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Oleanolic acid Modulates the Immune-Inflammatory Response in Mice with Experimental Autoimmune Myocarditis and Protects from Cardiac Injury. Therapeutic Implications for the Human Disease
Abstract
Myocarditis and dilated cardiomyopathy (DCM) are inflammatory diseases of the myocardium, for which appropriate treatment remains a major clinical challenge. Oleanolic acid (OA), a natural triterpene widely distributed in food and medicinal plants, possesses a large range of biological effects with beneficial properties for health and disease prevention. Several experimental approaches have shown its cardioprotective actions, and OA has recently been proven effective for treating Th1 cell-mediated inflammatory diseases; however, its effect on inflammatory heart disorders, including myocarditis, has not yet been addressed. Therefore, the present study was undertaken to determine the effectiveness of OA in prevention and treatment of experimental autoimmune myocarditis (EAM).
The utility of OA was evaluated in vivo through their administration to cardiac α-myosin (MyHc-α614-629)-immunized BALB/c mice from day 0 or day 21 post-immunization to the end of the experiment, and in vitro through their addition to stimulated-cardiac cells.
Prophylactic and therapeutic administration of OA dramatically decreased disease severity: the heart weight/body weight ratio as well as plasma levels of brain natriuretic peptide and myosin-specific autoantibodies production were significantly reduced in OA-treated EAM animals, compared with untreated ones. Histological heart analysis showed that OA-treatment diminished cell infiltration, fibrosis and dystrophic calcifications. OA also decreased proliferation of cardiac fibroblast in vitro and attenuated calcium and collagen deposition induced by relevant cytokines of active myocarditis. Furthermore, in OA-treated EAM mice the number of Treg cells and the production of IL-10 and IL-35 were markedly increased, while proinflammatory and profibrotic cytokines were significantly reduced.
We demonstrate that OA ameliorates both developing and established EAM by promoting an antiinflammatory cytokine profile and by interfering with the generation of cardiac-specific autoantibodies, as well as through direct protective effects on cardiac cells. Therefore, we envision this natural product as novel helpful tool for intervention in inflammatory cardiomyopathies including myocarditis.
... There are two subclasses of triterpenoids based on their chemical structure: pentacyclic triterpenes and tetracyclic triterpenes [7]. Among them, oleanolic acid (OA, Figure 1) and its isomer ursolic acid (UA, Figure 1) are pentacyclic triterpenoid bioactive substances commonly found in fruits and vegetables, and both possess similar physicochemical and biological properties, such as anti-inflammatory, antioxidant, antiviral, anticancer, antidiabetic, hepatoprotective, and cardioprotective effects [8][9][10][11][12][13][14][15]. OA research has gained increasing attention due to its rich biological properties. ...
... The researchers pretreated BV2 cells with OA (0.5 to 10 µM) for 1 h and then with LPS (100 ng/mL) for 24 h at 37 • C. The results showed that OA reduced the expression levels of TNF-α, IL-1β, and IL-6 in BV2 cells [98]. Researchers have demonstrated that OA ameliorates experimental autoimmune myocarditis (EAM) in several ways, including by promoting anti-inflammatory cytokines (IL-10 and IL-35), interfering with cardiac-specific autoantibody production, and exerting direct protective effects on cardiac cells [15]. In female C57BL/J6 mice with experimental autoimmune encephalomyelitis, OA has also been revealed to decrease proinflammatory mediators (TNF-α, IL-1β, IL-23, IL-17A, chemokine KC, and the growth factor IGF-1) both in serum and colonic tissue, prevent lipid peroxidation and superoxide anion accumulation in intestinal tissue, and induce the expression of the ROS scavenger Sestrin-3 [99]. ...
... The researchers discovered that certain doses of OA independently inhibit cell cycle progression. In cell lines pretreated with different doses of OA (15,30,45, and 60 µM), there was a significant increase in the percentage of cells in the G0/G1 phase but a considerate reduction in the percentage of cells in S phase, as compared to controls [42]. According to previous findings, OA-treated DU145 cells are arrested in G2 because of the activation of p-AKT, p-JNK, p21, and p27, accompanied by the downregulation of p-ERK, cyclin B1, and CDK2 expression. ...
Like other pentacyclic triterpenoids, oleanolic acid, a natural plant metabolite prevalent in plant peels, stems, and leaves, is regarded as a possible drug candidate. A growing number of studies have shown that oleanolic acid exhibits a variety of beneficial properties, including antiviral, anti-inflammatory, antioxidant, anticancer, and hepatoprotective effects. Additionally, the rapid advance of nanotechnology has dramatically improved oleanolic acid’s bioavailability and minimized its disadvantages, leading to unexpected changes in its pharmacological activity and use. Therefore, our aim was to review the progress of research on the distribution and biological properties of oleanolic acid in plants and to discuss new pharmaceutical approaches for oleanolic acid.
... Oleanolic acid (3βhydroxyolean-12-en-28-oic acid, OA) is one of the major pentacyclic triterpenes that exists in nature either as free acid or as aglycone precursor and is especially prevalent in plants belonging to the Oleaceae family. OA, as well as herbal extracts containing OA, is well known for its diverse bioactivities, including anti-oxidant, anti-tumour, antiinflammatory, anti-diabetic, anti-microbial, as well as cardioprotective, neuroprotective, hepatoprotective, and hypolipidemic effects [8][9][10][11][12]. Likewise, several experimental approaches have demonstrated that OA is therapeutically effective without apparent side effects [13,14]. ...
... d After 24 h, IL-8 concentration in the cell-culture supernatant was measured by commercial ELISA. The assays were performed in duplicates, n = 3. Results were expressed as the mean ± SEM. *p < 0.001 and **p < 0.01 vs control; and ‡ p < 0.001, ‡ ‡ p < 0.01, and ‡ ‡ ‡ p < 0.05 vs stimuli without OA myocarditis [12], we observed that OA-treatment significantly increased the percent of Treg compared with those of the control mice group, without affecting the frequency of CD3+, CD4+, and CD8+ T cells, CD14+ macrophages/monocytes, and CD19+ B cells. These results highlight that OA has profound effects in the prevention of this degenerative disease not only by restraining clinical symptoms, such as paralysis of the limbs, production of specific autoantibodies, and BBB dysfunction, as we previously demonstrated [10], but also by protecting against disruption of the intestinal homeostasis. ...
... OA was previously found to abolish a harmful profile of cytokines at both systemic and local levels, as well as to block NF-κB activation [8,10,12,57]. Therefore, another possible mechanism by which OA treatment might protect against EAE and its associated GI disturbances would be by preserving a healthy balance of pro-inflammatory-, anti-inflammatory-, and regulatory-cytokines/factors. ...
Background
Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease affecting the CNS. Recent studies have indicated that intestinal alterations play key pathogenic roles in the development of autoimmune diseases, including MS. The triterpene oleanolic acid (OA), due to its anti-inflammatory properties, has shown to beneficially influence the severity of the experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS. We herein investigate EAE-associated gut intestinal dysfunction and the effect of OA treatment.
Methods
Mice with MOG35–55-induced EAE were treated with OA or vehicle from immunization day and were daily analyzed for clinical deficit. We performed molecular and histological analysis in serum and intestinal tissues to measure oxidative and inflammatory responses. We used Caco-2 and HT29-MTX-E12 cells to elucidate OA in vitro effects.
Results
We found that OA protected from EAE-induced changes in intestinal permeability and preserved the mucin-containing goblet cells along the intestinal tract.
Serum levels of the markers for intestinal barrier damage iFABP and monocyte activation sCD14 were consistently and significantly reduced in OA-treated EAE mice. Beneficial OA effects also included a decrease of pro-inflammatory mediators both in serum and colonic tissue of treated-EAE mice. Moreover, the levels of some immunoregulatory cytokines, the neurotrophic factor GDNF, and the gastrointestinal hormone motilin were preserved in OA-treated EAE mice. Regarding oxidative stress, OA treatment prevented lipid peroxidation and superoxide anion accumulation in intestinal tissue, while inducing the expression of the ROS scavenger Sestrin-3. Furthermore, short-chain fatty acids (SCFA) quantification in the cecal content showed that OA reduced the high iso-valeric acid concentrations detected in EAE-mice. Lastly, using in vitro cell models which mimic the intestinal epithelium, we verified that OA protected against intestinal barrier dysfunction induced by injurious agents produced in both EAE and MS.
Conclusion
These findings reveal that OA ameliorates the gut dysfunction found in EAE mice. OA normalizes the levels of gut mucosal dysfunction markers, as well as the pro- and anti-inflammatory immune bias during EAE, thus reinforcing the idea that OA is a beneficial compound for treating EAE and suggesting that OA may be an interesting candidate to be explored for the treatment of human MS.
... Ursane, Olean and Lupan are three major pentacyclic triterpenoids found in fruits, vegetables and many medicinal plants with numerous pharmacological functions including antioxidant, anti-inflammatory, anti-cancer, immunomodulatory and cardioprotective effects [83][84][85]. ...
... Oleanolic acid can prevent myocarditis due to its antioxidant, antiinflammatory, anti-apoptosis and immunoregulatory properties. It reduced cardiac damage markers (CK-MB, BNP) following myocarditis in both in vitro and in vivo studies [2,84,85]. ...
Myocarditis is an inflammatory disease of the myocardium that mostly affects young adults. The disease is commonly caused by viral infection, medications, autoimmune disorders, and inflammatory conditions. Nearly 50% of the cases of myocarditis are due to post-viral immune response in a setting of an identifiable or non-identifiable infection. The clinical manifestation is nonspecific ranging from asymptomatic courses to sudden death in infants and young patients. This review describes the properties of phytochemicals as plant-derived active ingredients which can be used in the prevention and treatment of myocarditis and its associated risk factors. Meanwhile, it has illustrated epidemiological analyses, mechanism of action, and the metabolism of phytochemicals in animal and human clinical trials. We also mentioned the precise mechanism of action by which phytochemicals elicit their anti-viral, anti-inflammatory, antioxidant, and immunomodulatory effects and how they regulate signal transduction pathways. Nevertheless, comprehensive clinical trials are required to study the properties of phytochemicals in vivo, in vitro, and in silico for a proper management of myocarditis. Our findings indicate that phytochemicals function as potent adjunctive therapeutic drugs in myocarditis and its related complications.
... Disease was induced in 6-8 week-old male mice by immunisation at day 0 with 50 µg of the murine specific α-myosin-heavy chain-derived acetylated peptide (MyHCα 614-629 ), as was previously described [25]. MyHCα 614-629 was generated in the peptide synthesis laboratory of Dr. F. Barahona (CBM, Madrid, Spain). ...
... Primary cultures of CFs were obtained from male Wistar rats weighing 250-300 g by differential centrifugation of cardiac cells released after mechanical and enzymatic digestion of the hearts [25]. Cells were grown on poly-L-lysine coated flasks in DMEM supplemented with 10% FCS, 10 mM Cells 2020, 9,396 4 of 20 l-glutamine, 100 U/mL penicillin/streptomycin, 10 mM pyruvate and 2 mM HEPES. ...
Secreted phospholipase A2-IIA (sPLA2-IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA2-IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA2-IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA2-IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA2-IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA2-IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA2-IIA. In conclusion, sPLA2-IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects.
... Quercetin [2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one] is a dietary polyphenol widely spread in food sources such as citrus fruits, red onions, apples, tea, capers, and berries. It is also a major polyphenol in Oleanolic acid Inhibits the production of pro-inflammatory cytokines and CAM molecules Yang et al. (2012), Lee et al. (2013), Martin et al. (2014), and Wang et al. (2013b) Suppresses NF-κB signaling pathway Lee et al. (2013) Diminishes production of iNOS, NO, COX-2, matrix metalloproteinase-9 (MMP-9), cyclin D1, Jun, Fos, and p65 Shishodia et al. (2003), Suh et al. (1998), Ryu et al. (2000), and Subbaramaiah et al. (2000) Downregulates the activation of MAPKs signaling molecules Subbaramaiah et al. (2000) Inactivates Wnt signaling pathway by inhibiting Myc and cyclin D1 Zhang et al. (2016) Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
... Likewise, Lee et al. (2013) proposed that OA lessened the pro-inflammatory reactions through downregulation of NF-κB expression and also TNFα in vivo and in vitro which was induced by LPS. In a mouse model of autoimmune myocarditis, OA promoted anti-inflammatory cytokines, reduced the production of pro-inflammatory cytokines, and lessened the other symptoms (Martin et al. 2014). Moreover, OA mitigated the hepatic insulin resistance by calming anti-inflammatory activity by decreasing the levels of IL-1, IL-6, and TNFα in mice livers . ...
The causal and functional connection between inflammation and cancer has become a subject of much research interest. Modulation of cell signaling pathways, such as those involving mitogen activated protein kinases (MAPKs), nuclear factor kappa β (NF-κB), phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt), and Wnt, and their outcomes play a fundamental role in inflammation and cancer. Activation of these cell signaling pathways can lead to various aspects of cancer-related inflammation. Hence, compounds able to modulate inflammation-related molecular targets are sought after in anticancer drug development programs. In recent years, plant extracts and their metabolites have been documented with potential in the prevention and treatment of cancer and inflammatory ailments. Plants possessing anticancer and anti-inflammatory properties due to their bioactive constituents have been reported to modulate the molecular and cellular pathways which are related to inflammation and cancer. In this review we focus on the flavonoids (astragalin, kaempferol, quercetin, rutin), lignans (phyllanthin, hypophyllanthin, and niranthin), tannins (corilagin, geraniin, ellagic acid, gallic acid), and triterpenes (lupeol, oleanolic acid, ursolic acid) of Phyllanthus amarus, which exert various anticancer and anti-inflammatory activities via perturbation of the NF-κB, MAPKs, PI3K/Akt, and Wnt signaling networks. Understanding the underlying mechanisms involved may help future research to develop drug candidates for prevention and new treatment for cancer and inflammatory diseases.
... Furthermore, treatment of EAM animals with oleanolic acid was associated with a significantly elevated number of T regulatory cells (Treg cells), increased IL-10 and IL-35 production, and reduced secretion of proinflammatory and profibrotic cytokines. Therefore, enhancement of an antiinflammatory cytokine response and inhibition of anti-MyHCα production are cardioprotective actions whereby oleanolic acid can improve EAM [53]. ...
... These compounds could suppress the infiltration of inflammatory cells and protect from myocardial damage and remodeling by a number of anti-inflammatory and immunomodulatory mechanisms. Upregulation of serum levels of the Th1-type cytokines and elevation of the Th2-type cytokines (IL-4 and IL-10) [1], decreasing serum levels of proinflammatory cytokines TNF-α, IL-1β and IL-6, suppressing NF-κBp65 which regulates proinflammatory cytokines [48], restoring the excessive expression of phosphorylated (p)-STAT1, STAT3 and STAT4 and further suppressing Th17/Th1 responses [1], suppressing ICAM-1, VCAM-1, E-selectin, and collagen type 1 expression [45,73], reducing anti-MyHCα, increasing the number of Treg cells [53], modulation of MAPK signaling pathway [16] and the activity of SIRT1 [61], alleviating oxidative stress caused by NADPH oxidase, suppressing the expression of RAGE, phospho-p38 MAPK and phospho-JNK, osteopontin and increasing SERCA2 levels are among the most important mechanisms against myocardial damage and remodeling [6]. ...
