to toxic insults, including inflammation and oxidative stress. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, brain HO-1 expression is increased, presumably reflecting an endogenous neuroprotective response against ongoing cellular injury. In contrast,we have found in human immunodeficiency virus (HIV) infection of the brain, which is also associated with inflammation, oxidative stress, and neurodegeneration, HO-1 expression is decreased, likely reflecting a unique role for HO-1 deficiency in neurodegeneration pathways activated by HIV infection. We have also shown that HO-1 expression is markedly suppressed by HIV replication in cultured macrophages, which represent the primary cellular reservoir for HIV in the brain. HO-1 deficiency is associated with release of neurotoxic levels of glutamate from both HIV-infected and immune-activated macrophages; this glutamate mediated neurotoxicity is suppressed by pharmacological induction of HO-1 expression in the macrophages.Thus, HO-1 induction could be a therapeutic strategy for neuroprotection against HIV infection and other neuroinflammatory brain diseases. Here, we review various stimuli and signaling pathways regulating HO-1 expression in macrophages, which could promote neuronal survival through HO-1-modulation ofendogenous antioxidant and immune modulatory pathways, thus limiting the oxidative stress that can promote HIV disease progression in the CNS. The use of pharmacological inducers of endogenous HO-1 expression as potential adjunctive neuroprotective therapeutics in HIV infection is also discussed.
Background: Chemotherapy-induced neuropathic pain (CINP) is a debilitating side effect in individuals undergoing cancer treatment. Treatment of CINP with the current available classes of drugs is limited and often yields unsatisfactory results. Finding therapeutic alternatives of plant origin could provide a new way for the management of CINP. Commiphora myrrha (CM) resin extract has been reported to have anti-inflammatory and analgesic activities, but the effect of CM on neuropathic pain is yet to be investigated in CINP.
Objectives: The aim of this study was to investigate the antinociceptive effect of CM extract in a mouse model of paclitaxel-induced neuropathic pain (PINP).
Methods: The effects of CM on thermal hyperalgesia and mechanical allodynia were assessed in female BALB/c mice with PINP using a hot plate and a plantar aesthesiometer, respectively. Motor coordination was evaluated using a rotarod apparatus. The involvement of transient receptor potential vanilloid channel 1 (TRPV1) in CM actions was investigated using a capsaicin (a TRPV1 agonist)-induced nociception test. The genetic expression of Trpv1, Nrf2, Sod2, and Hmox1 was assessed using real-time PCR, while protein expression of TRPV1, Iba-1, and CD11b was assessed using Wes™.
Results: Administration of CM to mice with established PINP produced a dose-dependent reduction in thermal hyperalgesia. Prophylactic treatment of mice with CM prevented the development of paclitaxel-induced thermal hyperalgesia and mechanical allodynia. CM did not change the motor coordination of mice, as the reaction latency and the rotational velocity of animals pretreated with CM extract were similar to those of animals pretreated with vehicle. CM significantly decreased the number and duration of the flick responses following capsaicin injection into the dorsal surface of the hind paw of mice. The protein expression of TRPV1 was upregulated in the spinal cord of paclitaxel-treated animals compared to vehicle-only-treated control animals, while CM-treated animals had values similar to vehicle-only-treated control animals. The mRNA expression of Nrf2, a major antioxidant transcription factor, was upregulated in the paw skin of mice treated with CM compared to those treated with paclitaxel alone.
Conclusion: These results indicate that CM may both treat established and prevent the development of paclitaxel-induced thermal hyperalgesia and mechanical allodynia without any impairment in the motor activity of mice. CM may mediate its action through the peripheral inhibition of TRPV1 channel activity, restoration of normal TRPV1 protein expression in the spinal cord, and elevation of cellular antioxidant defenses. CM has the potential to be used as a therapeutic alternative to treat CINP.
Chlorogenic acid (CA) and sodium alginate (SA) each have good therapeutic effects on ulcerative colitis (UC) owing to their antioxidant and anti-inflammatory activity. This study aimed to investigate the effects of CA alone and in combination with SA on inflammatory cells and UC mice. In the Lipopolysaccharide (LPS)-induced RAW 264.7 inflammatory cell model, Nitric oxide (NO) and interleukin-6 (IL-6) levels were significantly lower after treatment with CA plus SA than with CA alone. In the DSS-induced UC mouse model, compared with CA alone, CA plus SA showed a better ability to alleviate weight loss, reduce the disease activity index (DAI), improve the colonic mucosa, reduce the expression of inflammatory factors in the serum and myeloperoxidase (MPO) in colonic tissue, increase superoxide dismutase (SOD) levels, protect the intestinal mucosa and regulate the abundance of Actinobacteriota, Lactobacillus, Bifidobacterium, Bacteroides, Subdoligranulum and Streptococcus. Thus, CA plus SA can improve the therapeutic efficacy of CA in UC by regulating inflammatory factors, oxidative stress, and the intestinal flora and by protecting ulcerative wounds. These findings broaden our understanding of the role of the combination of SA and CA in enhancing the effects of CA on UC and provide strategies for prevention and treatment.
This study aimed to investigate whether activation of haeme oxygenase (HO)-1 enzyme by haemin would have beneficial effects on the functional and histological outcome against gentamicin-induced renal damage in rats and sought to elucidate the underlying mechanisms of the therapeutic action.
Nephrotoxicity was induced by injection of gentamicin (80 mg/kg, i.p.) once daily for seven days. Haemin (50 μmol/kg, i.p.) was given to the control and gentamicin-treated rats in the presence or absence of a HO-1 inhibitor, zinc protoporphyrin IX (ZnPP, 50 μmol/kg per day, i.p.).
Haemin treatment prevented gentamicin-induced elevated serum creatinine, urinary protein levels and ameliorated the impaired creatinine clearance. Haemin compensated the deficits in antioxidant enzyme activity and attenuated lipid peroxidation along with decreased reactive oxygen species (ROS) production in renal tissues due to gentamicin. Moreover, haemin pre-administration evoked increased renal HO-1 activity. Additionally, haemin significantly attenuated elevated renal tumour necrosis factor-α (TNF-α), nuclear factor-kappaB (NF-κB) levels and caspase-3 activity alongside ameliorating glomerular pathology. These therapeutic effects were abolished by ZnPP pretreatment.
Here is the first evidence demonstrating the protective effect of HO-1 against gentamicin-associated nephrotoxicity. Suppression of oxidative/inflammatory insults alongside the corresponding decline of apoptosis were presumably responsible for this renoprotection.
To examine the role of trypsin in the immune response of macrophages and to determine whether protease-activated receptors (PARs) are involved in the effects of trypsin.
We used RAW264.7 cells and peritoneal macrophages isolated from C57BL/6 wild-type mice, PAR2 knockout mice, and ddY mice. Macrophages were stimulated with lipopolysaccharide (LPS) in the presence or absence of trypsin, thrombin, and PAR subtype-specific agonists (PARs-AP). Activation of macrophages was quantified by nitric oxide production and expression of inflammatory mediators, such as inducible nitric oxide synthase, interleukin-1β, and interleukin-6. To clarify the effect of trypsin on LPS receptors, we also investigated the expression of toll-like receptor 4 (TLR4), soluble MD-2 (sMD-2), membrane-bound MD-2 (mMD-2), soluble CD14 (sCD14), and membrane-bound CD14 (mCD14). To directly investigate the effect of trypsin on CD14 protein, we expressed recombinant CD14 protein.
Trypsin inhibited LPS-induced nitric oxide production and expression of inducible nitric oxide synthase, interleukin-1β, and interleukin-6. The same inhibitory effects of trypsin were observed in wild-type macrophages and in PAR2 knockout macrophages. Furthermore, the other PAR agonists, thrombin, PAR1-AP, PAR2-AP, and PAR4-AP, did not mimic the effect of trypsin. Although trypsin did not affect TLR4 or mMD-2 expression, sCD14, mCD14, and sMD-2 expressions were decreased by trypsin. Furthermore, trypsin also degraded recombinant CD14 protein.
Trypsin inhibited LPS signaling PAR-independently via degradation of TLR4 accessory molecules. This observation provides a better understanding of the complicated immune response in acute pancreatitis.
The resinous exudates of the Commiphora species, known as 'myrrh', are used in traditional Chinese medicine for the treatment of trauma, arthritis, fractures and diseases caused by blood stagnation. Myrrh has also been used in the Ayurvedic medical system because of its therapeutic effects against inflammatory diseases, coronary artery diseases, gynecological disease, obesity, etc.
Based on a comprehensive review of traditional uses, phytochemistry, pharmacological and toxicological data on the genus Commiphora, opportunities for the future research and development as well as the genus' therapeutic potential are analyzed.
Information on the Commiphora species was collected via electronic search (using Pubmed, SciFinder, Scirus, Google Scholar and Web of Science) and a library search for articles published in peer-reviewed journals. Furthermore, information also was obtained from some local books on ethnopharmacology. This paper covers the literature, primarily pharmacological, from 2000 to the end of December 2011.
The resinous exudates from the bark of plants of the genus Commiphora are important indigenous medicines, and have a long medicinal application for arthritis, hyperlipidemia, pain, wounds, fractures, blood stagnation, in Ayurvedic medicine, traditional Chinese medicine and other indigenous medical systems. Phytochemical investigation of this genus has resulted in identification of more than 300 secondary metabolites. The isolated metabolites and crude extract have exhibited a wide of in vitro and in vivo pharmacological effects, including antiproliferative, antioxidant, anti-inflammatory and antimicrobial. The bioactive steroids guggulsterones have attracted most attention for their potent hypolipidemic effect targeting farnesoid X receptor, as well as their potent inhibitory effects on tumor cells and anti-inflammatory efficiency.
The resins of Commiphora species have emerged as a good source of the traditional medicines for the treatment of inflammation, arthritis, obesity, microbial infection, wound, pain, fractures, tumor and gastrointestinal diseases. The resin of C. mukul in India and that of C. molmol in Egypt have been developed as anti-hyperlipidemia and antischistosomal agents. Pharmacological results have validated the use of this genus in the traditional medicines. Some bioassays are difficult to reproduce because the plant materials used have not been well identified, therefore analytical protocol and standardization of extracts should be established prior to biological evaluation. Stem, bark and leaf of this genus should receive more attention. Expansion of research materials would provide more opportunities for the discovery of new bioactive principles from the genus Commiphora.
Chronic inflammatory response in the brain is a characteristic etiopathology of various neurodegenerative diseases; consequently increasing the intrinsic anti-inflammatory potency could be an especially desirable strategy to prevent inflammation-related neuronal injuries. Transcription factor NF-E2-related factor-2 (Nrf2)-mediated control of redox homeostasis may participate in the modulation of microglial responses by regulating expression of important antioxidant and phase II detoxification genes. In our present work, we show that artesunate, a semi-synthetic derivative of anti-malarial agent artemisinin, attenuates LPS-induced inflammatory responses in microglial BV2 cells. Artesunate activates Nrf2-ARE system, and leads to an increase in the level of downstream heme oxygenase-1. Artesunate also activates PI3K/Akt, ERK, and JNK MAPKs signaling, but artesunate-induced activation of Nrf2 signaling and up-regulation of heme oxygenase-1 are ERK pathway-dependent. Collectively, this study demonstrates that artesunate is a potential activator of the Nrf2/ARE-dependent pathway and is therapeutically relevant to inflammatory responses of microglial cells.
Heme oxygenase (HO)-1 is an inducible enzyme that catalyzes the first and rate-limiting step in the oxidative degradation of free heme into ferrous iron, carbon monoxide (CO), and biliverdin (BV), the latter being subsequently converted into bilirubin (BR). HO-1, once expressed during inflammation, forms high concentrations of its enzymatic by-products that can influence various biological events, and this expression is proven to be associated with the resolution of inflammation. The degradation of heme by HO-1 itself, the signaling actions of CO, the antioxidant properties of BV/BR, and the sequestration of ferrous iron by ferritin all concertedly contribute to the anti-inflammatory effects of HO-1. This review focuses on the anti-inflammatory mechanisms of HO-1 actions and its roles in inflammatory diseases.
Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe(2+), carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism underlying this cytoprotective effect relies on the ability of HO-1 to catabolize free heme and prevent it from sensitizing cells to undergo programmed cell death. This cytoprotective effect inhibits the pathogenesis of a variety of immune-mediated inflammatory diseases.
The first known human case of heme oxygenase-1 (HO-1) deficiency is presented in this report. The patient is a six-year-old boy with severe growth retardation. He has been suffering from persistent hemolytic anemia characterized by marked erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum haptoglobin and low bilirubin. An abnormal coagulation/fibrinolysis system, associated with elevated thrombomodulin and von Willebrand factor, indicated the presence of severe, persistent endothelial damage. Electron microscopy of renal glomeruli revealed detachment of endothelium, with subendothelial deposition of an unidentified material. Iron deposition was noted in renal and hepatic tissue. Immunohistochemistry of hepatic tissue and immunoblotting of a cadmium-stimulated Epstein-Barr virus-transformed lymphoblastoid cell line (LCL) revealed complete absence of HO-1 production. An LCL derived from the patient was extremely sensitive to hemin-induced cell injury. Sequence analysis of the patient's HO-1 gene revealed complete loss of exon-2 of the maternal allele and a two-nucleotide deletion within exon3 of the paternal allele. Growth retardation, anemia, iron deposition, and vulnerability to stressful injury are all characteristics observed in recently described HO-1 targeted mice. This study presents not only the first human case of HO-1 deficiency but may also provide clues to the key roles played by this important enzyme in vivo.