Myocarditis is an inflammatory disease of the myocardium associated with immune dysfunction which may frequently lead to the development of dilated cardiomyopathy. Experimental autoimmune myocarditis is an animal model which mimics myocarditis in order to allow assessment of the therapeutic effects of different molecules on this disease. We aimed to review the inflammatory and immunological mechanisms involved in the pathogenesis of the myocarditis and finding natural products and phytochemicals with anti-myocarditis activities based on studies of cardiac myosin-induced experimental autoimmune myocarditis in rodents. A number of natural molecules (e.g. apigenin, berberine and quercetin) along with some plant extracts were found to be effective in alleviating experimental autoimmune myocarditis. Upregulation of Th1-type cytokines and elevation of the Th2-type cytokines (IL-4 and IL-10), mitigation of oxidative stress, modulation of mitogen-activated protein kinase signaling pathways and increasing Sarco-endoplasmic reticulum Ca²⁺-ATPase levels are among the most important anti-myocarditis mechanisms for the retrieved molecules and extracts. Interestingly, there are structural similarities between the anti-EAM compounds, suggesting the presence of similar pharmacophore and enzymatic targets for these molecules. Naturally occurring molecules discussed in the present article are potential anti-myocarditis drugs and future additional animal studies and clinical trials would shed more light on their effectiveness in the treatment of myocarditis and prevention of dilated cardiomyopathy.
... In recent years, the mTOR pathway regulates a variety of cell functions, including cell proliferation, survival, growth, apoptosis, metabolism, and plasticity. Tuberous sclerosis complex (TSC) negatively regulates activation of mTOR pathway via Rheb, 2 Evidence-Based Complementary and Alternative Medicine [20][21][22][23][24][25] Herba Ecliptae (Han Mo Lian) 50% Oleanolic acid; eclalbasa ponins Liver protection; antioxidant; anti-inflammatory [26][27][28] which is an upstream protein of mTOR signaling pathway and including TSC1 and TSC2. The Rheb is required for activation of mTOR towards examining all substrates and leading to many human diseases [13]. ...
... EZP is composed of Fructus Ligustri Lucidi and Herba Ecliptae (Table 1) and serves as a basic formula to effectively treat hepatic diseases [18,19]. An increasing number of studies have explored the pharmacology of EZP and herbs composed of EZP, showing their antioxidant, anti-inflammatory, and antiaging properties and potential in immunoregulation, liver protection, antinerve cell apoptosis, and cell proliferation (Table 1) [20][21][22][23][24][25][26][27][28]. At present, most researches are focused on evaluating the therapeutic effect of EZP on hepatic diseases by liver function examination in animal or cell models with acute hepatic injury induced by carbon tetrachloride (CCl4), H2O2, and ethanol [29][30][31]. ...
The present study aimed to investigate the mechanism of hepatoprotective effect of Erzhi Pill (EZP) on the liver injury via observing TSC/mTOR signaling pathway activation. The experimental liver injury was induced by 2-acetylaminofluorene (2-AAF) treatment combined with partial hepatectomy (PH). EZP treated 2-AAF/PH-induced liver injury by the therapeutic and prophylactic administration. After the administration of EZP, the activities of aspartic transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AKP), and gamma-glutamyl transpeptidase ( γ -GT) were decreased, followed by the decreased levels of hepatocyte apoptosis and caspase-3 expression. However, the secretion of albumin, liver weight, and index of liver weight were elevated. Microscopic examination showed that EZP restored pathological liver injury. Meanwhile, Rheb and mammalian target of rapamycin (mTOR) activation were suppressed, and tuberous sclerosis complex (TSC) expression was elevated in liver tissues induced by 2-AAF/PHx and accompanied with lower-expression of Bax, Notch1, p70S6K, and 4E-EIF and upregulated levels of Bcl-2 and Cyclin D. Hepatoprotective effect of EZP was possibly realized via inhibiting TSC/mTOR signaling pathway to suppress excessive apoptosis of hepatocyte.
... Several pharmacological attributes of OA have been reported, such as anti-fibrosis (Zhao and Luan, 2020), regulation of mitophagy (Gong et al., 2022), anti-apoptosis (J. Y. Chen et al., 2014), anti-inflammatory (Martin et al., 2014), and reduction of oxidative stress (Peng et al., 2017). Excitingly, the preventive effect of OA on cardiac remodeling has been validated in the pressure overload mouse model (Liao et al., 2015), even if there is still a lack of profound research to elucidate its underlying mechanism and specific target. ...
... Single-cell RNA sequencing analysis of CD45 + cells extracted from the hearts of EAM model mice revealed that Tregs were the predominant T-cell population detected during the subacute inflammatory phase (143). Extracellular vesicles secreted by human-derived heart stromal/Progenitor cells (144), adenovirus vector-mediated gene transfer of CTLA4 Ig fusion protein (145), CD28 superagonists (146), and Oleanolic Acid (147) interventions can protect the heart function and alleviate inflammation of EAM model rodents by increasing the number of Tregs and enhancing the immunosuppressive function of Tregs. Overexpression of Mir-223-3p (148) and Protosappanin A intervention (149) can promote the phenotypic transformation from DCs to tDCs, induce Tregs generation, and inhibit cardiac inflammation and cardiac remodeling in EAM model mice. ...
Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. The CVDs are accompanied by inflammatory progression, resulting in innate and adaptive immune responses. Regulatory T cells (Tregs) have an immunosuppressive function and are one of the subsets of CD4+T cells that play a crucial role in inflammatory diseases. Whether using Tregs as a biomarker for CVDs or targeting Tregs to exert cardioprotective functions by regulating immune balance, suppressing inflammation, suppressing cardiac and vascular remodeling, mediating immune tolerance, and promoting cardiac regeneration in the treatment of CVDs has become an emerging research focus. However, Tregs have plasticity, and this plastic Tregs lose immunosuppressive function and produce toxic effects on target organs in some diseases. This review aims to provide an overview of Tregs’ role and related mechanisms in CVDs, and reports on the research of plasticity Tregs in CVDs, to lay a foundation for further studies targeting Tregs in the prevention and treatment of CVDs.
... Other properties Antimicrobial [131][132][133] Oleanolic acid Pentacyclic triterpenoid Olive oil, American pokeweed, and Syzygium spp., and garlic Increased production of IL-6 and TNF-α Inhibited HCV replication at least partly through directly targeting HCV NS5B RdRp activity Other properties Antibacterial, antiviral, anticancer, antioxidant, and antimycotic [131,[134][135][136] 600 mg twice daily. In addition to having potent anti-inflammatory and antiasthmatic properties, onions also have strong antiviral properties. ...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in Wuhan, China, in early December 2019 is a censorious global emergency after World War II. Research on the coronavirus uncovered essential information that aided in the development of the vaccine, and specific coronavirus disease 2019 (COVID-19) vaccines were later developed and were approved for usage in humans. But then, mutations in the coronavirus gave rise to new variants and questioned the vaccine's efficacy against them. On the other hand, the investigation of traditional medicine was also on its path to find a novel outcome against COVID-19. On a comparative analysis between India and the United States, India had low death rate and high recovery rate than the latter. The dietary regulation of immunity may be the factor that makes the above difference. The immunity gained from the regular diet of Indian culture nourishes Indian people with essential phytochemicals that support immunity and metabolism. Dietary phytochemicals or nutraceuticals possess antioxidant, anti-inflammatory, and anticancer properties, out of which our concern will be on immune-boosting phytochemicals from our daily nutritional supplements. In several case studies, dietary substance like lemon, ginger, and spinach was reported in the recovery of COVID-19 patients. Thus in this review, we discuss coronavirus and its available variants, vaccines, and the effect of nutraceuticals against the coronavirus. Further, we denote that the immunity of the Indian population may be high because of their diet, which adds natural phytochemicals to boost their immunity and metabolism.
... Oleanolic acid mainly exists in the form of glycosides in Chinese herbal medicine and has various bioactivities such as anti-inammatory and anti-bacterial. Martín et al. 68 proved that oleanolic acid is effective for the treatment of Th1 cell-mediated inammatory diseases. Zhang et al. 69 found that glycyrrhizic acid can effectively reduce the severity of Coxsackievirus B3 (CVB3)-induced myocarditis and may serve as a new treatment for viral myocarditis. ...
Covering: up to 2022Pentacyclic triterpenoids are important natural bioactive substances that are widely present in plants and fungi. They have significant medicinal efficacy, play an important role in reducing blood glucose and protecting the liver, and have anti-inflammatory, anti-oxidation, anti-fatigue, anti-viral, and anti-cancer activities. Pentacyclic triterpenoids are derived from the isoprenoid biosynthetic pathway, which generates common precursors of triterpenes and steroids, followed by cyclization with oxidosqualene cyclases (OSCs) and decoration via cytochrome P450 monooxygenases (CYP450s) and glycosyltransferases (GTs). Many biosynthetic pathways of triterpenoid saponins have been elucidated by studying their metabolic regulation network through the use of multiomics and identifying their functional genes. Unfortunately, natural resources of pentacyclic triterpenoids are limited due to their low content in plant tissues and the long growth cycle of plants. Based on the understanding of their biosynthetic pathway and transcriptional regulation, plant bioreactors and microbial cell factories are emerging as alternative means for the synthesis of desired triterpenoid saponins. The rapid development of synthetic biology, metabolic engineering, and fermentation technology has broadened channels for the accumulation of pentacyclic triterpenoid saponins. In this review, we summarize the classification, distribution, structural characteristics, and bioactivity of pentacyclic triterpenoids. We further discuss the biosynthetic pathways of pentacyclic triterpenoids and involved transcriptional regulation. Moreover, the recent progress and characteristics of heterologous biosynthesis in plants and microbial cell factories are discussed comparatively. Finally, we propose potential strategies to improve the accumulation of triterpenoid saponins, thereby providing a guide for their future biomanufacturing.
... Moreover, the available reports suggest that therapeutic interventions for the treatment of myocarditis and viral infection-induced active inflammatory destruction of the myocardium are limited to immunosuppressive and immunomodulatory therapies (Pollack et al. 2015). No wonder that the triterpenoids are well reported to exert these properties and demonstrated their beneficial effects in myocarditis as well (Martín et al. 2014;Xu et al. 2020). ...
Triterpenes are naturally occurring derivatives biosynthesized following the isoprene rule of Ruzicka. The triterpenes have been reported to possess a wide range of therapeutic applications including anti-viral properties. In this review, the recent studies (2010–2020) concerning the anti-viral activities of triterpenes have been summarized. The structure activity relationship studies have been described as well as brief biosynthesis of these triterpenes is discussed. © 2022, The Author(s), under exclusive licence to Springer Nature B.V.
... Oleanolic acid also exhibits antimicrobial properties on a large number of bacteria, HIV, HCV, and Plasmodium protozoa strains that cause malaria [19]. It has been determined in many studies that oleanolic acid and its synthetic derivatives have anticancer, antidiabetic, antiarrhythmic, antihyperlipidemic, antimicrobial, anti-hypercholesterolemic, and anticardiovascular effects [20][21][22][23][24][25][26][27][28][29][30][31][32]. ...
In this study, 13 new hybrid compounds were synthesized starting from the natural product oleanolic acid and their in vitro cytotoxic activities were investigated on BEAS-2B and A549 cell lines. For this purpose, initially, the secondary OH group at the C3 position of oleanolic acid was protected as methoxy and the carboxyl group was converted to a hydrazide. The hybrid compounds 12(a-m) were synthesized starting from the above hydrazide and using 13 different aromatic aldehydes. The biological activity of the resulting compounds was evaluated with doxorubicin as the standard. The IC50 values of the cytotoxic effects of doxorubicin on BEAS-2B and A549 cells are 0.09 and 0.14 µM, respectively. The hybrid compounds with the lowest cytotoxicity on BEAS-2B cells were 12b (IC50= 2.96 µM) and 12f (IC50= 2.53 µM). The corresponding cytotoxic activity of the same two compounds on A549 cells was 0.08 and 0.22 µM, respectively. Compound 12b was found to have an equivalent cytotoxic activity to doxorubicin on A549 cells, whereas its activity on BEAS-2B cells was determined to be approx. 32 times as less potent as doxorubicin. According to the in vitro test results, the hybrid compound 12b may be a promising candidate for further investigation as an anticancer agent.
... In China, for a long time, OA has been clinically used to treat hepatitis (Liu, 2005;Xu et al., 2014). Consequently, there has been growing research interest in OA and its derivatives, and it has also been reported to have multiple pharmacological effects including anti-inflammatory, anti-oxidative, anti-microbial, anticancer, hepatoprotective, anti-diabetic, and cardioprotective effects (Castellano et al., 2013;Martin et al., 2014;Ayeleso et al., 2017;Ziberna et al., 2017;Niu et al., 2018;Wang et al., 2018b). Moreover, OA can attenuate brain damage in several central nervous system (CNS) diseases including ischemic stroke (Rong et al., 2011;Shi et al., 2021), hypoxia (Caltana et al., 2014), multiple sclerosis (Martin et al., 2010), spinal cord injury (Wang et al., 2020), and Alzheimer's disease (Wang et al., 2018a;Gudoityte et al., 2021). ...
Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to exert protective effects against several neurological diseases through its anti-oxidative and anti-inflammatory activities. The goal of the present study was to evaluate the therapeutic potential of OA against acute and chronic brain injuries after ischemic stroke using a mouse model of transient middle cerebral artery occlusion (tMCAO, MCAO/reperfusion). OA administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, functional neurological deficits, and neuronal apoptosis. Moreover, delayed administration of OA (at 3 h after reperfusion) attenuated brain infarction and improved functional neurological deficits during the acute phase. Such neuroprotective effects were associated with attenuation of microglial activation and lipid peroxidation in the injured brain after the tMCAO challenge. OA also attenuated NLRP3 inflammasome activation in activated microglia during the acute phase. In addition, daily administration of OA for 7 days starting from either immediately after reperfusion or 1 day after reperfusion significantly improved functional neurological deficits and attenuated brain tissue loss up to 21 days after the tMCAO challenge; these findings supported therapeutic effects of OA against ischemic stroke-induced chronic brain injury. Together, these findings showed that OA exerted neuroprotective effects against both acute and chronic brain injuries after tMCAO challenge, suggesting that OA is a potential therapeutic agent to treat ischemic stroke.
... macrophages in the spinal cords of mice (Kim et al. 2020). Numerous in vivo studies have reported that oleanolic acid lowers allergen-specific antibody levels (immunoglobulin (Ig)E, IgG, IgG1 and IgG2a) and suppresses general immune responses (Córdova et al. 2014;Choi et al. 2016;Martín et al. 2014Martín et al. , 2012. Oleanolic acid blocks the activation of NF-jB and related signaling pathways (Jehangir et al. 2019;Choi et al. 2016;Hwang et al. 2014;Kang et al. 2021). ...
The immune system is one of the main defence mechanisms of the human body. Inadequacy of this system or immunodeficiency results in increased risk of infections and tumours, whereas over-activation of the immune system causes allergic or autoimmune disorders. A well-balanced immune system is important for protection and for alleviation of these diseases. There is a growing interest to maintain a well-balanced immune system, especially after the Covid-19 pandemic. Many biological extracts, as well as natural products, have become popular due to their wide array of immunomodulatory effects and influence on the immune system. Triterpenes, one of the secondary metabolite groups of medicinal plants, exhibit immunomodulatory properties by various mechanisms. Different triterpenes, including components of commonly consumed plants, can promote some protection and alleviation of disease symptoms linked with immune responses and thus enhance overall well-being. This review aims to highlight the efficacy of triterpenes in light of the available literature evidence regarding the immunomodulatory properties of triterpenes. We have reviewed widely investigated immunomodulatory triterpenes; oleanolic acid, glycyrrhizin, glycyrrhetinic acid, pristimerin, ursolic acid, boswellic acid, celastrol, lupeol, betulin, betulinic acid, ganoderic acid, cucumarioside, and astragalosides which have important immunoregulatory properties. In spite of many preclinical and clinical trials were conducted on triterpenes related to their immunoregulatory actions, current studies have several limitations. Therefore, especially more clinical studies with optimal design is essential.