Septic shock, caused by exaggerated host responses to various microbial products typified by lipopolysaccharide (LPS), remains the leading cause of death in trauma patients. Gaining insight into the nature of host interactions with LPS will certainly facilitate attempts to develop effective anti-sepsis drugs. Tremendous progress has been made during the past few years in understanding the mechanisms of pathogen-induced host responses. Toll-like receptor (TLR) 4 and 2 have been implicated as major receptors for signaling initiated by LPS and many other microbial products following their binding to CD14. In addition, many signaling intermediates involved in LPS-induced cell activation, particularly activation of the transcription factor NF-kappaB, have been identified and characterized. Further investigations with these molecules will certainly reward us with more effective therapeutic drugs to treat septic shock as well as many other inflammatory and infectious disorders.
Occurrence, constituents and medicinal use of myrrh, obtained from the stem of different Commiphora species are reviewed. The constituents of the volatile oil, the resin and the gum are outlined in detail. Myrrh has considerable antimicrobial activity and is medicinally used in a variety of diseases.
The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress and modulates pro-inflammatory cytokines. As the sepsis syndrome results from the release of pro-inflammatory mediators, we postulated that heme oxygenase-1 and its enzymatic product CO would protect against lethality in a murine model of sepsis. Mice treated with a lethal dose of lipopolysaccharide (LPS) and subsequently exposed to inhaled CO had significantly better survival and lower serum interleukin (IL)-6 and IL-1beta levels than their untreated counterparts. In vitro, mouse macrophages exposed to LPS and CO had significantly attenuated IL-6 production; this effect was concentration-dependent and occurred at a transcriptional level. The same effect was seen with increased endogenous CO production through overexpression of heme oxygenase-1. Mutation within the AP-1-binding site in the IL-6 promoter diminished the effect of CO on promoter activity, and treatment of macrophages with CO decreased AP-1 binding in an electrophoretic mobility shift assay. Electrophoretic mobility supershift assay indicated that the JunB, JunD, and c-Fos components of AP-1 were particularly affected. Upstream of AP-1, CO decreased JNK phosphorylation in murine macrophages and lung endothelial cells. Mice deficient in the JNK pathway had decreased serum levels of IL-6 and IL-1beta in response to LPS compared with control mice, and no effect of CO on these cytokine levels was seen in Jnk1 or Jnk2 genedeleted mice. In summary, these results suggest that CO provides protection in a murine model of sepsis through modulation of inflammatory cytokine production. For the first time, the effect of CO is shown to be mediated via the JNK signaling pathway and the transcription factor AP-1.
Herbal extracts from Commiphora mukul (guggul) have been widely used in Asia as cholesterol-lowering agents, and their popularity is increasing in the United States. Recently, guggulsterones, the purported bioactive compounds of guggul, have been shown to be potent antagonists of 2 nuclear hormone receptors involved in cholesterol metabolism, establishing a plausible mechanism of action for the hypolipidemic effects of these extracts. However, there are currently no published safety or efficacy data on the use of guggul extracts in Western populations.
To study the short-term safety and efficacy of 2 doses of a standardized guggul extract (guggulipid, containing 2.5% guggulsterones) in healthy adults with hyperlipidemia eating a typical Western diet.
Double-blind, randomized, placebo-controlled trial using a parallel design, conducted March 2000-August 2001.
A total of 103 ambulatory, community-dwelling, healthy adults with hypercholesterolemia in the Philadelphia, Pa, metropolitan area.
Oral, 3 times daily doses of standard-dose guggulipid (1000 mg), high-dose guggulipid (2000 mg), or matching placebo.
Percentage change in levels of directly measured low-density lipoprotein cholesterol (LDL-C) after 8 weeks of therapy. Secondary outcome measures included levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and directly measured very low-density lipoprotein cholesterol (VLDL-C), as well as adverse events reports and laboratory safety measures including electrolyte levels and hepatic and renal function.
Compared with participants randomized to placebo (n = 36), in whom levels of LDL-C decreased by 5%, both standard-dose guggulipid (n = 33) and high-dose guggulipid (n = 34) raised levels of LDL-C by 4% (P =.01 vs placebo) and 5% (P =.006 vs placebo), respectively, at 8 weeks, for a net positive change of 9% to 10%. There were no significant changes in levels of total cholesterol, HDL-C, triglycerides, or VLDL-C in response to treatment with guggulipid in the intention-to-treat analysis. While guggulipid was generally well tolerated, 6 participants treated with guggulipid developed a hypersensitivity rash compared with none in the placebo group.
Despite plausible mechanisms of action, guggulipid did not appear to improve levels of serum cholesterol over the short term in this population of adults with hypercholesterolemia, and might in fact raise levels of LDL-C. Guggulipid also appeared to cause a dermatologic hypersensitivity reaction in some patients.
Guggulsterone, derived from Commiphora mukul and used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, has been recently shown to antagonize the farnesoid X receptor and decrease the expression of bile acid-activated genes. Because activation of NF-kappaB has been closely linked with inflammatory diseases affected by guggulsterone, we postulated that it must modulate NF-kappaB activation. In the present study, we tested this hypothesis by investigating the effect of this steroid on the activation of NF-kappaB induced by inflammatory agents and carcinogens. Guggulsterone suppressed DNA binding of NF-kappaB induced by tumor necrosis factor (TNF), phorbol ester, okadaic acid, cigarette smoke condensate, hydrogen peroxide, and interleukin-1. NF-kappaB activation was not cell type-specific, because both epithelial and leukemia cells were inhibited. Guggulsterone also suppressed constitutive NF-kappaB activation expressed in most tumor cells. Through inhibition of IkappaB kinase activation, this steroid blocked IkappaBalpha phosphorylation and degradation, thus suppressing p65 phosphorylation and nuclear translocation. NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK was also blocked by guggulsterone but without affecting p65-mediated gene transcription. In addition, guggulsterone decreased the expression of gene products involved in anti-apoptosis (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), proliferation (cyclin D1 and c-Myc), and metastasis (MMP-9, COX-2, and VEGF); this correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents. Overall, our results indicate that guggulsterone suppresses NF-kappaB and NF-kappaB-regulated gene products, which may explain its anti-inflammatory activities.
Bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause inducible (i) NO synthase (NOS) synthesis, which in turn produces massive amounts of nitric oxide (NO). NO, by inactivating enzymes and leading to cell death, is toxic not only to invading viruses and bacteria, but also to host cells. Injection of LPS induces interleukin (IL)-1beta, IL-1alpha, and iNOS synthesis in the anterior pituitary and pineal glands, meninges, and choroid plexus, regions outside the blood-brain barrier. Thereafter, this induction occurs in the hypothalamic regions (such as the temperature-regulating centers), paraventricular nucleus (releasing and inhibiting hormone neurons), and the arcuate nucleus (a region containing these neurons and axons bound for the median eminence). Aging of the anterior pituitary and pineal with resultant decreased secretion of pituitary hormones and the pineal hormone melatonin, respectively, may be caused by NO. The induction of iNOS in the temperature-regulating centers by infections may cause the decreased febrile response in the aged by loss of thermosensitive neurons. NO may play a role in the progression of Alzheimer's disease and parkinsonism. LPS similarly activates cytokine and iNOS production in the cardiovascular system leading to coronary heart disease. Fat is a major source of NO stimulated by leptin. As fat stores increase, leptin and NO release increases in parallel in a circadian rhythm with maxima at night. NO could be responsible for increased coronary heart disease as obesity supervenes. Antioxidants, such as melatonin, vitamin C, and vitamin E, probably play important roles in reducing or eliminating the oxidant damage produced by NO.
Foods of plant origin, especially fruits and vegetables, draw increased attention because of their potential benefits to human health. The aim of the present study was to determine in vitro anti-inflammatory activity of four different extracts obtained from the fruits of Rubus coreanus (aqueous and ethanol extracts of unripe and ripe fruits). Among the four extracts, the ethanol extract of unripe fruits of R. coreanus (URCE) suppressed nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages. We also demonstrated that URCE by itself is a potent inducer of heme oxygenase-1 (HO-1). Inhibition of HO-1 activity by tin protoporphyrin, a specific HO-1 inhibitor, suppressed the URCE-induced reductions in the production of NO and PGE(2) as well as the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2). Our data suggest that URCE exerts anti-inflammatory effects in macrophages via activation of the HO-1 pathway and helps to elucidate the mechanism underlying the potential therapeutic value of R. coreanus extracts.
Heme oxygenase-1 (HO-1) is a cytoprotective protein whose expression is consistently associated with therapeutic benefits in a number of pathologic conditions such as atherosclerotic vascular disease and inflammation. Although the expression of HO-1 in most tissues is low, a large number of clinical and experimental pharmacologic compounds have been demonstrated to induce HO-1. This induction is suggested to be at least partially responsible for the perceived therapeutic efficacy of these compounds. The increase in HO-1 expression in response to these compounds is the result of a complex regulatory network involving many signaling pathways and transcription factors. Understanding both the pathways by which HO-1 is induced and the mechanism through which the enzyme exerts its beneficial effects may facilitate the development of novel drugs.
Stressed mammalian cells up-regulate heme oxygenase 1 (Hmox1; EC 1.14.99.3), which catabolizes heme to biliverdin, carbon monoxide, and free iron. To assess the potential role of Hmox1 in cellular antioxidant defense, we analyzed the responses of cells from mice lacking functional Hmox1 to oxidative challenges. Cultured Hmox1(-/-) embryonic fibroblasts demonstrated high oxygen free radical production when exposed to hemin, hydrogen peroxide, paraquat, or cadmium chloride, and they were hypersensitive to cytotoxicity caused by hemin and hydrogen peroxide. Furthermore, young adult Hmox1(-/-) mice were vulnerable to mortality and hepatic necrosis when challenged with endotoxin. Our in vitro and in vivo results provide genetic evidence that up-regulation of Hmox1 serves as an adaptive mechanism to protect cells from oxidative damage during stress.
This review will discuss the recent literature on the molecular mechanism of NF-κB activation, with special focus on IκBα dynamism involved in iNOS- and chemokine-induction in glial cells. NF-κB, a heterotrimer composed of p50, p65 (Rel A) and IκBα, has been shown to be activated by elimination of the regulatory subunit IκBα from the heterotrimer. The elimination of IκBα (formation of active NF-κB, p50·p65) is due to phosplorylation of serines 32 and 36 of IκBα, followed by polyubiquitination and 26S proteasomal degradation of IκBα. Experiments using stable clones of rat C6 glioma cells transfected with dominant negative IκBα (serines 32 and 36 replaced by alanine) suggest that NF-κB activation (phosphorylation of IκBα) is involved in LPS/IFNγ- or IL-1β/IFNγ-induced iNOS expression. Furthermore, the time courses of phosphorylation, ubiquitination of IκBα and proteasome activity after IL-1β treatment also suggest that 26S proteasomal degradation of IκBα is more crucial for chemokine expression in glial cells.
From the essential oil of myrrh, Commiphora abyssimica (BERG) ENGLER (Burseraceae) have been isolated: nine sesquiterpenoid hydrocarbons, the sesquiterpene alcohol elemol and the furanosesquiterpenoids furanodiene, furanodienone, isofuranogermacrene, curzerenone and lindestrene.
The regulation of the transcription factor NF-κB activity occurs at several levels including controlled cytoplasmic-nuclear shuttling and modulation of its transcriptional activity. A critical component in NF-κB regulation is the IκB kinase (IKK) complex. This review is focused on recent progress as well as unanswered questions regarding the regulation and function of NF-κB and IKK.
The purification and structure characterization of seven aromatic sesquiterpenes from scented Commiphora myrrha are reported. Their structures were determined on the basis of spectral data, especially of NMR evidence. Among them, compound 1 is a new furanosesquiterpene and compound 2 is identified as a new natural aroma found in Commiphora spp. All compounds except 4 were isolated, for the first time, from Commiphora myrrha. Copyright © 2003 John Wiley & Sons, Ltd.
Patents secured on antiinflammatory plant drugs derived from 38 plants are reviewed. An attempt has been made to compare the modern and traditional use of plant drugs and to establish the relevance of folk claims in developing modern drugs. The role of plant botanicals such as polysaccharides, terpenes, curcuminoids, alkaloids, etc. in alleviating inflammatory diseases including arthritis, rheumatism, acne skin allergy and ulcers is highlighted. Chemicals that alleviate swelling are derived from plants including grape, boswellia, turmeric, devil's claw and some essential oils such as clove, eucalyptus, rosemary, lavender, mint, myrrh, millefolia and pine have been patented and used as mixed formulations. Plants containing polysaccharides are the most potent in curing inflammatory diseases. Copyright © 2004 John Wiley & Sons, Ltd.
Brazilin, the main constituent of Caesalpinia sappan L., is a natural red pigment that has been reported to possess anti-inflammatory properties. This study aimed to identify a novel anti-inflammatory mechanism of brazilin. We found that brazilin did not cause cytotoxicity below 300 μM, and activated heme oxygenase-1 (HO-1) protein synthesis in a concentration-dependent manner at 10–300 μM in RAW264.7 macrophages without affecting mRNA transcription of HO-1. Additionally, brazilin increased bilirubin production and HO-1 activity in RAW264.7 macrophages. In lipopolysaccharide (LPS)-stimulated macrophages, brazilin suppressed the release of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-1β and tumor necrosis factor-α (TNF-α), and reduced the expression of inducible nitric oxide synthase (iNOS). A specific inhibitor of HO-1, Zn(II) protoporphyrin IX, blocked the suppression of NO production, cytokines release and iNOS expression by brazilin. These results suggest that brazilin possesses anti-inflammatory actions in macrophages and works through a novel mechanism involving the action of HO-1.