... It has been found that quercetin has the biological effects of anti-oxidation, 19 anti-inflammation 20 and enhancing immunity. 21 oleanolic acid has the functions of anti-inflammatory, 22,23 improving glucose tolerance 24,25 and promoting insulin secretion. 26 icariin has the functions of anti-inflammatory, 28 protecting endothelial cells 24 and promoting gonadal function. ...
Objective:
To investigate the effect of quercetin, oleanolic acid, icariin and their compatibility on the apoptosis of hippocampal neurons of Sprague-Dawley (SD) rats cultured with high glucose medium and the possible mechanism.
Methods:
The extracts were purchased from China Food and Drug Control Institute and Sellect. Hippocampus was obtained from newborn 24 h SD rats. After culturing the hippocampus in different medium for 72 h, flow cytometry was used to detect the apoptosis of hippocampal neurons, and Western blot was utilized to test the expressions of p-p38, p38, p-c-Jun N-terminal kinase (JNK) and JNK.
Results:
Compared with the control group (CG), the neuronal apoptosis rate and the ratios of p-p38/p38 and p-JNK/JNK were significantly increased in the high glucose group (GG) (P < 0.01); Compared with the GG, the apoptosis rate and the ratios of p-p38/p38 and p-JNK/JNK were significantly decreased in other drug groups (P < 0.01); Compared with the monomer groups respectively, the apoptosis rate and the ratios of p-p38/p38 and p-JNK/JNK in the two-drug groups and the three-drug group all decreased (P < 0.01); Compared with the two-drug groups, the neuronal apoptosis rate and the ratio of p-JNK/JNK of the three-drug group decreased (P < 0.05).
Conclusion:
Under the condition of high glucose, the quercetin, oleanolic acid and icariin can alleviate the apoptosis of hippocampus neurons, reduce the phosphorylation of p38 and JNK in p38 mitogen-activated protein kinases and JNK signaling pathway. And the efficacy of the three drugs in combination with each other can be strengthened.
... In addition, SH479, a derivative of betulinic acid, ameliorated experimental autoimmune encephalomyelitis in a mouse model by modulating the Th17/Treg balance, on inhibiting the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) pathways and activating the STAT5 pathway [4]. Furthermore, oleanolic acid regulated the production of anti-inflammatory cytokines and decreased the production of pro-inflammatory cytokines in mice with experimental autoimmune myocarditis [5]. Similarly, in a mouse model of experimental autoimmune encephalomyelitis, oleanolic acid acetate suppressed the production of pro-inflammatory cytokines IL-1β, IL-6, INF-γ, and TNF-α by regulating toll-like receptor 2 (TLR2) signaling [6]. ...
Recent evidence has shown that inflammation can contribute to all tumorigenic states. We have investigated the anti-inflammatory effects of a diamine-PEGylated derivative of oleanolic acid (OADP), in vitro and in vivo with inflammation models. In addition, we have determined the sub-cytotoxic concentrations for anti-inflammatory assays of OADP in RAW 264.7 cells. The inflammatory process began with incubation with lipopolysaccharide (LPS). Nitric oxide production levels were also determined, exceeding 75% inhibition of NO for a concentration of 1 µg/mL of OADP. Cell-cycle analysis showed a reversal of the arrest in the G0/G1 phase in LPS-stimulated RAW 264.7 cells. Furthermore, through Western blot analysis, we have determined the probable molecular mechanism activated by OADP; the inhibition of the expression of cytokines such as TNF-α, IL-1β, iNOS, and COX-2; and the blocking of p-IκBα production in LPS-stimulated RAW 264.7 cells. Finally, we have analyzed the anti-inflammatory action of OADP in a mouse acute ear edema, in male BL/6J mice treated with OADP and tetradecanoyl phorbol acetate (TPA). Treatment with OADP induced greater suppression of edema and decreased the ear thickness 14% more than diclofenac. The development of new derivatives such as OADP with powerful anti-inflammatory effects could represent an effective therapeutic strategy against inflammation and tumorigenic processes.
... accumulation of metals in organs OA-Xs 40 µg/kg [169] OA-Xs 0.2-1 µmol/L [170] Muscle atrophy Anti-muscle atrophy mTORC-1/P70, S6K, PAX-7, MYO-D, Myogenin FOXO-1, MURF-1, Atrogi-n1 OA-Xs 1 µmol/L, 1-10 mg/kg [171] Myocarditismyocardial İnjury EA myocarditis IL-10, IL-33 HW/BW, BPN, IK-17, IL-6, TNF-α , Galectin OA 50 mg/kg·d, 21 d or 65 d [172] Obesity Anti-obesity octanoylated ghrelin production, PC-1/3, PC-2 OA 20-40 mg/kg, 7 d [173] Obesity Improves gustatory perception of lipids and exerts protective effects in obesity CD36 blood insulin and glucose, hepat,c TG, IL-6 OA 0.005% (w/v) for 16 wk [174] Renal injury Prevent nephropathy nNRF-2/tNRF-2, HO-1, KEAP-1, BAX urinary 8-OHdG and 8-iso-PGF-2 α, BCL-2 OA N.R. [175] Renal IRI Anti-Renal IRI; antioxidant, antiinflammatory, and anti-apoptotic activities SOD, GPX, GSH, CAT, IL-10, NRF-2, GGLc BUN, Cr, KIM-1, LDH, MDA, IL-6, INF-γ, MPO, OA 12.5-50 mg/kg·d, 15 d [176] Sepsis Lung damage, experimental sepsis SOD, GPX, IL-6, IL-10, KC iNOS, NRF-2, OA 10 mg/kg [177] Vascular injury Prevent oxidative ...
Oleanolic acid (OA) and its derivatives are widely found in diverse plants and are naturally effective pentacyclic triterpenoid compounds with broad prophylactic and therapeutic roles in various diseases such as ulcerative colitis, multiple sclerosis, metabolic disorders, diabetes, hepatitis and different cancers. This review assembles and presents the latest in vivo reports on the impacts of OA and OA derivatives from various plant sources and the biological mechanisms of OA activities. Thus, this review presents sufficient data proposing that OA and its derivatives are potential alternative and complementary therapies for the treatment and management of several diseases.
... Inflammation of cardiac tissue occurs typically 14-21 days after the first immunization. Resolution of the inflammation is followed by the progressive accumulation of fibrotic tissue in the myocardium, ventricular dilatation and impaired heart function in some mice (135)(136)(137)(138)(139)(140)(141)(142)(143)(144)(145)(146). Thus, this model allows to study not only autoimmune mechanisms, but also transition from myocarditis to DCM phenotype. ...
Myocarditis is defined as an inflammation of the cardiac muscle. In humans, various infectious and non-infectious triggers induce myocarditis with a broad spectrum of histological presentations and clinical symptoms of the disease. Myocarditis often resolves spontaneously, but some patients develop heart failure and require organ transplantation. The need to understand cellular and molecular mechanisms of inflammatory heart diseases led to the development of mouse models for experimental myocarditis. It has been shown that pathogenic agents inducing myocarditis in humans can often trigger the disease in mice. Due to multiple etiologies of inflammatory heart diseases in humans, a number of different experimental approaches have been developed to induce myocarditis in mice. Accordingly, experimental myocarditis in mice can be induced by infection with cardiotropic agents, such as coxsackievirus B3 and protozoan parasite Trypanosoma cruzi or by activating autoimmune responses against heart-specific antigens. In certain models, myocarditis is followed by the phenotype of dilated cardiomyopathy and the end stage of heart failure. This review describes the most commonly used mouse models of experimental myocarditis with a focus on the role of the innate and adaptive immune systems in induction and progression of the disease. The review discusses also advantages and limitations of individual mouse models in the context of the clinical manifestation and the course of the disease in humans. Finally, animal-free alternatives in myocarditis research are outlined.
... Olive leaf extracts is known to be a natural resource of various beneficial substances, such as polyphenols, oleuropein, and oleanolic acid, and have been used for various effects, including anti-inflammatory, anti-hypertensive, and hypocholesterolemic activities [17,18]. There are many reports stating that oleanolic acid has an anti-inflammatory effect both in vivo and in vitro [19][20][21][22]. Recently, a new product, an ethanol/water extract of olive leaves (OleaVita ® , Phytodia S.A.S., Illkirch-Graffenstaden, France), has been developed [23]. ...
The placenta is essential for pregnancy and produces both pro-inflammatory and anti-inflammatory cytokines. Excessive production of inflammatory cytokines, involving interleukin-1β (IL-1β), IL-6, and IL-8, from placental tissues is associated with pregnancy complications. Olive leaf extract has several health benefits, including anti-inflammatory functions. OleaVita is a new commercial olive leaf extract; it is hypothesized to suppress placental inflammation. In human placental tissue culture, OleaVita treatment inhibited the secretion of inflammatory cytokines and NF-κB p65 protein expression. OleaVita also suppressed toll-like receptor ligands-induced IL-1β secretion in human placental tissues. IL-1β is regulated by the NLRP3 inflammasomes, a pivotal regulator of various diseases. OleaVita significantly decreased NLRP3 and pro-IL-1β protein expression, suggesting that it has an inhibitory effect on NLRP3 inflammasome activation. Thus, OleaVita is beneficial as an inhibitor of inflammation and NLRP3 inflammasome activation, and may be used as a supplement for the treatment and prevention of inflammatory diseases.
... Myocarditis is an inflammatory disease of the heart muscle which can progress into chronic heart failure [98]. The anti-inflammatory effect of OA has also been demonstrated in mice with experimental autoimmune myocarditis where it promoted the production of anti-inflammatory cytokines, reduced the production of pro-inflammatory cytokines and ultimately alleviates other symptoms of the disease [99]. Furthermore, the ability of OA to alleviate hepatic insulin resistance in a db/db mouse was partly attributed to its anti-inflammatory activity as evidenced by reduction in the levels of IL-1 β, IL-6, and TNFα in the liver of the mice upon treatment with OA [7]. ...
The increasing demand for natural products as an alternative therapy for chronic diseases has encouraged research into the pharmacological importance of bioactive compounds from plants. Recently, there has been a surge of interest in the therapeutic potential of oleanolic acid (OA) in the prevention and management of chronic diseases. Oleanolic acid is a pentacyclic triterpenoid widely found in plants, including fruits and vegetables with different techniques and chromatography platforms being employed in its extraction and isolation. Several studies have demonstrated the potential therapeutic effects of OA on different diseases and their symptoms. Furthermore, oleanolic acid also serves as a framework for the development of novel semi-synthetic triterpenoids that could prove vital in finding therapeutic modalities for various ailments. There are recent advances in the design and synthesis of chemical derivatives of OA to enhance its solubility, bioavailability and potency. Some of these derivatives have also been therapeutic candidates in a number of clinical trials. This review consolidates and expands on recent reports on the biological effects of oleanolic acid from different plant sources and its synthetic derivatives as well as their mechanisms of action in in vitro and in vivo study models. This review suggests that oleanolic acid and its derivatives are important candidates in the search for alternative therapy in the treatment and management of chronic diseases.
... 145 Finally, OA was found to inhibit COX-2 enzyme and Th1 responses, which can reduce the risk of inflammation. [146][147] ...
Cardiovascular diseases (CVDs), whether congenital or acquired, are considered as a leading cause of death worldwide. Acquired CVDs are greatly correlated to dietary and other life style factors including inadequate nutrition style, exposure to oxidative stress and lack of exercise. In fact, CVDs can be easily prevented and/or controlled, as advised by physicians, through quit of smoking, consumption of diet rich in polyunsaturated fatty acids, control of blood pressure, increase in physical activity, and maintenance of weight within normal limits. In addition, certain functional foods and dietary supplements are reported to contain diverse physiologically active components with established potential in the management and/or prevention of CVDs, especially those acquired. The present chapter is intended to survey the beneficial role of these products and their individual ingredients with special emphasis on their chemical composition and mode/mechanism of action. The role of dietary plant metabolites, viz. polyphenols, phytosterols and phytostanols, terpenoids and saponins as cardioprotective, are separately overviewed in this chapter. Besides, examples of commonly used herbs and herbal products, claimed to reduce CVD-risk incidence and suggested for incorporation in daily diets, are also mentioned. © 2018 by World Scientific Publishing Co. Pte. Ltd. All rights reserved.
... Targeting CXCR3 might be more effective in treating chronic heart inflammation in combination with approaches to enhance Treg numbers or activity, which are generally reduced in cardiovascular diseases (Table 1). Regulatory T cells are immunosuppressive and anti-inflammatory, and a growing number of experimental studies have shown their beneficial effects on the heart in various experimental models of coronary artery disease [109,110], Kawasaki disease [111], myocarditis and dilated cardiomyopathies [112][113][114][115][116][117], Chagas heart disease [118,119], hypertensive LV hypertrophy [95,96], and nonischemic heart failure [94,109,120]. Although not discussed here, boosting Treg numbers or activity in the heart is reported to be beneficial as well in experimental models of infarction-driven remodeling [121][122][123][124]. Increasing levels of IL-10-secreting Treg/Tr1 cells may be particularly advantageous, as IL-10 has anti-inflammatory and protective actions on the vasculature and heart [125][126][127][128][129][130][131][132]. ...
Accumulating evidence reveals involvement of T lymphocytes and adaptive immunity in the chronic inflammation associated with infectious and noninfectious diseases of the heart, including coronary artery disease, Kawasaki disease, myocarditis, dilated cardiomyopathies, Chagas, hypertensive left ventricular (LV) hypertrophy, and nonischemic heart failure. Chemokine CXCL10 is elevated in cardiovascular diseases, along with increased cardiac infiltration of proinflammatory Th1 and cytotoxic T cells. CXCL10 is a chemoattractant for these T cells and polarizing factor for the proinflammatory phenotype. Thus, targeting the CXCL10 receptor CXCR3 is a promising therapeutic approach to treating cardiac inflammation. Due to biased signaling CXCR3 also couples to anti-inflammatory signaling and immunosuppressive regulatory T cell formation when activated by CXCL11. Numbers and functionality of regulatory T cells are reduced in patients with cardiac inflammation, supporting the utility of biased agonists or biologicals to simultaneously block the pro-inflammatory and activate the anti-inflammatory actions of CXCR3. Other immunotherapy strategies to boost regulatory T cell actions include intravenous immunoglobulin (IVIG) therapy, adoptive transfer, immunoadsorption, and low-dose interleukin-2/interleukin-2 antibody complexes. Pharmacological approaches include sphingosine 1-phosphate receptor 1 agonists and vitamin D supplementation. A combined strategy of switching CXCR3 signaling from pro- to anti-inflammatory and improving Treg functionality is predicted to synergistically lessen adverse cardiac remodeling.
... OA withal suppresses the acetic acidinduced hyperpermeability and carboxymethylcelluloseinduced leukocyte migration as well as activation of TNF-, and of NF- [43]. In a study, using EAM mice model, Martín et al., investigated that OA effectively increases the number of Treg cells along with expression of IL-10 and IL-35 whereas significantly reduced the pro-inflammatory and profibrotic cytokines [44]. In the presence of allergens, OA suppresses the eosinophil infiltration, allergic airway inflammation, and Penh via down-regulation of IL-5, IL-13, IL-17, ovalbumin-concrete IgE, GATA-3, (Gr-1 expression through the T-bet) and ROR t and up-regulation of T-bet and Foxp3 (forkhead box p3) [45]. ...
Background:
Plant derived products are not only served as dietary components but also used to treat and prevent the inflammatory associated diseases like cancer. Among the natural products pentacyclic terpenoids including ursolic acid and oleanolic acid are considered as the promising anti-inflammatory therapeutic agents.
Objectives:
The current review extensively discusses the anti-inflammatory therapeutic potential of these pentacyclic moieties along with their proposed mechanisms of action. Furthermore, the relevant patents have also been listed to present the health benefits of these promising therapeutic agents to pin down the inflammatory diseases.