The hepatic conversion of cholesterol to bile acids is an important mechanism for the elimination of excess dietary cholesterol. Bile acid biosynthesis and transport are regulated by the farnesoid X receptor (FXR), a member of the of nuclear hormone receptor gene superfamily. Thus, therapeutic strategies that target FXR represent a promising new approach for the treatment of hypercholesterolemia. Recent studies have provided new evidence in support of the potential for FXR ligands as antihypercholesterolemic agents.
From the essential oil of myrrh, Commiphora abyssimica (Berg) Engler (Burseraceae) have been isolated: nine sesquiterpenoid hydrocarbons, the sesquiterpene alcohol elemol and the furanosesquiterpenoids furanodiene, furanodienone, isofuranogermacrene, curzerenone and lindestrene.
Safflower, whose botanic name is Carthamus tinctorius L., is a member of the family Compositae or Asteraceae. Carthamus yellow (CY) is the main constituent of safflower and is composed of safflomin A and safflomin B. Dried safflower petals are used in folk medicine and have been shown to invigorate blood circulation, break up blood stasis, and promote menstruation. In addition, dried safflower petals contain yellow dyes that are used to color food and cosmetics. In this study, we investigated the effects of dried safflower petals aqueous extracts (SFA) and CY on lipopolysaccharide (LPS)-induced inflammation using RAW264.7 macrophages.
Our data showed that treatment with SFA (1-1000 microg mL(-1)) and CY (1-2000 microg mL(-1)) does not cause cytotoxicity in cells. SFA and CY inhibited LPS-stimulated nitric oxide (NO), prostaglandin E(2) (PGE(2)), and interleukin 1β (IL-1β) release, through attenuation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression. Further, SFA and CY suppressed the LPS-induced phosphorylation of nuclear factor-κB, which was associated with the inhibition of IκB-α degradation.
These results suggest that SFA and CY provide an anti-inflammatory response through inhibiting the production of NO and PGE(2) by the downregulation of iNOS and COX-2 gene expression. Thus safflower petals have the potential to provide a therapeutic approach to inflammation-associated disorders.
Sappanchalcone has been demonstrated to possess several biological effects. However, the molecular mechanism underlying these effects is not fully understood. In this study, we examined the effects of sappanchalcone on hydrogen peroxide (H(2)O(2))-induced cytotoxicity using human dental pulp (HDP) cells, and lipopolysaccharide (LPS)-induced inflammation using human periodontal ligament (HPDL) cells. Sappanchalone concentration proportionately increased heme oxygenase (HO)-1 protein expression and enzyme activity in both HDP and HPDL cells. It also protected HDP cells from H(2)O(2)-induced cytotoxicity and reactive oxygen species production. The cytoprotective effect of sappanchalcone was nullified by HO-1 inhibitor, Tin protoporphyrin (SnPP). Sappanchalcone is seen to inhibit LPS-stimulated nitric oxide (NO), prostaglandin E(2) (PGE(2)), interlukine-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interlukine-6 (IL-6) and interlukine-12 (IL-12) release in addition to inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in HPDL cells. SnPP, a specific inhibitor of HO-1, partly blocked sappanchalcone mediated suppression of inflammatory mediator production, in LPS-stimulated HPDL cells. HDP and HPDL cells treated with sappanchalcone exhibited the transient activation of c-Jun NH2-terminal kinase (JNK) and NF-E2-related factor-2 (Nrf2). The expression of HO-1 protein by sappanchalcone was significantly reduced by pretreatment with JNK inhibitor. In conclusion, induction of HO-1 is an important cytoprotective mechanism by which sappanchalcone protects HDP cells from H(2)O(2) and in addition it also exhibits anti-inflammatory effects in LPS-stimulated HPDL cells. Thus, sappanchalcone could potentially be a therapeutic approach for periodontal, pulpal and periapical inflammatory lesion.
Myrrh (Commiphora molmol) has been widely used as an anti-inflammatory and wound healing commercial product. As white blood cell (WBC)/leukocyte counts have been used as an indicator by clinicians to monitor progress of healing in patients, the purpose of this study was to examine effects of myrrh supplementation on blood WBC numbers before an injury and during healing. Male rats (7-8-wk-of-age) were randomly assigned to four groups. Group 1 (SIM) served as "skin injury treated + myrrh treatment (500 mg/kg/day)," Group 2 (SI) as "skin injury alone", Group 3 (GUM) as "gastric ulcer treated + myrrh treatment", and Group 4 (GU) as gastric ulcer only. Myrrh treatments (via drinking water) began 4 wk before induction of injury and continued for a 2 wk period post-injury. Baseline values for each WBC type were recorded before start of the myrrh treatments. Counts were performed again on Day 1 of the 5th wk (1-2 hr before injury) and post-injury on Days 4 and 7 of the 5th wk, and a final time on Day 4 of the 6th wk. Results showed that levels of all WBC types were significantly (P < 0.05) elevated before either injury in myrrh-treated rats (Groups 1 and 3) as compared with levels in rats in Groups 2 and 4. At all timepoints, there were neither significant differences between the values seen with rats in Groups 1 and 3, nor between those in Groups 2 and 4. Treatment with myrrh also induced an initial increase in WBC levels that persisted through the post-injury healing period. Levels of most cell types only increased in the Group 2 and 4 rats once the injury was induced, but then declined over the healing period. Since myrrh enhanced WBC levels before injury, we conclude that myrrh likely contains substances that could induce an apparent antigen-driven response. As the myrrh also helped maintain elevated WBC levels throughout the healing period, this implied it was also able to induce maturation/differentiation/activation of both myeloid and lymphoid cell types during the effector phase of the immune responses involved in wound healing.
The possible role of Commiphora molmol emulsion (CME) in protecting against lead (PbAc)-induced hepatotoxicity, oxidative stress and immunotoxicity in rabbits was assessed. Six groups of animals were used: groups I (control) and II (PbAc) were not supplemented with CME. Groups III (CME50) and IV (CME50+PbAc) were administered with CME in a dose rate of 50mg/kg bwt, while groups V (CME100) and VI (CME100+PbAc) were received 100mg CME/kg bwt daily p.o for successive 14 weeks. Groups II, IV and VI were given 80 mg PbAc/kg bwt/day orally for 6 weeks starting from the 9th week. At the 12th week, animals were subjected to immunization by a single dose of sheep RBCs. The PbAc-group showed 220% increase in hepatic malondialdehyde levels, while glutathione, glutathione s-transferase and glutathione peroxidase levels decreased. Lead-acetate induced hypoproteinemia and hypoalbuminemia, and increased aminotransferases activity. It reduced the values of lymphocyte transformation test, phagocytic activity, phagocytic index and antibody titer against sheep SRBCs. Interestingly, pretreatment with CME attenuated these adverse effects in a dose-dependent protection. CME, therefore, is a potent antioxidant, and can protect against PbAc-induced hepatic oxidative damage and immunotoxicity by reducing lipid peroxidation and enhancing the antioxidant and immune defense mechanisms.
Nitrosative stress caused by reactive nitrogen species such as nitric oxide and peroxynitrite overproduced during inflammation leads to cell death and has been implicated in the pathogenesis of many human ailments. However, relatively mild nitrosative stress may fortify cellular defense capacities, rendering cells tolerant or adaptive to ongoing and subsequent cytotoxic challenges, a phenomenon known as 'preconditioning' or 'hormesis'. One of the key components of cellular stress response is heme oxygenase-1 (HO-1), the rate limiting enzyme in the process of degrading potentially toxic free heme into biliverdin, free iron and carbon monoxide. HO-1 is upregulated by a wide array of stimuli and has antioxidant, anti-inflammatory and other cytoprotective functions. This review is intended to provide readers with a welldocumented account of the research done in the area of cellular adaptive survival response against nitrosative stress with special focus on the role of HO-1 upregulation, especially through activation of the transcription factor, Nrf2.
Guggul, herbal extract from resin of the Commiphora mukul tree, is widely used in Asia as a cholesterol-lowering agent based on Indian Ayurvedic medicine. Its popularity for this use is increasing in the US and Western Europe. Guggulsterones, the presumed bioactive compounds of guggul, may antagonise two nuclear hormone receptors involved in cholesterol metabolism, which is a possible explanation for hypolipidemic effects of these extracts. However, publications of efficacy data on the use of guggul extracts in Western populations are scarce.
Oxidative damage is involved in the pathogenesis of various hepatic injuries. In the present study the capacity of Commiphora berryi (Arn) Engl bark as an antioxidant to protect against CCl(4)-induced oxidative stress and hepatotoxicity in Albino Wistar rats was investigated. Intraperitoneal injection of CCl(4), administered twice a week, produced a marked elevation in the serum levels of aspartate transaminase, alanine transaminase, alkaline phosphatase and bilirubin. Histopathological analysis of the liver of CCl(4)-induced rats revealed marked liver cell necrosis with inflammatory collections that were conformed to increase in the levels of SOD, GPx and CAT. Daily oral administration of methanolic extract of C. berryi (Arn) Engl bark at 100 and 200mg/kg doses for 15 days produced a dose-dependent reduction in the serum levels of liver enzymes. Treatment with C. berryi normalized various biochemical parameters of oxidative stress and was compared with standard Silymarin. Therefore, the results of this study show that C. berryi (Arn) Engl bark can be proposed to protect the liver against CCl(4)-induced oxidative damage in rats, and the hepatoprotective effect might be correlated with its antioxidant and free radical scavenger effects.
The anticarcinogenic potential of Commiphora molmol (oleoresin) was studied in Ehrlich-solid-tumor-bearing mice. The antitumor activity of C. molmol was evaluated from the total count and viability of Ehrlich solid tumor cells and their nucleic acid, protein, malondialdehyde and glutathione levels at the end of 25 and 50 days of treatment. Furthermore, observations of animal survival rate and measurements of the tumor and body weight were made. The Ehrlich solid tumors were also evaluated for histopathological changes. Treatment with C. molmol (250 and 500 mg/kg/day) was found to be cytotoxic in Ehrlich solid tumors cells. The antitumor potential of C. molmol was comparable to the standard cytotoxic drug cyclophosphamide. This effect of C. molmol was less pronounced after 50 days of treatment. The present study confirmed the cytotoxic and anticarcinogenic potential of C. molmol. Further studies are warranted to explore its mode of action and safety for medicinal use in cancer therapy.
The transcription factor NF-kappa B has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-kappa B is through interactions with an inhibitor protein called I kappa B. Recent evidence confirms the existence of multiple forms of I kappa B that appear to regulate NF-kappa B by distinct mechanisms. NF-kappa B can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-kappa B to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of I kappa B. Exciting new research has elaborated several important and unexpected findings that explain mechanisms involved in the activation of NF-kappa B. In the nucleus, NF-kappa B dimers bind to target DNA elements and activate transcription of genes encoding proteins involved with immune or inflammation responses and with cell growth control. Recent data provide evidence that NF-kappa B is constitutively active in several cell types, potentially playing unexpected roles in regulation of gene expression. In addition to advances in describing the mechanisms of NF-kappa B activation, excitement in NF-kappa B research has been generated by the first report of a crystal structure for one form of NF-kappa B, the first gene knockout studies for different forms of NF-kB and of I kappa B, and the implications for therapies of diseases thought to involve the inappropriate activation of NF-kappa B.
The cardiovascular effects of aqueous extracts from the branches of Commiphora opobalsamum tree were investigated. The intravenous administration of 4 mg/kg of the aqueous extract depressed systemic arterial blood pressure by 20% (P < 0.01) and reduced heart rate of anaesthetised rats by 14% (P < 0.05). The hypotensive and the bradycardiac effects were immediate and in a dose related manner. The hypotensive effect of C. opobalsamum was inhibited by the pretreatment with atropine sulfate (1-4 mg/kg). These results suggest that the hypotensive effect of C. opobalsamum is due to the activation of muscarinic cholinergic receptors.
Stressed mammalian cells up-regulate heme oxygenase 1 (Hmox1; EC 1.14.99.3), which catabolizes heme to biliverdin, carbon monoxide, and free iron. To assess the potential role of Hmox1 in cellular antioxidant defense, we analyzed the responses of cells from mice lacking functional Hmox1 to oxidative challenges. Cultured Hmox1(-/-) embryonic fibroblasts demonstrated high oxygen free radical production when exposed to hemin, hydrogen peroxide, paraquat, or cadmium chloride, and they were hypersensitive to cytotoxicity caused by hemin and hydrogen peroxide. Furthermore, young adult Hmox1(-/-) mice were vulnerable to mortality and hepatic necrosis when challenged with endotoxin. Our in vitro and in vivo results provide genetic evidence that up-regulation of Hmox1 serves as an adaptive mechanism to protect cells from oxidative damage during stress.
The in vitro cytotoxicology of triclosan, the active ingredient in some mouthrinses and dentifrices used in the prevention and treatment of gingivitis and plaque, was studied using the Smulow-Glickman (S-G) human gingival epithelial cell line. The 24 h midpoint cytotoxicity value was 0.05-0.06 mM triclosan as assessed with the neutral red (NR) assay. Triclosan is used in dentifrices in combination with either zinc citrate or sodium fluoride (NaF). The sequence of potencies of these test agents, as assessed with the NR assay, was triclosan>zinc citrate>NaF; combinations of triclosan + zinc citrate and triclosan + NaF were additive in their toxicities. Damage to the integrity of the plasma membrane, as assessed by the leakage of lactic acid dehydrogenase during a 3-h exposure, was initially evident with 0.1 mM triclosan. When exposed to triclosan for 3 d, a lag in the growth kinetics of the S-G cells was first observed at 0.01 mM triclosan. A reduction in attachment of S-G cells to dentin chips, previously exposed to triclosan for 1 h, was noted at 0.25 mM triclosan and greater. Triclosan-induced cell death was apparently by apoptosis, as noted by fluorescence microscopy and DNA agarose gel electrophoresis of extracted oligonucleosomal fragments.