Expert opinion:
Pentacyclic terpenoids are known to negatively down-regulate a variety of extracellular and intracellular molecular targets associated with disease progression. The major anti-inflammatory effects of these molecules have been found to be mediated via inactivation of NFкβ, STAT3/6, Akt/mTOR pathways. A number of patents on UA & OA based moieties have been reported between 2010 and 2016. Still there have been only a few compounds which meet the need of sufficient hydro solubility and bioavailability along with higher anti-inflammatory activities. Thus, it has been essential to develop novel derivatives of terpenpoids which may not only overcome the solubility issues but also may improve their therapeutic effects. In addition, scientific community may utilize nanotechnology based drug delivery systems so as to increase the bio-availability, selectivity and dosages related problems.
... Oleuropein shows prevention against cardiac remodelling after myocardial infarction in Wistar rat through inhibiting angiotensin-converting enzyme activity [26]. OA modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury Martin, et al. [27]. Therefore, the unprejudiced of study was to evaluate the effect of OA in an animal model of Dox-induced cardiomyopathy and compare it with amifostine (AMF) a well-known organ protective agent. ...
The prevention of doxorubicin (Dox) induced cardiotoxicity may be co-operative to recover future Dox treatment. The aim of this study was to explore the cardioprotective effects of oleanolic acid (OA), an antioxidant agent, on Dox induced cardiotoxicity. OA is a triterpenoid compound, which exist widely in plant kingdom in free acid form or as a glycosidic triterpenoids saponins. Cardiotoxicity was induced in Wistar rats with single intravenous injection of doxorubicin at dose of 67.75 mg/kg i.v for 48 hrs. At 12 hrs of interval following Dox administration the cardioprotective effect of OA (1.5 mg/kg, i.v.) and Amifostine (AMF) (90 mg/kg i.v., single dose prior 30 min) were evaluated. Induction of cardiotoxicity was confirmed by increase in systolic, diastolic, mean arterial pressures, maximal positive rate of developed left ventricular pressure (+LVdP/dtmax, an indicator of myocardial contraction), maximal negative rate of developed left ventricular pressure (-LVdP/dtmax, a meter of myocardial relaxation) and an increase in left ventricular end-diastolic pressure (LVEDP, a marker of pre-load). Cardiac markers in such as CK-MB, LDH and alterations in ECG. Dox administration showed alteration in Biochemical parameters and endogenous antioxidants. Administration of OA Showed maximal protection against Dox induced cardiac toxicity as observed by reduction in blood pressure, prevention of left ventricular function and attenuation of biochemical and antioxidant parameters. Based on the findings, its concluded that OA can be used as an adjuvant with Dox therapy in treating cancers.
... M2 macrophages reduce colitis through IL-10 expression in mice (Zhu et al. 2014). Several studies have demonstrated the anti-inflammatory effects of pentacyclic triterpenes through the induction of IL-10 (Chen et al. 2012;Martín et al. 2014). Ursolic acid, αand β-amyrin increase the expression of IL-10 protein in mouse colons (Vitor et al. 2009;Jang et al. 2014). ...
Obesity induces chronic, low-grade inflammation, which increases the risk of colon cancer. We investigated the preventive effects of Bardoxolone methyl (BARD) on high-fat diet (HFD)-induced inflammation in a mouse colon. Male C57BL/6J mice (n=7) were fed a HFD (HFD group), HFD plus BARD (10 mg/kg) in drinking water (HFD/BARD group), or normal laboratory chow diet (LFD group) for 21 weeks. In HFD mice, BARD reduced colon thickness and decreased colon weight per length. This was associated with an increase in colon crypt depth and the number of goblet cells per crypt. BARD reduced the expression of F4/80 and CD11c but increased CD206 and IL-10, indicating an anti-inflammatory effect. BARD prevented an increase of the intracellular pro-inflammatory biomarkers (NF-қB, p NF-қB, IL-6, TNF-α) and cell proliferation markers (Cox2 and Ki67). BARD prevented fat deposition in the colon wall and prevented microbial population changes. Overall, we report the preventive effects of BARD on colon inflammation in HFD-fed mice through its regulation of macrophages, NF-қB, cytokines, Cox2 and Ki67, fat deposition and microflora.
... Oleuropein shows prevention against cardiac remodelling after myocardial infarction in Wistar rat through inhibiting angiotensin-converting enzyme activity [26]. OA modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury Martin, et al. [27]. Therefore, the unprejudiced of study was to evaluate the effect of OA in an animal model of Dox-induced cardiomyopathy and compare it with amifostine (AMF) a well-known organ protective agent. ...
... Considerable attention on myocarditis therapeutic strategies have focused on different stages of the disease, targeting the elimination of the infecting agent, suppression of the heart-specific autoimmune response, reduction of inflammation and inflammatory-associated tissue remodeling [18]. However, toxicity, limited efficacy, and a higher expense are serious disadvantages of new antiinflammatory and/or immunosuppressive agents. ...
This study aims to investigate the protective effect of apigenin on the development of experimental autoimmune myocarditis (EAM) and the underlying mechanisms. An EAM model was induced in BALB/c mice by the injection of porcine cardiac myosin. Apigenin was orally administered from day 1 to 21. The severity of myocarditis was assessed by determination of heart weight/body weight ratio (HW/BW) and histopathological evaluation. Echocardiography was conducted to evaluate the cardiac function and heart structure. Antigen-specific T cell proliferation responses to cardiac myosin were evaluated by the lymphocyte proliferation assay. ELISA was used to determine serum levels of type 1 helper (Th1) and Th2 cytokines. Apigenin treatment significantly decreased HW/BW. Histopathologic analysis showed that the infiltration of inflammatory cells was reduced significantly by apigenin treatment. Meanwhile, apigenin administration effectively ameliorated autoimmune myocarditis-induced cardiac hypertrophy and cardiac dysfunction as well as inhibited lymphocyte proliferation in mice immunized with myosin. Furthermore, Th1 cytokines tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-2 (IL-2) were significantly downregulated, while Th2 cytokines IL-4 and IL-10 were markedly upregulated. The results indicated that apigenin can alleviate EAM due to its immunomodulatory reactions in modification of helper T cell balance.
The immune system is one of the essential defense mechanisms. Immune system inadequacy increases the risk of infections and cancer diseases, whereas over-activation of the immune system causes allergies or autoimmune disorders. Immunomodulators have been used in the treatment of immune-related diseases. There is growing interest in using herbal medicines as multicomponent agents to modulate the complex immune system in immune-related diseases. Many therapeutic phytochemicals showed immunomodulatory effects by various mechanisms. This mechanism includes stimulation of lymphoid cell, phagocytosis, macrophage, and cellular immune function enhancement. In addition increased antigen-specific immunoglobulin production, total white cell count, and inhibition of TNF-α, IFN-γ, NF-kB, IL-2, IL-6, IL-1β, and other cytokines that influenced the immune system. This review aims to overview, widely investigated plant-derived phytoconstituents by targeting cells to modulate cellular and humoral immunity in in vivo and in vitro. However, further high-quality research is needed to confirm the clinical efficacy of plant-based immunomodulators.
Plants are used as food, drink, dye, perfume, the wood industry, and most importantly for medicine in most countries of the world. These countries use herbal medicines as much as possible, although limited, instead of chemical medicines to treat various diseases such as digestive diseases, skin and hair diseases, as well as cardiovascular diseases. One of these herbal medicines is oleanolic acid, which has been shown to have a positive effect on cardiac fibrosis in various research conducted in several countries on fibrosis. Also, several other studies have shown that oleanolic acid has cardioprotective effects and plays a role in regulating cardiovascular homeostasis through Akt/mTOR regulatory signaling pathway. After a cardiac injury, the level of angiotensin II, followed by the release of TGF-β, increases rapidly, and by activating fibroblast cells, it causes the proliferation and overexpression of collagen, and the mismatch in the overexpression of collagen causes fibrosis in the heart. On the other hand, cardiovascular diseases are the main cause of death worldwide, with about 800,000 deaths worldwide due to fibrotic diseases, most of which are pulmonary and cardiac fibrosis. This medicine is obtained from different plants, especially olive plants, and apple skin. In this review, we provide an overview of what plants and vegetables do to improve heart diseases, including the role of oleanolic acid in cardiac fibrosis.
In recent years, there has been great scientific interest in the study of the therapeutic properties of natural organic compounds, highlighting such important biological activities as their anti-inflammatory and anticancer effects. Within this range of organic compounds, we find compounds of natural origin such as terpenes, secondary metabolites that are present in the plant kingdom. Within the terpenes we highlight the triterpenes that are characterized by having 30 carbon atoms, constituting one of the groups with the largest number of bioactive compounds. On the other hand, we find another type of organic compounds such as non-steroidal anti-inflammatory drugs, highlighting diclofenac, which is classified as a phenolic compound (derived from phenylacetic acid) with anti-inflammatory properties. Based on this, this doctoral thesis is divided into two parts, the first corresponds to the extraction and purification of oleanolic acid (OA), synthesis of the amino PEGylated derivative of oleanolic acid (OADP) and the characterization of the anticancer and anti-inflammatory activities of this derivative, determining its molecular mechanisms of action. The second part corresponds to a preliminary study of the anticancer and anti-inflammatory activities of different amino derivatives of diclofenac.
Myocarditis is defined as an inflammatory disease of the myocardium, and the autoimmune response specific to myocardium plays an important role in chronic myocarditis. Inhibiting myocardial-specific autoimmune response and inflammation is crucial to treat myocarditis. Myricetin is a plant-derived flavonoid in nature which has potent anti-inflammatory and cardiovascular protective properties. However, the pharmacological effect of myricetin in autoimmune myocarditis is undefined. It is necessary to investigate the role and potential mechanisms of myricetin in autoimmune myocarditis. Therefore, purified cardiac myosin was subcutaneously injected to mice to establish the experimental autoimmune myocarditis (EAM) model. Myricetin was solubilized in normal saline and administered everyday by gavage from the day of immunization. After 21 days of treatment, it was found that myricetin significantly alleviated myocardial injury in EAM mice. The serum anti-cardiac myosin antibody, immunoglobulin (Ig) G, IgM levels and the proportion of T helper 17 (Th17) cells were decreased and the proportion of regulatory T (Treg) cells was increased with the treatment of myricetin in EAM mice. The myosin-specific T cell proliferation was inhibited by myricetin. Meanwhile, myricetin suppressed the expressions of monocyte chemoattractant protein-1 (MCP-1), phospho (p)-p65, p-c-Jun and Act1/TRAF6/TAK1 in H9C2 cells and myocardial tissues of EAM mice. These results revealed that myricetin inhibited the autoimmune response specific to myocardium and the expression of MCP-1 in cardiomyocytes, which suggested that myricetin ameliorated autoimmune myocarditis by modulating immune response and the expression of MCP-1. Therefore, myricetin may be a promising therapeutic strategy for autoimmune myocarditis.
The immune response is of great significance in the initiation and progression of a diversity of cardiovascular diseases involving pro-and anti-inflammatory cytokines. Interleukin-35 (IL-35), a cytokine of the interleukin-12 family, is a novel anti-inflammation and immunosuppressive cytokine, maintaining inflammatory suppression and regulating immune homeostasis. The role of IL-35 in cardiovascular diseases (CVDs) has aroused enthusiastic attention, a diversity of experimental or clinical evidence has indicated that IL-35 potentially has a pivot role in protecting against cardiovascular diseases, especially atherosclerosis and myocarditis. In this review, we initiate an overview of the relationship between Interleukin-35 and cardiovascular diseases, including atherosclerosis, acute coronary syndrome, pulmonary hypertension, abdominal aortic aneurysm, heart failure, myocardial ischemia-reperfusion, aortic dissection and myocarditis. Although the specific molecular mechanisms entailing the protective effects of IL-35 remain an unsolved issue, targeted therapies with IL-35 might provide a promising and effective solution to prevent and cure cardiovascular diseases.
Oleanolic acid (OA, 3 β - hydroxyoleanolic acid-12-en-28-oic acid) is a pentacyclic triterpenoid present in many plants. As a new framework for development of semi synthetic triterpenoids, OA is of great significance in the discovery of anticancer drugs. Some of these derivatives, such as CDDO (2-cyano-3,12-dioxooleana-1, 9 (11)-dien-28-oic acid) have been verified in clinical trials, while other derivatives studied previously, such as SZC014, SZC015 and SZC017 (OA derivatives respectively), are also candidate drugs for cancer treatment. This paper reviews the preclinical studies, literature evidence, target analysis and anticancer mechanism of OA and its derivatives. The mechanism of action of its derivatives mainly includes anti-cancer cell proliferation, inducing tumor cell apoptosis, inducing autophagy, regulating cell cycle regulatory proteins, inhibiting vascular endothelial growth, anti angiogenesis, inhibiting tumor cell migration and invasion. In recent years, the molecular mechanism of OA and its derivatives has been elucidated. These effects seem to be mediated by the alterations in a variety of signaling pathways induced by OA and its derivatives. In conclusion, OA and its derivatives are considered as important candidate drugs for the treatment of cancer, indicating that OA and its derivatives have the potential to be used as anticancer drugs in practice.
Oleanolic acid (OA) is a well-known natural product possessing many important pharmacological activities; however, its weak bioactivities significantly restrict the potential application in drug development. The structural modification of oleanolic acid is an effective mean to enhance its bioactivity with lower toxicity but it is challenging. In the present study, we systematically synthesized a series of new 11-oxooleanolic acid derivatives and evaluated their anti-inflammatory activities with a LPS induced BV2 cells inflammation model and a 12-O-tetradecanoyl phorbol-13-acetate (TPA) induced ear inflammation mice model. It was found that compounds 8 and 9 show more potent anti-inflammatory effects than OA and exhibit a low cytotoxicity. The possible mechanism of action was also investigated. The in vitro and in vivo results revealed that these two new 11-oxooleanolic acid derivatives may exert anti-inflammatory activities through the inhibition of NO, pro-inflammatory cytokines and chemokines (IL-1β, IL-6, IL-12, TNF-α, MCP-1 and MIP-1α) and upregulation of anti-inflammatory cytokines (IL-10), which may be caused by inhibiting the activation of NF-κB, MAPKs and PI3K/Akt related inflammatory signaling pathways and the activation of Nrf2/HO-1 signaling pathway. The results suggest that these two 11-oxooleanolic acid derivatives may be potential candidates for further anti-inflammatory drug development and our study demonstrated an important and practical strategy for drug discovery through the rational modification of natural products.
Inflammation and Natural Products brings together research in the area of the natural products and their anti-inflammatory action in medical, nutraceutical and food products, addressing specific chronic inflammatory diseases like cancer and the mechanistic aspects of the mode of action of some key natural products. Inflammation is a complicated process, driven by infection or injury or genetic changes, which results in triggering signalling cascades, activation of transcription factors, gene expression, increased levels of inflammatory enzymes, and release of various oxidants and pro-inflammatory molecules in inflammatory cells. Excessive oxidants and inflammatory mediators have a harmful effect on normal tissue, including toxicity, loss of barrier function, abnormal cell proliferation, inhibiting normal function of tissues and organs and finally leading to systemic disorders. The emerging development of natural product formulations utilizing the unique anti-inflammatory compounds such as polyphenols, polysaccharides, terpenes, fatty acids, proteins and several other bioactive components has shown notable successes. Inflammation and Natural Products: Recent Development and Current Status provides a comprehensive resource, ranging from detailed explanation on inflammation to molecular docking strategies for naturally occurring compounds with anti-inflammatory activity. It is useful for graduate students, academic and professionals in the fields of pharmaceutical and medical sciences and specialists from natural product-related industries.