We extracted, purified and characterized 8 sesquiterpene fractions from Commyphora molmol. In particular, we focused our attention on a mixture of furanodiene-6-one and methoxyfuranoguaia-9-ene-8-one, which showed antibacterial and antifungal activity against standard pathogenic strains of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans, with minimum inhibitory concentrations ranging from 0.18 to 2.8 micrograms/ml. These compounds also had local anaesthetic activity, blocking the inward sodium current of excitable mammalian membranes.
This review will discuss the recent literature on the molecular mechanism of NF-kappaB activation, with special focus on IkappaB alpha dynamism involved in iNOS- and chemokine-induction in glial cells. NF-kappaB, a heterotrimer composed of p50, p65 (Rel A) and IkappaB alpha, has been shown to be activated by elimination of the regulatory subunit IkappaB alpha from the heterotrimer. The elimination of IkappaB alpha (formation of active NF-kappaB, p50-p65) is due to phosplorylation of serines 32 and 36 of IkappaB alpha, followed by polyubiquitination and 26S proteasomal degradation of IkappaB alpha. Experiments using stable clones of rat C6 glioma cells transfected with dominant negative IkappaB alpha (serines 32 and 36 replaced by alanine) suggest that NF-kappaB activation (phosphorylation of IkappaB alpha) is involved in LPS/IFNgamma- or IL-1beta/IFNgamma-induced iNOS expression. Furthermore, the time courses of phosphorylation, ubiquitination of IkappaB alpha and proteasome activity after IL-1beta treatment also suggest that 26S proteasomal degradation of IkappaB alpha is more crucial for chemokine expression in glial cells.
Prostaglandins are potent lipid molecules that affect key aspects of immunity. The original view of prostaglandins was that they were simply immunoinhibitory. This review focuses on recent findings concerning prostaglandin E2 (PGE2) and the PGD2 metabolite 15-deoxy-Delta(12,14)-PGJ2, and their divergent roles in immune regulation. We will highlight how these two seminal prostaglandins regulate immunity and inflammation, and play an emerging role in cancer progression. Understanding the diverse activities of these prostaglandins is crucial for the development of new therapies aimed at immune modulation.
Nitric oxide (NO) plays an important regulatory/modulatory role in a variety of inflammatory conditions. NO is a small, short-lived molecule that is released from a variety of cells in response to homeostatic and pathologic stimuli. It may act as a vasodilator and a platelet inhibitor and may interfere with adhesion molecules to prevent neutrophil adhesion. NO release may also lead to the formation of highly reactive species such as peroxynitrite and stable nitrosothiols and may cause mitochondrial damage and nitration of protein tyrosine residues. In addition, NO inhibits cell proliferation via inhibition of polyamine synthesis and cell uptake and may well act as a 'brake' on the proliferative response following cytokine exposure. All three isoforms of nitric oxide synthases are found in the kidney during inflammation. The site of NO release impacts significantly on its net function and structural impact. NO plays a protective role in many forms of immune injury, such as nephrotoxic serum-induced glomerulonephritis, autoimmune tubular interstitital nephritis, and experimental allergic encephalomyelitis. NO overproduction in sepsis, after cytokine exposure, inducible NO synthase transcription, and local inflammation can autoinhibit endothelial NO synthase, leading to selective renal and mesenteric vasoconstriction.
Three new (1-3) and five known compounds (4-8) were isolated from the oleogum resin of Commiphora wightii (Arnott.) Bhanol. Their structures were elucidated by spectroscopic and chemical methods. The MeOH extract and the EtOAc-sol. fraction were found to demonstrate significant inhibition of NO formation in lipopolysaccharide (LPS)-activated murine macrophages J774.1 in vitro (IC(50) values of 16.4 and 12.8 microg/ml, respectively). When compared with curcumin (IC(50) value of 12.3 microM), Z- and E-Guggulsterones (4 and 5, respectively) were the most potent inhibitors of NO production (IC(50) values of 1.1 and 3.3 microM, respectively), followed by myrrhanol A (7) and myrrhanone A (8) (IC(50) values of 21.1 and 42.3 microM, respectively). Guggulsterone-M (1) and its didehydro derivative (2) were weak inhibitors, while guggulsterols I (6) and Y (3) were inactive (IC(50) >500 microM).
The resin of the Commiphora mukul tree has been used in Ayurvedic medicine for more than 2000 years to treat a variety of ailments. Studies in both animal models and humans have shown that this resin, termed gum guggul, can decrease elevated lipid levels. The stereoisomers E- and Z-guggulsterone have been identified as the active agents in this resin. Recent studies have shown that these compounds are antagonist ligands for the bile acid receptor farnesoid X receptor (FXR), which is an important regulator of cholesterol homeostasis. It is likely that this effect accounts for the hypolipidemic activity of these phytosteroids.
Ayurveda, the traditional system of healthcare in India, has many remedies for Osteoarthritis (OA). One of the ingredients most commonly found in Ayurvedic arthritis formulas is guggul, an oleoresin of the herb Commiphora mukul (CM). The authors have conducted both preclinical and clinical investigations of guggul for reduction of pain, stiffness, and improved function, and to determine tolerability in older patients with a diagnosis of OA of the knee.
The study was conducted using an outcome, quasi-experimental, model. Thirty male and female participants meeting the inclusion/exclusion criteria, with a score of 2 or more on the Kellegran-Lawrence scale for at least 1 knee, were admitted in the study. CM was administered in capsule form (500 mg concentrated exact delivered TID) along with food. The WOMAC Total Score was used as a primary outcome measure. VAS scales, 6-minute walk-test, and WOMAC subscales were used as outcome measures.
At the end of treatment, there was a significant difference in the scores of the primary and secondary outcome measures. On the primary measure, WOMAC total score, participants were significantly improved (P < 0.0001) after taking the supplement for 1 month and continued to improve at the 2-month marker and follow-up. Secondary measures of pain in the VAS format demonstrated participant improvement; however, mood state, and current pain were not significantly different (P < 0.05) than baseline until the 2 month assessment (P < 0.001).
Overall data indicate significant improvement for participants during the trial in both scales and objective measures used for assessment purposes. There were no side effects reported during the trial. CM appears to be a relatively safe and effective supplement to reduce symptoms of OA.