Over the course of human history, natural products derived from nature through extraction processes provided promising pharmacological activities. They have become an attractive alternative for various diseases. This chapter accords for a panoramic snapshot of various natural products with antiinflammatory activities, which are beneficial for the management of autoimmune myocarditis. Exhaustive knowledge on the etiology and pathogenesis of myocarditis is described to identify and discover possible pathways through which relevant green products could work efficiently and effectively. In addition, prominent illustration from the current inventory of green drugs that possess antiinflammatory activities against autoimmune diseases is reviewed. Thus this comprehensive outlook on the varied antiinflammatory mechanism such as inhibition of Th1 and Th17 immunity and macrophage infiltration of these natural products promise to contribute to the evolution of rational development of natural products encouraging future evidenced-based approach for autoimmune myocarditis.
Nowadays chronic inflammation is remarked as one of the main causes of several diseases such as cancer, cardiovascular diseases, or neurological diseases. Lifestyle and diet are key factors of the development of chronic inflammation. Because of that, in the last years Mediterranean diet has been granted as an antiinflammatory diet, where virgin olive oil from vegetable origin is one of the main actors because it is use as the main fat of Mediterranean diet. Virgin olive oil is mainly composed by oleic acid; but there are many minor compounds present in it, such as squalene, pinoresinol, uvaol, erythrodiol, oleanolic acid, or maslinic acid, which possess per se many bioactive activities in inflammation, as long as in other diseases as cancer or cardiovascular diseases. Because of their presence, it is believed that virgin olive oil possesses the beneficial actions described in the last decades. In this chapter, inflammation properties of several minor compounds present in virgin olive oil have been described and explained.
Background
Oleanolic acid (OA) is a ubiquitous product of triterpenoid compounds. Due to its inexpensive availability, unique bioactivities, pharmacological effects and non-toxic properties, OA has attracted tremendous interest in the field of drug design and synthesis. Furthermore, many OA derivatives have developed for ameliorating the poor water solubility and bioavailability.
Objective
Over the past few decades, various modifications of the OA framework structure have led to the observation of an enhancement in bioactivity. Herein, we focused on the synthesis and medicinal performance of OA derivatives modified on A-ring. Moreover, we clarified the relationship between structures and activities of OA derivatives with different functional groups in A-ring. The future application of OA in the field of drug design and development also was discussed and inferred.
Conclusion
This review concluded the novel achievements that could add paramount information to the further study of OA-based drugs.
Oleanolic acid is an analogue of pentacyclic triterpenoids. It has been used as a hepatic drug for over 20 years in China. Currently, there are only five approved drugs derived from pentacyclic triterpenoids including oleanolic acid (liver diseases), asiaticoside (wound healing), glycyrrhizinate (liver diseases), isoglycyrrhizinate (liver disease) and sodium aescinate (hydrocephalus). To understand more about the bioactivity and functional mechanisms of oleanolic acid is able to develop potent therapeutic agents, in particular for the prevention and treatment of heart diseases, which are the leading cause of death for people worldwide. The primary aim of this mini-review is to summarize concisely the new applications of oleanolic acid and its derivatives as cardioprotective agents reported in recent years and to highlight their therapeutic perspectives in cardiovascular diseases.
Introduction: Fibrosis makes numerous diseases in all organs more complicated and leads to severe consequences in the lung, liver, heart, kidney and skin. In essence, fibrosis results from excessive, persistent and oftentimes nonreversible aggregation of extracellular matrix (ECM) or simply as collagen during the process of tissue injury and repair. Recent studies suggest the pathology of fibrosis, especially in pulmonary and liver fibrosis, involves various types of immune cells and soluble mediators including interleukin (IL)-35, a recently identified heterodimeric cytokine that belongs to the IL-12 cytokine family. Furthermore, IL-35 may inhibit fibrotic diseases. However, the side effects of inhibiting IL-35 also need attention and we have a long way to go to make better use of it in fibrotic diseases.
Areas covered: This review focuses on recent evidence regarding the role of IL-35 in the pathogenesis of pulmonary, hepatic, cardiac, renal and skin fibrosis. It also discusses targeting of IL-35 as a promising novel strategy for treatment of fibrotic diseases.
Expert commentary: Understanding as fully as possible the relationship between IL-35 and fibrotic diseases is important for the development of new therapeutic approaches.
Cardiovascular diseases (CVDs) are the most prevalent cause of morbidity and mortality worldwide. Oxidative stress and chronic inflammation are the major causes of CVDs. In the vasculature, inflammation occurs due to injury, oxidation of lipids, infection, etc. that result in damage to cells of the blood vessels and progression towards plaque formation. Inflammation portrays an important role in all stages of plaque formation which leads to cardiac arrest or heart failure, peripheral vascular diseases and stroke and could be fatal. Unlike plaque formation, the birth defect in cardiovascular system also leads to short and poor quality of life. Among all preventive and therapeutic strategies for CVDs, herbal interventions are known to be effective with little or no side effects. Herbal interventions have been in use for medical treatments from the beginning of civilisation. WHO report states that approximately 80% of the global population depends on the herbal resources, of which many have moved to clinical use in the recent times. Phytochemicals have a wide array of properties especially anti-inflammatory, anti-oxidative and anti-lipidaemic which are effective in preventing and treating CVDs. They increase the expression of antioxidant and anti-inflammatory molecules mainly via nuclear factor erythroid 2-related factor 2 (Nrf2) activation and reduce the levels of cholesterol, low-density lipoprotein (LDL) and inflammatory cytokines, hence effective in treatment of CVDs. In this chapter, herbal derivative-induced alteration in the mechanisms pertaining to pathophysiology of CVDs has been discussed.
Oleanolic acid (OA) has shown promising antitumor activity. However, it is difficult to formulate because of its poor water solubility and low bioavailability. In this study, self-assembled nanoparticles based on poly(ethylene glycol)–oleanolic acid conjugates (mPEG–OA) for co-delivery of anticancer drugs were developed to enhance the properties of OA. The mPEG–OA was synthesized by conjugating oleanolic acid (OA) to methoxy poly(ethylene glycol) carboxylic acid (mPEG–COOH). Then hydroxycamptothecin (HCPT), another anticancer drug was encapsulated into the mPEG–OA conjugates by the nanoprecipitation method. The mPEG–OA/HCPT nanoparticles (NPs) had an appropriate size, high drug loading of OA and HCPT, high stability, slow drug release and low cytotoxicity. In vivo studies revealed that the nanoparticles significantly improved the antitumor activity compared with free drugs. As no systemic toxicity was observed, the mPEG–OA NPs can serve as a promising drug delivery system for cancer therapy.
Teucrium polium L. is a species with ancient ethno-botanical uses for its anti-inflammatory action which is mainly due to the phenolics content. On the other side, the presence of neo-clerodanes, which exert hepatotoxic action, may explain why in recent years the medicinal uses of this species have drastically diminished. In this paper we report on the isolation of a new natural neo-clerodane diterpenoid, namely 20-O-acetyl-teucrasiatin (2), together with other twelve relevant compounds in the fields of chemotaxonomy and ethnomedicine. Nevertheless, the total absence of iridoids and in particular of the chemotaxonomic markers of the family and of the genus itself, may reveal an intraspecific variability of T. polium with different chemotypes which may contain or not iridoids.
A rapid and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and validated for simultaneous quantification of oleanolic acid and hederagenin in rat plasma. After the two analytes were extracted with liquid-liquid extraction, chromatographic separation was performed on a C18 column with acetonitrile and water (85:15, v/v) as mobile phase at a flow rate of 0.4 mL/min. Calibration curves exhibited good linearity (r > 0.995) over the ranges of 0.41-82.0 ng/mL for oleanolic acid and 0.32-64.0 ng/mL for hederagenin, respectively. The lower limit of quantifications (LLOQs) in plasma were 0.41 ng/mL for oleanolic acid and 0.32 ng/mL for hederagenin. The established LLOQs were within the concentration needed for the assay in plasma, which met the requirements to evaluate their pharmacokinetics of oleanolic acid and hederagenin. This developed assay was successfully applied in the pharmacokinetic study of oleanolic acid and hederagenin in rats after oral administration of Rhizoma Clematidis extract.
Ethnopharmacological relevance:
Plinia edulis (Vell.) Sobral (Myrtaceae) is native and endemic to the Brazilian Atlantic Rainforest. Popularly known as "cambucá", it has been used in folk medicine for the treatment of stomach disorders, diabetes, bronchitis, inflammation and as tonic. Although there are numerous records concerning its popular use as analgesic and anti-inflammatory, scientific information regarding these pharmacological activities is limited. Therefore, the aim of this study was to characterize the anti-inflammatory and antinociceptive activity of P. edulis leaf infusion (AEPe) in mice.
Materials and methods:
The acetic acid-induced writhing response and mechanical nociceptive paw tests were used to evaluate the antinociceptive activity. Carrageenan-induced paw edema and lipopolysaccharide-induced peritonitis were used to investigate the anti-inflammatory activity. The substances in AEPe were identified by HPLC-MS analysis.
Results:
At the test doses 30-300mg/kg p.o., AEPe has clearly exhibited anti-inflammatory effects, reducing carrageenan-induced paw edema and inhibiting leukocyte recruitment into the peritoneal cavity. The infusion has shown significant antinociceptive activity in both models of nociception. Gallic acid, myricitrin, guaijaverin, quercitrin, quercetin, corosolic acid, maslinic acid, oleanolic acid and ursolic acid were identified in AEPe.
Conclusion:
P. edulis infusion presented antinociceptive and anti-inflammatory activities in all experiments realized in this study, which could be related to the presence of triterpenoids and flavonoids. These results provide scientific support for the traditional use of this species in the management of pain and inflammation.
The current study focuses on the synthesis of several hybrid individuals combining a natural oleanolic acid skeleton and synthetic nonsteroidal anti-inflammatory drug moieties (NSAIDs). It studied structural modifications of the oleanolic acid structure by use of the direct reactivity of hydroxyl or hydroxyimino groups at position C-3 of the triterpenoid skeleton with the carboxylic function of anti-inflammatory drugs leading to new perspective compounds with high potential pharmacological activities. Novel ester- and iminoester-type derivatives of oleanolic unit with the different NSAIDs, such as ibuprofen, aspirin, naproxen, and ketoprofen, were obtained and characterized. Moreover, preliminary research of compounds obtaining structure stability under acidic conditions was examined and the PASS method of prediction of activity spectra for substances was used to estimate the potential biological activity of these compounds.
In a preliminary experiment, it was found that oleanolic acid (OA), which is widely distributed in food and medicinal plants, inhibited interleukin (IL)-6/tumor growth factor beta-induced differentiation of splenic T cells into Th17 cells. Moreover, OA induced the differentiation of splenic T cells into Treg cells. Therefore, we examined the anti-inflammatory effect of OA in mice with dextran sodium sulfate (DSS)-induced colitis. Oral administration of OA significantly inhibited DSS-induced colon shortening, macroscopic score, and myeloperoxidase activity. Treatment with OA inhibited DSS-induced differentiation to Th17 cells and downregulated the expression of RORγt and IL-17 in the lamina propria of colon and Treg cell differentiation and Foxp3 and IL-10 expression were increased. OA treatment increased the DSS-suppressed expression of tight junction proteins such as ZO-1, occludin, and claudin-1 in the colon. Moreover, OA treatment inhibited DSS-induced expression of tumor necrosis factor-α, interleukin (IL)-1β, and IL-17, the activation of NF-κB and mitogen-activated protein kinases, and increased IL-10 expression. OA also inhibited the activation of NF-κB and expression of proinflammatory cytokines in LPS-stimulated peritoneal macrophages. These findings suggest that OA may ameliorate inflammatory diseases such as colitis by inhibiting Th17 cell differentiation and increasing Treg cell differentiation.
We analysed the ethanolic extract from Ajuga genevensis L. (Lamiaceae) growing in Dolomites, part of Italian Alps. Three new compounds for this species were identified: rosmarinic acid (1), oleanolic acid (2) and maslinic acid (3), representative of two different classes of chemical compounds (phenylpropanoids and pentacyclic triterpenes). A. genevensis resulted to be a valuable source of these compounds endowed with interesting biological activities (i.e. antioxidant, neuroprotective, anti-inflammatory, antiproliferative). The recognition of compounds (1), (2) and (3) may also confirm the ethnomedicinal uses of this plant. From a chemotaxonomical point of view, it is worth noting that iridoids were not evidenced in this accession. Iridoids are considered chemotaxonomic marker in Lamiales, and, in contrast with a previous study on this species, the presence of aucubin was not confirmed. In addition, the presence of large amounts of rosmarinic acid (1) was unexpected for a species that does not belong to subfamily Nepetoideae.
Oleanolic acid (OA), contained in more than 1620 plants and as an aglycone precursor for naturally occurred and synthesized triterpenoid saponins, is used in China for liver disorders in humans. However, the underlying liver-protecting mechanisms remain largely unknown. Here, we found that treatment of rats with OA (25 mg/kg/day, gavage, once daily) over 10 weeks diminished liquid fructose-induced excess hepatic triglyceride accumulation without effect on total energy intake. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in OA-treated rats. Hepatic gene expression profile demonstrated that OA suppressed fructose-stimulated overexpression of sterol regulatory element-binding protein-(SREBP-) 1/1c mRNA and nuclear protein. In accord, overexpression of SREBP-1c-responsive genes responsible for fatty acid synthesis was also downregulated. In contrast, overexpressed nuclear protein of carbohydrate response element-binding protein and its target genes liver pyruvate kinase and microsomal triglyceride transfer protein were not altered. Additionally, OA did not affect expression of peroxisome proliferator-activated receptor-gamma- and -alpha and their target genes. It is concluded that modulation of hepatic SREBP-1c-mediated expression of the genes responsible for de novo fatty acid synthesis plays a pivotal role in OA-elicited diminishment of fructose-induced fatty liver in rats.
To study the effect of oleanolic acid (OA) on streptozotocin induced diabetic nephropathy in Sprague Dawley rats.
Four weeks after intra-peritoneal injection of streptozotocin (STZ; 55 mg/kg), the rats with proteinuria were grouped as: Control (non-diabetic, treated orally with vehicle), diabetic control (treated orally with vehicle) and three diabetic groups receiving 20, 40 and 60 mg/kg/day oral doses of OA. At the end of 8 weeks, urine and serum samples from the rats were processed for determination of creatinine, BUN and GFR. The kidney samples were processed for determination of weight changes, oxidative stress related parameters like catalase, superoxide dismutase and reduced glutathione levels. A part of one kidney from each rat was used for transmission electron microscopy (TEM).
As evident in TEM, OA inhibited the nephropathy induced alterations in podocyte integrity, basement membrane thickness and spacing between the podocytes at 60 mg/kg dose. It increased GFR and reduced oxidative stress in the kidneys in a dose dependent manner. These findings conclusively demonstrate the efficacy of OA in diabetic nephropathy. Significant decrease in the oxidative stress in kidneys indicates the role of anti-oxidant mechanisms in the effects of OA. However, OA is known to act through multiple mechanisms like inhibition of the generation of advanced glycation end products and improving the insulin secretion. These mechanisms might have contributed to its efficacy.
These results conclusively demonstrate the efficacy of OA in diabetic nephropathy through its possible antioxidant activity.
Chronic chagasic cardiomyopathy is a leading cause of heart failure in Latin American countries, being associated with intense inflammatory response and fibrosis. We have previously shown that bone marrow mononuclear cell (BMC) transplantation improves inflammation, fibrosis, and ventricular diameter in hearts of mice with chronic Chagas disease. Here we investigated the transcriptomic recovery induced by BMC therapy by comparing the heart transcriptomes of control, chagasic, and BMC transplanted mice. Out of the 9390 unique genes quantified in all samples, 1702 had their expression altered in chronic chagasic hearts compared to those of normal mice. Major categories of significantly upregulated genes were related to inflammation, fibrosis and immune responses, while genes involved in mitochondrion function were downregulated. When BMC-treated chagasic hearts were compared to infected mice, 96% of the alterations detected in infected hearts were restored to normal levels, although an additional 109 genes were altered by treatment. Transcriptomic recovery, a new measure that considers both resotrative and side effects of treatment, was remarkably high (84%). Immunofluorescence and morphometric analyses confirmed the effects of BMC therapy in the pattern of inflammatory-immune response and expression of adhesion molecules. In conclusion, by using large-scale gene profiling for unbiased assessment of therapeutic efficacy we demonstrate immunomodulatory effects of BMC therapy in chronic chagasic cardiomyopathy and identify potentially relevant factors involved in the pathogenesis of the disease that may provide new therapeutic targets.
Cardiac dysfunction is a common complication associated with major burns. While recent findings have linked the Th-17 T-cell response to the development of autoimmune myocarditis, the role of IL-17 and the Th-17 T-cell response in the development of post-burn cardiac dysfunction remains unknown.
Male C57BL/6 mice were subjected to a major burn (3rd degree, 25% TBSA) or sham treatment. Three hours after injury plasma and tissue (i.e., heart, lung, liver, small intestine) samples were collected and analyzed for the expression of Th-17 cytokine (i.e., IL-6, IL-17, IL-22, IL-23, TGF-beta) levels by ELISA.
Cardiac tissue levels of the Th-17 cytokines, IL-6, IL-17 and IL-22 were significantly elevated at 3 hrs after burn as compared to sham levels. IL-17 was analyzed 1, 3 and 7 days after burn and showed a return to baseline levels and without a difference in the burn group. Burn-induced alterations in the level of these cytokines in plasma or other tissues were not evident. The cardiac Th-17 cytokine response after burn injury was specific, as cardiac levels of Th-1 (IFN-gamma) and Th-2 (IL-10) cytokines were not significantly affected after injury. The cardiac Th-17 response correlated with a significant increase in Troponin levels at 3 hr. after burn.
These findings indicate that early after burn, cardiac tissue is associated with significantly elevated levels of Th-17 cytokines. The early Th-17 response after burn appears to be specific for cardiac tissue and may promote myocardial inflammation and dysfunction associated with this form of trauma.
IL-35 is produced by regulatory T cells, and this novel cytokine can downregulate Th17 cell development and inhibit autoimmune inflammation. In this work, an rIL-35, as a single-chain fusion between murine IL-12p35 and EBV-induced gene 3, was expressed in yeast. This rIL-35 inhibited OVA-specific cellular and Ab responses in OVA-challenged recipients of DO11.10 CD4+ T cells. Likewise, IL-35 inhibited clinical manifestation of collagen-induced arthritis or could cease further disease exacerbation upon initiation of IL-35 treatment. Exogenous IL-35 treatments suppressed Th1 and Th17 cells and promoted CD39 expression by CD4+ T cells. Sorted CD25-CD39+CD4+ T cells from IL-35-treated mice produced IL-10 and, upon adoptive transfer, were sufficiently potent to inhibit subsequent development of inflammation in mice with collagen-induced arthritis, whereas sorted CD25+CD39+CD4+ T cells showed reduced potency. IL-35 treatments of IL-10-/- mice failed to induce protective CD39+CD4+ T cells, demonstrating the effector role of IL-10 by IL-35 immunosuppression.
Lipopolysaccharides (LPS) induce tumor necrosis factor-alpha (TNF-alpha) production in cardiomyocytes, which contributes to myocardial depression during sepsis. However, the underlying mechanisms remain not fully understood. This study was undertaken to investigate the contribution of histone deacetylase (HDAC) to TNF-alpha expression in cardiomyocytes and the signaling mechanism of LPS-induced HDAC activation. Here, we show for the first time that LPS increases HDAC activity and that inhibition of HDAC decreases LPS-stimulated TNF-alpha expression via the accumulation of NF-kappaB/p65 at the TNF-alpha promoter in cardiomyocytes. Using a positive screen, we have further identified HDAC3 as a specific member of the HDAC family able to regulate TNF-alpha production. Furthermore, our data reveal that LPS-induced HDAC activity is mediated through reactive oxygen species from mitochondria and c-Src signaling. In summary, this study demonstrates a novel signaling mechanism by which LPS via mitochondrial reactive oxygen species/c-Src/HDAC3 pathways mediate TNF-alpha expression in cardiomyocytes.
Triterpenes, which comprise a broad chemical group of active principles, are implicated in the mechanisms of action and pharmacological effects of many medicinal plants used in folk medicine against diseases in which the immune system is implicated. They have been described as anti-inflammatory, antiviral, antimicrobial, and antitumoral agents, as well as being immunomodulator compounds. Several of them are implicated in the resolution of immune diseases, although their effects have not always been clearly correlated.
The aim of this review is to compile relevant data on the mechanisms of action of triterpenes isolated from active ethnomedicinal plants and their role in the resolution of diseases in which the immune system is implicated to examine the mechanism by which they are useful as ethnopharmacological medicines.
The selection of papers was made using the most relevant databases for the biomedical sciences on the basis of their ethnopharmacological use. We principally chose those studies that examined the resolution of allergic responses in vivo and those that studied the effects of the more relevant mediators implicated in the immune response in vitro.
The number of compounds actually studied is limited compared with the high number of principles that have been isolated and identified. Many studies focus on specific pathologies such cancer or inflammation, but in many cases they are clearly correlated with the immune response. Lanostanes, cucurbitanes, and oleananes are probably the most interesting groups; however, other compounds are also of potential importance.
Studies of specific mechanisms against mediators or transcription factors could be the objective for future research on ethnomedicinal plants used to combat immune diseases since the results obtained with cucurbitacins or derivatives of oleanolic acid support the use of different medicinal plants, thereby opening up a new frontier for future studies.
Galectin-3 (Gal-3) is a member of the beta-galactoside-binding lectin family and plays an important role in inflammation. However, the precise role of Gal-3 in autoimmune diseases remains obscure. We have investigated the functional role of Gal-3 in experimental autoimmune encephalomyelitis (EAE) following immunization with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. Gal-3 deficient (Gal-3-/-) mice developed significantly milder EAE and markedly reduced leukocyte infiltration in the CNS compared with similarly treated wild-type (WT) mice. Gal-3-/- mice also contained fewer monocytes and macrophages but more apoptotic cells in the CNS than did WT mice. Following Ag stimulation in vitro, lymph node cells from the immunized Gal-3-/- mice produced less IL-17 and IFN-gamma than did those of the WT mice. In contrast, Gal-3-/- mice produced more serum IL-10, IL-5, and IL-13 and contained higher frequency of Foxp3+ regulatory T cells in the CNS than did the WT mice. Furthermore, bone marrow-derived dendritic cells from Gal-3-/- mice produced more IL-10 in response to LPS or bacterial lipoprotein than did WT marrow-derived dendritic cells. Moreover, Gal-3-/- dendritic cells induced Ag-specific T cells to produce more IL-10, IL-5, and IL-12, but less IL-17, than did WT dendritic cells. Taken together, our data demonstrate that Gal-3 plays an important disease-exacerbating role in EAE through its multifunctional roles in preventing cell apoptosis and increasing IL-17 and IFN-gamma synthesis, but decreasing IL-10 production.
Immunization with cardiac myosin induces T cell-mediated myocarditis in genetically predisposed mice and serves as a model for autoimmune heart disease. This study was undertaken to identify pathogenic epitopes on the myosin molecule. Our approach was based on the comparison of the pathogenicity between cardiac (alpha-)myosin and soleus muscle (beta-)myosin. We show that alpha-myosin is the immunodominant isoform and induces myocarditis at high severity and prevalence whereas beta-myosin induces little disease. Therefore the immunodominant epitopes of alpha-myosin must reside in regions of different amino acid sequence between alpha- and beta-myosin isoforms. Cardiac myosin peptides corresponding to these regions of difference were synthesized and tested for their ability to induce inflammatory heart disease. Three pathogenic peptides were identified. One peptide that is located in the head portion of the molecule induced severe myocarditis, whereas two others that reside in the rod portion possessed only minor pathogenicity. The identification of pathogenic epitopes on the cardiac myosin molecule will allow detailed studies on the recognition of this antigen by the immune system and might be used to downmodulate ongoing heart disease.
T cells constitute the pathogenic effector cell population in autoimmune myocarditis in BALB/c mice. Using mice rendered deficient for B cells by a targeted disruption to the IgM transmembrane domain or by treatment with anti-IgM Ab from birth, we asked whether B cells are a critical APC in the induction of autoimmune myocarditis. B cell-deficient mice immunized with cardiac myosin develop myocarditis comparable in incidence and severity to that in wild-type mice, suggesting that autoreactive T cells that cause myocarditis in BALB/c mice are activated by macrophages or dendritic cells. Since it does not appear that presentation of cryptic epitopes is critical for the breakdown of self tolerance, potentially pathogenic T cells recognizing dominant myosin epitopes must have escaped tolerization. Either anatomic sequestration of cardiac myosin peptide-MHC complexes or subthreshold presentation of cardiac myosin peptides by conventional APC can explain the survival of these autoreactive T cells.
The beneficial effect of immunosuppressive treatment on myocarditis is still controversial, possibly because the immunologic and virological profile of potential candidates is largely unknown.
Out of 652 biopsied patients, 112 had a histological diagnosis of active lymphocytic myocarditis; 41 of these 112 patients were characterized by progressive heart failure despite conventional therapy and were treated with prednisone and azathioprine for 6 months. All were resubmitted to cardiac catheterization, angiography, and endomyocardial biopsy at 1 and 6 months and followed-up for 1 year. A total of 21 patients responded with prompt improvement in left ventricular ejection fraction from 25.7+/-4.1% to 47.1+/-4.4% and showed evidence of healed myocarditis at control biopsy. Conversely, 20 patients failed to respond and showed a histological evolution toward dilated cardiomyopathy: 12 remained stationary, 3 underwent cardiac transplantation, and 5 died. We retrospectively performed a polymerase chain reaction on frozen endomyocardial tissue for the most common cardiotropic viruses and assessed circulating serum cardiac autoantibodies. Viral genomes were present in biopsy specimens of 17 nonresponders (85%), including enterovirus (n=5), Epstein-Barr virus (n=5) adenovirus (n=4), both adenovirus and enterovirus (n=1), influenza A virus (n=1), parvovirus-B19 (n=1), and in 3 responders, who were all positive for hepatitis C virus. Cardiac autoantibodies were present in 19 responders (90%) and in none of the nonresponders.
In patients with active lymphocytic myocarditis, those with circulating cardiac autoantibodies and no viral genome in the myocardium are the most likely to benefit from immunosuppression. The beneficial effect of immunosuppression in hepatitis C virus myocarditis suggests a relevant immunomediated component of damage.
A series of synthetic triterpenoid (TP) analogues of oleanolic acid are powerful inhibitors of cellular inflammatory processes such as the induction by IFN-γ of inducible nitric oxide synthase (iNOS) and of cyclooxygenase 2 in mouse macrophages. Here, we show that these analogues are also extremely potent inducers of the phase 2 response [e.g., elevation of NAD(P)H-quinone oxidoreductase and heme oxygenase 1], which is a major protector of cells against oxidative and electrophile stress. Moreover, like previously identified phase 2 inducers, the TP analogues use the antioxidant response element–Nrf2–Keap1 signaling pathway. Thus, induction of the phase 2 response and suppression of the iNOS induction was abrogated in nrf2 –/– and keap1 –/– mouse embryonic fibroblasts. The high potency of TP analogues in inducing the phase 2 response and blocking inflammation depends on the presence of activated Michael reaction (enone) functions at critical positions in rings A and C. The most potent TP doubles NAD(P)H–quinone oxidoreductase in murine hepatoma cells at 0.28 nM and has an IC50 for suppression of iNOS induction in primary mouse macrophages of 0.0035 nM. The direct interaction of this TP with thiol groups of the Keap1 sensor for inducers is demonstrated spectroscopically. The antiinflammatory and phase 2 inducer potencies of 18 TP are closely linearly correlated (r ² = 0.91) over 6 orders of magnitude of concentration. Thus, in addition to blocking inflammation and promoting differentiation, these TP exhibit another very important protective property: the induction of the phase 2 response.
• inflammation
• Nrf2 Keap1
• oxidative stress
• phase 2 enzymes
• NAD(P)H-quinone acceptor oxidoreductase
Covering: 1990–2005. Previous review: Nat. Prod. Rep., 2005, 22, 487
Aims:
This study was conducted to determine whether galectin-3, a β-galactoside-binding lectin, plays a role in the pathogenesis of heart failure (HF).
Methods and results:
Galectin-3 was measured at baseline (n = 1650), after 4 months (n = 1346), and after 12 months (n = 1097) in the Valsartan Heart Failure Trial (Val-HeFT). Galectin-3 levels at baseline ranged from 4.8 to 53 ng/mL. Higher levels were associated with features of worse HF. In a fully adjusted Cox regression model comprising 23 other prognostic variables, baseline galectin-3 was not associated with the risks of all-cause mortality, the composite of the first morbid event, or hospitalization for HF. However, when changes in galectin-3 over time were examined, the increases in galectin-3 between baseline and 4 months were independently and significantly associated with the risks of subsequent all-cause mortality, first morbid event, and hospitalizations for HF, even after adjusting for all baseline and concurrent changes in all variables including estimated glomerular filtration rate (eGFR) and NT-proBNP. The strongest correlate of galectin-3 levels was eGFR, which accounted for 20% of the variability in galectin-3 levels at baseline. There was a significant interaction (P = 0.03) between baseline galectin-3 and the effect of valsartan on hospitalizations for HF. Valsartan caused a significant 44% reduction in hospitalizations for HF in patients with galectin-3 levels below the median level of 16.2 ng/mL, but not in patients with levels above the median.
Conclusions:
Galectin-3 levels are elevated in a substantial proportion of patients with HF, particularly those with more severe HF and renal dysfunction. Galectin-3 increased over time in this cohort, and the increase was independently associated with worse outcomes. Valsartan use was associated with a reduction in hospitalizations for HF in patients with low galectin-3, but not in those with higher levels of galectin-3.
Circulating biomarkers of collagen turnover reflect extracellular cardiac matrix (ECCM) remodelling. The extent to which the success of cardiac resynchronization therapy (CRT) is influenced by the degree of cardiac fibrosis and whether CRT can influence matrix remodelling has yet to be studied. Our aim was to determine, in patients with heart failure (HF) and cardiac dyssynchrony, whether ECCM biomarkers are influenced by CRT and can predict cardiovascular outcomes and response to CRT.
Serum levels of ECCM biomarkers [galectin-3 (Gal-3), N-terminal propeptides of type I and III procollagens (PINP and PIIINP), type I collagen telopeptide (ICTP), and matrix metalloproteinase 1 (MMP-1)] were measured in 260 patients, in a substudy of CARE-HF, a randomized controlled trial which evaluated the effects of CRT in patients with left ventricular systolic dysfunction and cardiac dyssynchrony. ECCM biomarkers did not change throughout the 18-month follow-up period. In age- and gender-adjusted analyses, Gal-3 and PIIINP were associated with death or HF hospitalization. In a further multivariate model, Gal-3 >30 ng/mL was associated [OR (95% CI):2.98 (1.43-6.22), P = 0.004] with death or HF hospitalization, along with left ventricular end-systolic volume >200 mL [3.42 (OR: 1.65-7.10), P = 0.001]. The outcome death or left ventricular ejection fraction (LVEF) ≤35% was associated with MMP-1 [≤3 ng/mL: 3.04 (1.37-6.71), P = 0.006]. No significant interaction was observed between the tested biomarkers and the treatment group.
Increased Gal-3 and PIIINP, and low MMP-1 are associated with adverse long-term cardiovascular outcomes but did not predict response to CRT. CRT did not favourably affect serum concentrations of ECCM markers.