Limited scientific studies suggest that myrrh (Commiphora molmol) has antibacterial and anti-inflammatory activities. This study determined myrrh oil (MO) cytotoxicity to human gingival fibroblasts and epithelial cells and its effect, measured by ELISA, on interleukin (IL)-1beta-stimulated IL-6 and IL-8 production. Cell viability and cytotoxicity were determined by metabolic reduction of a tetrazolium salt to a formazan dye (MTT assay) and by release of lactate dehydrogenase (LDH) from membrane damaged (LDH release assay) cells, respectively. Based on the MTT assay, 24- and 48-h exposures to </=0.001% MO had little effect on fibroblast and epithelial cell (24-h only) viability. At 48 h, 0.0005-0.001% MO decreased epithelial cell viability 30-50%. After 24 and 48 h, MO, at >/=0.005%, maximally decreased viability of all cell lines. In the LDH release assay, exposure to </=0.0001% MO caused <10% cytotoxicity to all cells. At 24 h, >/=0.0025% MO caused maximal cytotoxicity; </=0.001% MO caused 10-70% cytotoxicity. At longer exposure times, epithelial cells were more susceptible to cytotoxic effects of MO. There was little or no detectable IL-1beta-stimulated production of IL-6 or IL-8 by cells exposed to >/=0.0025% MO, probably reflective of loss of viability. At subtoxic MO levels (0.00001-0.001%), there was a significant reduction of IL-1beta-stimulated IL-6 and IL-8 production by fibroblasts, but not by epithelial cells.
Heme oxygenase (HO)-1 catabolizes heme into three products: carbon monoxide (CO), biliverdin (which is rapidly converted to bilirubin) and free iron (which leads to the induction of ferritin, an iron-binding protein). HO-1 serves as a "protective" gene by virtue of the anti-inflammatory, anti-apoptotic and anti-proliferative actions of one or more of these three products. Administration of CO, biliverdin, bilirubin or iron-binding compounds is protective in rodent disease models of ischemia-reperfusion injury, allograft and xenograft survival, intimal hyperplasia following balloon injury or as seen in chronic graft rejection and others. We suggest that the products of HO-1 action could be valuable therapeutic agents and speculate that HO-1 functions as a "therapeutic funnel", mediating the beneficial effects attributed to other molecules, such as interleukin-10 (IL-10), inducible nitric oxide synthase (NOS2; iNOS) and prostaglandins. This Review is the third in a series on the regulation of the immune system by metabolic pathways.
The methanolic extract from guggul-gum resin, the resin of Balsamodendron mukul, was found to inhibit nitric oxide production in lipopolysaccharide-activated mouse peritoneal macrophages (IC(50) = 13 microg/mL). From the methanolic extract, three new polypodane-type triterpenes, myrrhanol B and myrrhanones B and A acetate, and a new octanordammarane-type triterpene, epimansumbinol, were isolated together with 17 known compounds including progesterone and the related steroids. The absolute stereostructures of new triterpenes were elucidated on the basis of chemical and physicochemical evidence. The several constituents showed inhibitory effects on nitric oxide production and induction of inducible nitric oxide synthase.
The inducible isoform of heme oxygenase (HO), HO-1, has been shown to play an important role in attenuating tissue injury. Because HO-1 catalyzes the rate-limiting step in bilirubin synthesis, we examined the hypothesis that bilirubin is a key mediator of HO-1 cytoprotection, employing a rat model of endotoxemia. Bilirubin treatment resulted in improved survival and attenuated liver injury in response to lipopolysaccharide infusion. Serum levels of NO and tumor necrosis factor alpha, key mediators of endotoxemia, and hepatic inducible nitric oxide synthase (iNOS) expression were significantly lower in bilirubin-treated rodents versus control animals. Both intraperitoneal and local administration of bilirubin also was found to ameliorate hindpaw inflammation induced by the injection of lambda-carrageenan. Consistent with in vivo results, bilirubin significantly inhibited iNOS expression and suppressed NO production in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. In contrast, bilirubin treatment induced a threefold increase in LPS-mediated prostaglandin synthesis in the absence of significant changes in cyclooxygenase expression or activity, suggesting that bilirubin enhances substrate availability for eicosanoid synthesis. Bilirubin had no effect on LPS-mediated activation of nuclear factor kappaB or p38 mitogen-activated protein kinase, consistent with a nuclear factor kappaB-independent mechanism of action. Taken together, these data support a cytoprotective role for bilirubin that is mediated, at least in part, through the inhibition of iNOS expression and, potentially, through stimulation of local prostaglandin E2 production. In conclusion, our findings suggest a role for bilirubin in mollifying tissue injury in response to inflammatory stimuli and support the possibility that the phenomenon of "jaundice of sepsis" represents an adaptive physiological response to endotoxemia. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
Anecdotal and scientific evidence suggest that myrrh oil (MO) has anti-inflammatory properties. Subtoxic MO levels decrease interleukin (IL)-1beta-stimulated production of the inflammatory cytokine IL-6 by human gingival fibroblasts, but not epithelial cells. IL-1beta upregulates IL-6 via PGE(2), and via NF-kappaB, a transcription factor for many inflammatory mediator genes. NF-kappaB is inhibited by sesquiterpene compounds (from plants other than myrrh). This study determined MO effect on IL-1beta-stimulated PGE(2) production and NF-kappaB activation in gingival fibroblasts and epithelial cells. Cells were preincubated with MO, exposed to IL-1beta, cytoplasmic and nuclear fractions were isolated, and activated NF-kappaB was measured using an ELISA-based assay. IL-1beta increased nuclear activated NF-kappaB levels in fibroblasts and epithelial cells [10- and 2.5-fold over controls, respectively (p=0.0001)], and these increases were not significantly affected by MO. PGE(2) was measured in cell supernatants by ELISA, after preincubation with MO and exposure to IL-1beta. MO inhibited IL-1beta-stimulated PGE(2) production by fibroblasts (p=0.001), but not epithelial cells. The data suggest that gingival epithelial cells and fibroblasts may differ in the magnitude of NF-kappaB activation after IL-1beta stimulation, and that MO inhibition of IL-1beta-stimulated IL-6 production in fibroblasts is due in part to inhibition of PGE(2), but not NF-kappaB activation. (Supported by NIDCR DE-0725.).
Sanguis Draconis (SD) is a kind of dragon's blood resin that is obtained from Daemomorops draco (Palmae). It is used in traditional medicine and has shown anti-inflammatory activity in some diseases. In this study, we examined the effects of Sanguis Dranonis ethanol extract (SDEE) on LPS-induced inflammation using RAW 264.7 cells. Our data indicated that SDEE inhibits LPS-stimulated NO, PGE2, IL-1 beta and TNF-alpha release, and iNOS and COX-2 expression. Furthermore, SDEE suppressed the LPS-induced p65 expression of NF-kappa B, which was associated with the inhibition of I kappa B-alpha degradation. We also found that the expression of HO-1 was significantly increased in RAW 264.7 cells by SDEE. These results suggest among possibilities of anti-inflammation that SDEE inhibits the production of NO and PGE2 by the down-regulation of iNOS and COX-2 gene expression via the suppression of NF-kappaB (p65) activation. SDEE can induce HO-1 over-expression in macrophage cells, which indicates that it may possess antioxidant properties. This result means that SEDD its anti-inflammatory effects in macrophages may be through a novel mechanism that involves the action of HO-1. Thus, SD could provide a potential therapeutic approach for inflammation-associated disorders.