Oleanolic acid (OA) is a plant triterpenoid steroid with potentially antiatherogenic properties. We investigated whether OA affected atherosclerosis development and vascular function in apolipoprotein E knockout (ApoE(-/-)) mice. ApoE(-/-) mice were fed a high cholesterol Western-type diet in combination with OA (100 mg/kg/day), fluvastatin (5 mg/kg/day) or vehicle, with wild type (WT) mice serving as controls. After 8 weeks of treatment atherosclerotic plaque areas in the aortic arch and plasma lipid concentrations were determined. Vasoconstriction and relaxation of the proximal part of aorta were investigated in vitro. Inducible nitric oxide synthase (iNOS) was visualized using immunoblotting. As opposed to WT and fluvastatin- and vehicle-treated mice, OA-fed ApoE(-/-) mice gained no weight during the treatment period. Plasma concentrations of total-cholesterol and triglyceride were not significantly reduced by OA- or fluvastatin treatment. Plaque area of vehicle-treated mice was 25%, but only 14% in OA- and 19% in fluvastatin-treated mice. As compared to WT, vasoconstriction to phenylephrine was attenuated in ApoE(-/-) mice. The NOS inhibitor asymmetric dimethylarginine (ADMA) enhanced phenylephrine constriction, but significantly more so in vehicle- and fluvastatin-treated than in OA-treated and WT mice. Relaxation to acetylcholine was only slightly attenuated in ApoE(-/-) mice and not affected by OA or fluvastatin treatment. ADMA abolished acetylcholine relaxation almost completely. In ApoE(-/-) mice iNOS expression was reduced by OA treatment. In conclusion OA exerts potent antiatherogenic effects independent of plasma lipid levels and without major changes in eNOS-mediated acetylcholine relaxation. However, OA reduced iNOS expression possibly altering vascular reactivity to phenylephrine.
Infectious disease is frequently cited as a precursor of subsequent autoimmune disease in genetically susceptible hosts. However, the precise mechanisms required for the transition from infection to autoimmunity have not been well defined. We have developed a mouse model of autoimmune myocarditis initiated by infection with Coxsackievirus B3 to trace the cytokine pathways involved. We found that greater production of interleukin-1β (IL-1β) and tumor necrosis factor-α during the early innate response to virus infection is necessary and sufficient to induce a later heart-specific autoimmune disease. Severity of the autoimmune myocarditis is determined by the profile of a number of T helper 1 (Th1) and Th2 cytokines. Th2 responses are especially pronounced in the most severe forms of myocarditis where eosinophils are prominent. The Th1 pathway can lead to infiltration of the heart, but may be dampened by concurrent INF-γ production. Th17 cytokines also contribute to disease, but the signature Th17 cytokine, IL-17A, is not required for cardiac inflammation. Rather, IL-17A is needed for progression to dilated cardiomyopathy. These findings may provide useful markers to identify individuals prone to develop an autoimmune sequel after infection and suggest future early interventions.
We analysed the effects of oleanolic acid (OA) on lung mechanics and histology and its possible mechanisms of action in experimental acute lung injury (ALI). BALB/c mice were randomly divided into Control (saline, ip) and ALI (paraquat, 25 mg/kg, ip) groups. At 1 h, both groups were treated with saline (SAL, 50 μl ip), OA (10 mg/kg ip), or dexamethasone (DEXA, 1 mg/kg ip). At 24 h, lung static elastance, viscoelastic pressure, and alveolar collapse reduced more after OA compared to DEXA administration. Tumour necrosis factor-α, macrophage migration inhibitory factor, interleukin-6, interferon-γ, and transforming growth factor-β mRNA expressions in lung tissue diminished similarly after OA or DEXA. Conversely, only OA avoided reactive oxygen species generation and yielded a significant decrease in nitrite concentration. OA and DEXA restored the reduced glutathione/oxidized glutathione ratio and catalase activity while increasing glutathione peroxidase induced by paraquat. In conclusion, OA improved lung morphofunction by modulating the release of inflammatory mediators and oxidative stress.
Human regulatory T cells (T(reg)) are essential for the maintenance of immune tolerance. However, the mechanisms they use to mediate suppression remain controversial. Although IL-35 has been shown to play an important role in T(reg)-mediated suppression in mice, recent studies have questioned its relevance in human T(reg). In this study, we show that human T(reg) express and require IL-35 for maximal suppressive capacity. Substantial upregulation of EBI3 and IL12A, but not IL10 and TGFB, was observed in activated human T(reg) compared with conventional T cells (T(conv)). Contact-independent T(reg)-mediated suppression was IL-35 dependent and did not require IL-10 or TGF-β. Lastly, human T(reg)-mediated suppression led to the conversion of the suppressed T(conv) into iTr35 cells, an IL-35-induced T(reg) population, in an IL-35-dependent manner. Thus, IL-35 contributes to human T(reg)-mediated suppression, and its conversion of suppressed target T(conv) into IL-35-induced T(reg) may contribute to infectious tolerance.
This study evaluated the anti-inflammatory efficacy of the crude extract (CE), the fractions derived from hexane (HEX), ethyl acetate (AcOEt), n-butanol (BuOH), and aqueous (Aq) and isolated compounds (oleanolic acid or kaempferitrin) obtained from the aerial parts of Lotus corniculatus var. São Gabriel in mice with bradykinin-induced pleurisy. Swiss mice were used for the In Vivo experiments. Inflammatory parameters [leukocytes; exudate concentrations; myeloperoxidase and adenosine-deaminase activities, and nitric oxide and interleukin-17 levels] were evaluated 4 h after pleurisy induction. The crude extract of Lotus corniculatus, its derived fractions, and isolated compounds inhibited leukocytes and the exudate. This inhibitory effect was associated with decreased of myeloperoxidase and adenosine-deaminase activities, nitric oxide products, and IL-17A levels. Lotus corniculatus presented important anti-inflammatory action by inhibiting leukocyte influx and exudate concentrations. This effect was directly related to the inhibition of nitric oxide and interleukinin17 levels. Oleanolic acid and kaempferitrin can account for these anti-inflammatory effects.
Regardless of the origin, injury to the heart can result in cardiomyocyte hypertrophy, fibrosis, and cell death. Myocarditis often progresses to dilated cardiomyopathy (DCM), a major cause of heart failure. In our study, we used a rat model of myosin-induced experimental autoimmune myocarditis (EAM), in which the heart transits from an acute phase (inflammatory myocarditis) to a chronic phase (remodeling and DCM). Our objective was to investigate whether T-3999, a novel phenylpyridazinone, can reduce this progression. Four weeks after myosin injection, T-3999 was administered daily to male Lewis rats in two doses (3 and 10 mg/kg, orally). Four weeks later, treatment was terminated; hemodynamic and echocardiographic measurements were performed; hearts were excised for histopathology and estimation of histamine, mRNA, and protein levels. Mortality rate was reduced by drug treatment. T-3999 reduced % fibrosis and tissue collagen III. Profibrotic markers-transforming growth factor-β(1), tumor necrosis factor-α, and galectin-3--were attenuated by treatment. Mast cell density and degranulation, and tissue histamine concentration were also reduced. This indicates an anti-inflammatory effect of the drug in reducing fibrosis. Hypertrophy was reduced as reflected by reduced myocyte diameter and natriuretic peptide expression. T-3999 treatment increased the sarcoendoplasmic reticulum Ca(2+) ATPase 2 protein level and improved several cardiac function parameters. The reduction of the remodeling process and improvement in myocardial function suggest an effect of T-3999 in attenuating ventricular remodeling in post-myocarditis DCM.
One-third of myocarditis cases progresses to dilated cardiomyopathy (DCM), but the mechanisms controlling this process are largely unknown. CD4(+) T helper (Th)17 cells have been implicated in the pathogenesis of autoimmune diseases, but the role of Th17-produced cytokines during inflammation-induced cardiac remodeling has not been previously studied.
We examined the importance of interleukin (IL)-17A in the progression of myocarditis to DCM using a mouse model.
Immunization of mice with myocarditogenic peptide in complete Freund's adjuvant induced the infiltration of IL-17A-producing Th17 cells into the inflamed heart. Unexpectedly, IL-17A-deficient mice developed myocarditis with similar incidence and severity compared to wild-type mice. Additionally, IL-17A deficiency did not ameliorate the severe myocarditis of interferon (IFN)gamma-deficient mice, suggesting that IL-17A plays a minimal role during acute myocarditis. In contrast, IL-17A-deficient mice were protected from postmyocarditis remodeling and did not develop DCM. Flow cytometric and cytokine analysis revealed an important role for IL-17A in heart-specific upregulation of IL-6, TNFalpha, and IL-1beta and the recruitment of CD11b(+) monocyte and Gr1(+) granulocyte populations into the heart. Furthermore, IL-17A-deficient mice had reduced interstitial myocardial fibrosis, downregulated expression of matrix metalloproteinase-2 and -9 and decreased gelatinase activity. Treatment of BALB/c mice with anti-IL-17A monoclonal antibody administered after the onset of myocarditis abrogated myocarditis-induced cardiac fibrosis and preserved ventricular function.
Our findings reveal a critical role for IL-17A in postmyocarditis cardiac remodeling and the progression to DCM. Targeting IL-17A may be an attractive therapy for patients with inflammatory dilated cardiomyopathy.
Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease for which there exist no therapies without undesired side effects. Thus, the establishment of less toxic treatments is an ongoing challenge. Nowadays, research on medicinal plants has been attracting much attention, since screening of its active principles could prove useful in identification of safe and innovative pharmaceutical molecules. In this study we investigated the therapeutic effect of oleanolic acid (OA) a plant-derived triterpene with potent anti-inflammatory and immunomodulatory activities, whose actions on CNS diseases remain far from completely characterized. We focussed on the potential therapeutic effect of oleanolic acid (OA) on an accepted experimental model of MS, the experimental autoimmune encephalomyelitis (EAE). We have found that OA treatment, before or at the early onset of EAE, ameliorates neurological signs of EAE-mice. These beneficial effects of OA seem to be associated with a reduction of blood-brain barrier leakage and lower infiltration of inflammatory cells within the CNS, as well as with its modulatory role in Th1/Th2 polarization: inhibition of proinflammatory cytokines and chemokines, and stimulation of anti-inflammatory ones. Moreover, EAE-animals that were treated with OA had lower levels of anti-MOG antibodies than untreated EAE-mice. Our findings show that the administration of the natural triterpenoid OA reduces and limits the severity and development of EAE. Therefore, OA therapy might be of clinical interest for human MS and other Th1 cell-mediated inflammatory diseases.
Oxidative stress is one of the earliest events in the pathogenesis of Alzheimer's disease (AD) and can markedly exacerbate amyloid pathology. Modulation of antioxidant and anti-inflammatory pathways represents an important approach for AD therapy. Synthetic triterpenoids have been found to facilitate antioxidant response and reduce inflammation in several models. We investigated the effect of the triterpenoid, 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic acid-MethylAmide (CDDO-MA) in Tg19959 mice, which carry the human amyloid precursor protein with two mutations. These mice develop memory impairments and amyloid plaques as early as 2-3 months of age. CDDO-MA was provided with chow (800 mg/kg) from 1 to 4 months of age. CDDO-MA significantly improved spatial memory retention and reduced plaque burden, Abeta42 levels, microgliosis, and oxidative stress in Tg19959 mice.
Myocarditis is a disease with a variable clinical presentation, ranging from asymptomatic to a fatal outcome. Among the recognized causes of myocarditis are mutations in multiple genes; infection by bacterial, rickettsial, mycotic, protozoan, and viral agents; and exposure to drugs, toxins, and alcohol. Some subtypes of myocarditis, such as giant cell myocarditis or eosinophilic necrotizing myocarditis, are suspected to be caused by an autoimmune inflammation. Several lines of evidence support the involvement of autoimmunity in myocarditis. These include the production of antibodies against relevant self-antigens, the fact that myocarditis symptoms can be relieved by immunosuppressive therapy in some patients, and a co-occurrence of myocarditis with other autoimmune diseases. Most of the evidence that myocarditis is an autoimmune disease comes from animal models. In this chapter, we discuss coxsackievirus B3-induced myocarditis and myosin-induced myocarditis as models of both viral and autoimmune inflammation in the heart. The latest advances in the study of autoimmunity have been concentrated on T helper cells, particularly the newly discovered subset, Th17 cells. Experimental autoimmune myocarditis (EAM), a mouse model of myocarditis induced by cardiac myosin, is partly an IL-17-driven disease. However, we have shown recently in IL-13 knockout mice that the disease can be driven through other pathways, and that the Th1 helper cells also lead to severe heart inflammation. Most importantly, IL-17A knockout mice are not fully protected against EAM and still develop mild myocarditis. The most abundant cells in heart infiltrate in human giant cell myocarditis or EAM are monocyte/macrophages, and there is now evidence that macrophages play a decisive role in the course of EAM.
The aim of this study was to evaluate the concentration of oleanolic acids (OA) in pomace, a winemaking byproduct, and its influence on the levels of plasma lipids in rats fed a high-fat diet and on hepatic gene expression using DNA microarray analysis in vivo. HPLC analyses of pomace ethanol extract (PEE) revealed a high amount of OA ranging from 4 to 11 g/100 g. Male Sprague-Dawley rats were fed a normal-fat diet (NF group), a high-fat diet with 21% lard (HF group), a high-fat diet with 0.05% OA (OA group, 50 mg/kg/day), or a high-fat diet with 0.45% PEE (PEE group, 450 mg/kg/day). Plasma triacylglycerol and phospholipid concentrations were significantly lower in the OA and PEE groups than in the HF group. The microarray analysis of hepatic mRNA revealed reduced expression levels of lipogenic genes including acetyl-CoA carboxylase and glycerol-3-phosphate acyltransferase, probably resulting from the suppression of transcription factor Srebf1 expression. Gene expression of gluconeogensis and inflammatory cytokines was also down-regulated in the OA and PEE groups, suggesting that administration of OA or PEE could ameliorate obesity-induced insulin resistance, as well as prevent hyperlipidemia.
The heart is a target organ in several autoimmune diseases, and therefore it is important to understand more about the effector cells involved in immune-mediated mechanisms of myocardial cell death. Because immune T lymphocytes are central to many immune responses, we wanted to study the role of T cells in causing cardiac specific inflammation. We used purified mouse cardiac myosin to cause acute myocarditis in mice. The adoptive transfer of purified T cells from C.B-17 mice with active myocarditis to SCID recipients successfully transferred the disease into SCID hosts. In contrast, transfer of serum with high-titer antimyosin antibodies to SCID hosts did not cause myocarditis. Using mAb to deplete A/J mice of CD4+ T cells, we showed that these mice were protected against the induction of myocarditis. Depletion of CD8+ T cells reduced the severity of inflammation but did not prevent induction of myocarditis. We were also able to prevent the induction of myocarditis using major histocompatibility class II protein-binding, nonimmunogenic, competitor peptides. These blocking studies also indicated that in H-2k mice, myocarditis is an I-Ak-restricted disease, and provided further evidence that CD4+ T cells are critical to the induction of disease. Together, these studies provide direct evidence that myosin-induced myocarditis is a T cell-mediated disease.
This study retrospectively assesses the underlying causes of sudden unexpected death and the occurrence of prodromal symptoms in 162 subjects (aged 9 to 39 years) over a 10-year period (1976 to 1985). Underlying cardiac diseases accounted for sudden death in 73% and noncardiac causes in 15% of subjects. In 12% of subjects, the causes were unidentifiable. Myocarditis (22%), hypertrophic cardiomyopathy (22%) and conduction system abnormalities (13%) were the major causes in 32 subjects aged less than 20 years. Major causes of 46 deaths in subjects 20 to 29 years were atherosclerotic coronary artery disease (24%), myocarditis (22%) and hypertrophic cardiomyopathy (13%). The largest number of deaths in 84 subjects aged greater than or equal to 30 years was attributed to coronary artery disease (58%), followed by myocarditis (11%). Among noncardiac causes of sudden death, intracranial hemorrhage was the most frequent (5%), followed by infectious disease (4%). Prodromal symptoms were reported by 54% of subjects; most frequent were chest pain (25%) in subjects aged greater than or equal to 20 years, and dizziness (16%) in those aged less than 20. Sudden death, which occurred during routine daily activity in 49% and during sleep in 23% of subjects, was related to physical exercise in 23% and emotional upset in 6%. Sudden unexpected death in the young is still an unresolved medical problem. The early recognition of prodromal symptoms could be crucial in the prevention of sudden death, specifically when exercise-related.
After infection with coxsackie virus B3 (CB3), H-2 congenic mice on an A- background develop immunologically mediated myocarditis associated with an increased titer of myosin autoantibody, part of which is specific for the cardiac myosin isoform. The present study demonstrates that cardiac myosin itself induces severe myocarditis and high titers of myosin autoantibodies in A/J, A.SW/SnJ, and A.CA/SnJ mice. As in CB3-induced myocarditis, one population of these autoantibodies was specific for cardiac myosin. A.BY/SnJ and B10.A/SgSnJ mice also developed the disease after immunization, but the prevalence and the myosin autoantibody titers were lower. In contrast, C57BL/6J and C57BL/10J mice were resistant to myocarditis induced by cardiac myosin and did not develop increased myosin autoantibodies or cardiac myosin-specific autoantibodies. Immunization with skeletal muscle myosin had no effect compared with controls injected with complete Freund's adjuvant, thereby suggesting that the immunogenic epitopes are unique to the cardiac myosin isoform. Furthermore, we found that susceptibility to myocarditis induced by cardiac myosin is influenced by the major histocompatibility complex and by genes not closely linked to the major histocompatibility complex. Because there are parallels between myocarditis induced by cardiac myosin and that induced by CB3, this new animal model can be used to analyze the pathologic mechanisms in autoimmune heart disease.
Idiopathic dilated cardiomyopathy (IDC) accounts for 25% of cases of heart failure in the United States. Understanding the relationship between an inciting event or agent and the development of IDC has progressed only recently. Once IDC has developed, treatment is palliative and little can be done to alter the natural course of the disease. Active myocarditis, a suspected precursor of IDC, is myocardial inflammation and injury without ischemia. The disease ranges from a self-limited flulike illness to one of serious consequence with arrhythmias, heart failure, or death. Many agents have been associated with myocarditis, and the clinical manifestations depend on an interplay between the inciting agent and the host response. The development of a murine model and the expanded use of endomyocardial biopsy using the Dallas criteria have increased our understanding of myocarditis and its sequelae. Therapy consists of managing symptoms using conventional medical regimens for heart failure. Immunosuppressive therapy should be reserved for patients with biopsy-proven disease who have failed conventional therapy. Continued deterioration warrants ventricular assistance and consideration of cardiac transplantation.
Autoimmune disease is characterised by the presence of circulating autoantibodies in the affected patients and in a proportion of their relatives. These antibodies are generally not pathogenic but are reliable markers of immune-mediated tissue damage. In organ-specific autoimmune disease, the destruction process is largely restricted to one organ within the body and the autoantibodies react with autoantigens which are unique to the diseased target organ. At least in a patient subset, myocarditis and dilated cardiomyopathy (DCM) may represent the acute and chronic stages of a progressive organ-specific autoimmune disease of the myocardium. Autoimmune features in patients with myocarditis/DCM include: familial aggregation, a weak association with HLA-DR4, abnormal expression of HLA class II on cardiac endothelium on endomyocardial biopsy, and detection of organ- and disease-specific cardiac autoantibodies, by immunofluorescence and absorption techniques, in the affected patients and in a proportion of their symptom-free relatives from both familial and non-familial DCM pedigrees. The organ-specific cardiac autoantibodies detected by immunofluorescence are directed against multiple antigens. One of these, first identified using immunoblotting and confirmed by ELISA, is the cardiac-specific alpha-myosin isoform. Myosin fulfils the expected criteria for organ-specific autoimmunity, in that immunisation with cardiac but not skeletal myosin reproduces, in susceptible mouse strains, the human disease phenotype of DCM; in addition, alpha-myosin is entirely cardiac-specific and is only expressed in the myocardium. Using ELISA, high titer organ- and disease-specific anti alpha-myosin antibodies have been found in 16% of the symptom-free relatives of DCM patients and in 38% of the pedigrees of the same cohort of relatives studied by immunofluorescence. The ELISA results provide additional evidence for autoimmunity in a subset of DCM families, and emphasise the importance of alpha-myosin as a target antigen.
The T helper cell type 2-associated cytokine interleukin (IL)-10 has a variety of immunomodulatory properties. However, the effects of the cytokine on viral myocarditis remain unclear.
We studied the effects of recombinant human IL-10 (rhIL-10) fully active on mouse cells in a murine experimental model of acute viral myocarditis caused by the encephalomyocarditis virus (EMCV). Four-week-old DBA/2 mice were inoculated with EMCV (day 0). rhIL-10 (10 microg/mouse) was administered once daily, starting on day 0, and control mice received vehicle only. Survival rates were determined on day 14. Myocardial histopathology, cytokine levels in the heart by ELISA assay, and myocardial virus concentration were examined on day 6, and the expression levels of myocardial inducible nitric oxide synthase (iNOS) mRNA were measured by competitive polymerase chain reaction. The 14-day survival in mice treated with rhIL-10 was significantly higher (80%) than in the control group (30%, n=10 in each, P<0.05). rhIL-10 treatment significantly attenuated myocardial lesions and suppressed tumor necrosis factor-alpha and IL-2 in the heart. rhIL-10 treatment had little effect on myocardial virus concentration. The expression levels of myocardial iNOS mRNA were significantly decreased in the group treated with rhIL-10 (8.6+/-4.7 amol/mg total RNA in treated versus 26.5+/-7.1 amol/mg total RNA in control mice, P<0.05).
These findings provide new insights into the in vivo effects of IL-10 on viral infection and suggest a therapeutic effect of IL-10 on viral myocarditis.
The study evaluates the clinical course and the development of systolic and diastolic left ventricular function in patients with chronic myocarditis with or without autoantibodies against cardiac myosin.
Patients with myocarditis often show autoantibodies against cardiac myosin. The clinical and pathophysiologic significance of these antimyosin autoantibodies (AMAAB) is yet unknown. The results from studies comparing the clinical course and the development of left ventricular function in patients with chronic myocarditis with or without AMAAB are not yet available.
Thirty-three patients with biopsy proven chronic myocarditis underwent analysis of AMAAB, right and left heart catheterization and left ventriculography at baseline and after six months. Left ventricular volumes and ejection fraction as well as the time constant of left ventricular relaxation "tau" and the constant of myocardial stiffness "b" were determined at baseline and at follow-up.
In 17 (52%) patients, AMAAB could be detected at baseline. After six months, AMAAB were still found in 13 (76%) initially antibody-positive patients. No initially antibody-negative (n = 16) patient developed AMAAB during follow-up. Clinical symptoms improved slightly in antibody-negative patients and remained stable in antibody-positive patients. Left ventricular ejection fraction developed significantly better in antibody-negative patients (+8.9 +/- 10.1%) compared with antibody-positive patients (-0.1 +/- 9.4%) (p < 0.012). Stroke volume (SV) and stroke volume index (SVI) also improved in antibody-negative patients (SV: +20 +/- 31 ml; SVI: +10 +/- 17 ml) compared with antibody-positive patients (SV: -14 +/- 43 ml; SVI: -8 +/- 22 ml) (SV: p < 0.015; SVI: p < 0.016). Left ventricular end-diastolic and end-systolic volumes and the time constant of left ventricular relaxation "tau" did not change significantly different in antibody-positive and antibody-negative patients. The constant of myocardial stiffness "b" improved significantly in antibody-negative patients (-6.1 +/- 10.8) compared with antibody-positive patients (+7.3 +/- 22.6) (p < 0.040). Analyzing only the persistently antibody-positive patients yielded essentially the same results.
Antimyosin autoantibodies are associated with worse development of left ventricular systolic function and diastolic stiffness in patients with chronic myocarditis.
Myocarditis in humans is often associated with an autoimmune process in which cardiac myosin (CM) is a major autoantigen. Experimental autoimmune myocarditis (EAM) is induced in mice by immunization with CM. We found that EAM in A/J mice exhibits a Th2-like phenotype demonstrated by the histological picture of the heart lesions (eosinophils and giant cells) and by the humoral response (association of IgG1 response with disease and up-regulation of total IgE). Blocking interleukin (IL)-4 with anti-IL-4 monoclonal antibody (mAb) reduced the severity of EAM. This reduction in severity was associated with a shift from a Th2-like to a Th1-like phenotype represented by a reduction in CM-specific IgG1; an increase in CM-specific IgG2a; an abrogation of total IgE response; a decrease in IL-4, IL-5, and IL-13; as well as a dramatic increase in interferon (IFN)-gamma production in vitro. Based on the latter finding, we hypothesized that IFN-gamma limits disease. Indeed, IFN-gamma blockade with a mAb exacerbated disease. The ameliorating effect of IL-4 blockade was abrogated by co-administration of anti-IFN-gamma mAb. Thus, EAM represents a model of an organ-specific autoimmune disease associated with a Th2 phenotype, in which IL-4 promotes the disease and IFN-gamma limits it. Suppression of IFN-gamma represents at least one of the mechanisms by which IL-4 promotes EAM.
Interleukin (IL)-6 regulates various aspects of the immune response. In the context of heart diseases, it has been recognized as a prognostic factor for dilated cardiomyopathy, which often results from myocarditis.
Using IL-6-deficient mice, we studied the role of IL-6 in a model of autoimmune myocarditis resulting from immunization with a peptide derived from cardiac alpha-myosin. Prevalence and severity of myocarditis were markedly reduced in the absence of IL-6. CD4+ T cells from immunized IL-6-deficient mice proliferated poorly on restimulation with specific antigen in vitro and did not mediate disease on adoptive transfer into IL-6-competent RAG-2-deficient mice, which otherwise lack B cells and T cells. Production of complement C3, a crucial factor for the development of myocarditis, was strongly upregulated in IL-6+/+ but not in IL-6-deficient mice after immunization.
Our results demonstrate that IL-6 is required for the expansion of autoimmune CD4+ T cells and the pathogenesis of autoimmune myocarditis, possibly by upregulation of complement C3.
The effect of naturally occurring triterpenoid compounds such as glycyrrhizic acid, ursolic acid, oleanolic acid, and nomilin on the immune system was studied using Balb/c mice. Intraperitoneal treatments with 5 doses of these terpenoid compounds were found to enhance the total white blood cells (WBC) count. In ursolic acid, oleanolic acid and nomilin treated animals the maximum total WBC count was observed on the 6th day, while in glycyrrhizic acid treated animals it was observed only on the 9th day after the drug treatment. In ursolic acid, oleanolic acid and nomilin treated animals the percentage of increase in the total WBC count was to 91.48 +/- 4.6%, 135.75 +/- 6.4% and 117.33 +/- 17.9% respectively. In the glycyrrhizic acid treated animals the total WBC count was increased to 114.9 +/- 18%. Bone marrow cellularity and alpha-esterase positive cells were also enhanced by the treatment with these terpenoids. Treatment with various triterpenoids along with antigen produced an enhancement in the specific antibody titre and the number of plaque forming cells (PFC) in the spleen. Triterpenoids remarkably inhibited delayed type hypersensitivity reaction (DTH). These results indicate the immunomodulatory activity of naturally occurring triterpenoids such as glycyrrhizic acid, ursolic acid, oleanolic acid and nomilin.
Besides genetic susceptibility and infections with cardiotropic viruses, autoimmune responses against heart tissue play a major role in the pathogenesis of dilated cardiomyopathy, the most common cause of heart failure in young patients. Recent findings suggest that the combination of tissue damage resulting in release of self-antigens, together with non-specific activation of the innate immune system triggers various responses that are crucial for the development of heart-specific autoimmunity. Understanding these mechanisms is critical for the design and development of novel treatment strategies against devastating heart diseases in the future.
Effective immune responses against pathogens are sometimes accompanied by strong inflammatory reactions. To minimize damage to self, the activation of the immune system also triggers anti-inflammatory circuits. Both inflammatory and anti-inflammatory reactions are normal components of the same immune response, which coordinately fight infections while preventing immune pathology. IL-10 is an important suppressive cytokine, produced by a large number of immune cells in addition to the antigen-driven IL-10-producing regulatory and the naturally occurring suppressor CD4+ T cells, which is a key player in anti-inflammatory immune responses. However, additional mechanisms have evolved to ensure that pathogen eradication is achieved with minimum damage to the host. Here we discuss those mechanisms that operate to regulate effector immune responses.
Oleanolic acid and ursolic acid are ubiquitous triterpenoids in plant kingdom, medicinal herbs, and are integral part of the human diet. During the last decade over 700 research articles have been published on their research, reflecting tremendous interest and progress in our understanding of these triterpenoids. This included the isolation and purification of these tritepernoids from various plants and herbs, the chemical modifications to make more effective and water soluble derivatives, the pharmacological research on their beneficial effects, the toxicity studies, and the clinical use of these triterpenoids in various diseases including anticancer chemotherapies. A briefly commentary is attempted here for their research perspectives.
This study was designed to investigate the protective effect of oleanolic acid (OA) against isoproterenol-induced myocardial ischemia in rat myocardium. Wistar strain rats were pretreated with OA (20, 40, and 60 mg/kg, s.c) for 7 days and then intoxicated with isoproterenol (ISO, 85 mg/kg, sc for 2 consecutive days). Heart were excised from the experimental animals and assessed for the activities of marker enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK)], the levels of lipid peroxide products [thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (HP) and conjugated dienes (CD)], myeloperoxidase (MPO), lipid profiles [total cholesterol (TC), free cholesterol, ester cholesterol, triglycerides (TG), free fatty acids (FFA) and phospholipids (PL)], and membrane-bound ATPase enzymes (total ATPase, Na(+)K(+) ATPase, Ca(2 +) ATPase, and Mg(2 +) ATPase). Troponin T and I were estimated in plasma. Leakage of cardiac markers, elevated lipid peroxidation with increased lipid profiles and decreased activities of membrane-bound ATPase enzymes were confirmed the severe myocardial damage occurring as a consequence of isoproterenol-induced ischemia, and they also showed the significant improvement effected by oleanolic acid pretreatment. These findings provided evidence that oleanolic acid was found to be protecting rat myocardium against ischemic insult and the protective effect could attribute to its anti-oxidative, anti-hyperlipedemic, and anti-arrhythmic properties as well as its membrane-stabilizing action.
The angiotensin converting enzyme inhibitor captopril prevents myosin-induced experimental autoimmune myocarditis. Captopril inhibits production of angiotensin II and increases bradykinin signaling, among other actions. To test whether captopril inhibits disease through blockade of angiotensin signaling, we tested the ability of losartan, an angiotensin II receptor blocker, to prevent myosin-induced myocarditis. A/J mice immunized with the heavy chain of cardiac myosin in complete Freund's adjuvant develop acute myocarditis by day 21 post-immunization, consisting of severe focal inflammation, necrosis and fibrosis. Administration of losartan (250 mg/L in the drinking water) or captopril (75 mg/L in the drinking water) significantly reduced inflammation, necrosis and fibrosis in myosin-immunized mice. The heart weights and the heart weight-to-body weight ratios were also significantly reduced in both treatment groups. However, whereas captopril reduced myosin-specific delayed-type hypersensitivity, losartan did not. Both captopril-treated mice and losartan-treated mice showed a decrease in myosin-specific autoantibody production. Because losartan treatment significantly reduced myocarditis, fibrosis and autoantibody production in EAM, it is likely that prevention of angiotensin II receptor stimulation is a major mechanism underlying the inhibition of myosin-induced myocarditis by captopril.