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10-Hydroxy-2-decenoic acid from Royal jelly: A potential medicine for RA
Abstract
Rheumatoid arthritis synovial fibroblasts (RASFs) are known to produce matrix metalloproteinases (MMPs) and cause joint destruction. The purpose of this study is to develop a potential medicine for rheumatoid arthritis (RA).
To this end, first, the MMPs inhibition factor was purified from an alkali-solubilized fraction of RJ (Apis mellifera) by C18 reverse-phase column chromatography and identified as 10-hydroxy-2-decenoic acid (10H2DA) by LTQ XL analysis. Next, Experimental test 10H2DA how to inhibited the activities of MMPs: with RASFs isolated from rheumatoid tissues by enzymatic digestion, cultures in monolayers were treated with 10H2DA (0.5mM, 1mM, and 2mM) or PBS for 2h followed by stimulation with TNF-alpha (10 ng/ml) for 2h, mRNA. Protein levels of MMP-1 and MMP-3 were measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA), the DNA-binding activity of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB) by electrophoretic mobility shift assay (EMSA), and the protein kinase activity of p38, ERK and JNK by kinase assay.
The molecular investigation revealed that the 10H2DA-mediated suppression was likely to occur through blocking p38 kinase and c-Jun N-terminal kinase-AP-1 signaling pathways. In contrast, 10H2DA had no effect on extracellular signal-regulated kinase activity, NF-kappaB DNA-binding activity and IkappaBalpha degradation.
These results suggest that 10H2DA may be of potential therapeutic value in inhibiting joint destruction in RA.
... In addition, this study showed that the antidiabetic and antisteatosis mechanisms by which RJ acts involve at least antioxidant potential, as well as the activation of the hepatic AMPK signaling-mediated upregulation of PPARα (fatty acid oxidation) and the suppression of SREBP1/2 (de novo lipogenesis) The treatment with RJ also reduced the serum levels of liver function enzymes, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and leptin, but significantly increased the serum levels of adiponectin. In addition, 10-HDA inhibits matrix metalloproteinases (MMPs) which degrade matrix and non-matrix proteins, resulting in tissue aging (e.g., skin) and chronic inflammatory diseases such as rheumatoid arthritis (RA) [85]. ...
... It has been shown that 10-HDA from the RJ may reduce joint destruction in RA. 10-HDA exerted its effects by reducing the TNF-αinduced gene expression of MMP-1 and MMP-3, and by inhibiting the activation of the p38 and JNK/AP-1 signaling pathways. On the contrary, it had no effect on the TNF-αinduced activation of the extracellular signal-regulated kinase (ERK) cascade, NF-κB activity, or IκBα degradation [85]. These findings also indicate that the inhibition of the p38 and JNK pathways could be a possible therapeutic target against inflammation-related joints' destruction in RA [85]. ...
... On the contrary, it had no effect on the TNF-αinduced activation of the extracellular signal-regulated kinase (ERK) cascade, NF-κB activity, or IκBα degradation [85]. These findings also indicate that the inhibition of the p38 and JNK pathways could be a possible therapeutic target against inflammation-related joints' destruction in RA [85]. ...
Royal jelly (RJ) is a highly nutritious natural product with great potential for use in medicine, cosmetics, and as a health-promoting food. This bee product is a mixture of important compounds, such as proteins, vitamins, lipids, minerals, hormones, neurotransmitters, flavonoids, and polyphenols, that underlie the remarkable biological and therapeutic activities of RJ. Various bioactive molecules like 10-hydroxy-2-decenoic acid (10-HDA), antibacterial protein, apisin, the major royal jelly proteins, and specific peptides such as apisimin, royalisin, royalactin, apidaecin, defensin-1, and jelleins are characteristic ingredients of RJ. RJ shows numerous physiological and pharmacological properties, including vasodilatory, hypotensive, antihypercholesterolaemic, antidiabetic, immunomodulatory, anti-inflammatory, antioxidant, anti-aging, neuroprotective, antimicrobial, estrogenic, anti-allergic, anti-osteoporotic, and anti-tumor effects. Moreover, RJ may reduce menopause symptoms and improve the health of the reproductive system, liver, and kidneys, and promote wound healing. This article provides an overview of the molecular mechanisms underlying the beneficial effects of RJ in various diseases, aging, and aging-related complications, with special emphasis on the bioactive components of RJ and their health-promoting properties. The data presented should be an incentive for future clinical studies that hopefully will advance our knowledge about the therapeutic potential of RJ and facilitate the development of novel RJ-based therapeutic opportunities for improving human health and well-being.
... RJ exhibits a variety of biological and pharmacological activities, such as antitumor (Bincoletto, C., Eberlin, S., Figueiredo, C. A. V, Luengo, M. B., & Queiroz, M. L. S., 2005), antimicrobial (Brudzynski & Abbreviations: 10-HAD, 10-hydroxydecanoic acid; 10-H 2 DA, 10-Hydroxy-2-Decenoic Acid; ACC, acetyl-CoA carboxylase; AMP, adenine monophosphate; ATP, adenosine triphosphate; AMPK, AMP-activated protein kinase; Ang II, Angiotensin II; ATG, autophagy-related; CR, Caloric restriction; CRM, CR mimetics; DC, dendritic cell; DMSO, dimethyl sulfoxide; EB, Evan's blue; EGCG, epigallocatechin-3-gallate; ELISA, enzyme-linked immunosorbent; ERK, Extracellular signal regulated Kinase; FLG, filaggrin; FoxO1a, Forkhead box O1; FoxO3a, Forkhead box O3; JNK, c-Jun N-terminal kinase; LKB1, Sirtuin-1 deacetylates liver kinase B1; LTA, lipoteichoic acid; MITF, Melanocyte Inducing Transcription Factor; MoDCs, monocyte-derived dendritic cells; mTOR, mammalian target of rapamycin; NF-κB, Nuclear factor kappa B; Nrf2, Nuclear factor-erythroid 2 related factor 2; PI3K, phosphatidylinositol 3-kinase; pRJ, protease-treated royal jelly; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PROSPERO, International Prospective Register of Systematic Reviews; QBA, queen bee acid; RAS, reninangiotensin system, RJ, Royal Jelly; ROS, reactive oxygen species; SC, stratum corneum; SIRT1, silent mating type information regulation two homolog one; SR, systematic review; SYRCLE, Systematic Review Centre for Laboratory Animal Experimentation; TA, tibial anterior; TEWL, transepidermal water loss; TGF-β1, transforming growth factor-β1; TLR, Tolerogenic Receptors; TNF-α, Tumor necrosis factor; TolDC, tolerogenic DCs; ULK1, UNC-51-like kinase; VSMC, rat vascular smooth muscle cells. Sjaarda, 2015), hypotensive (Matsui et al., 2002), antihypercholesterolemic (Vittek, 1995), anti-inflammatory (Kohno et al., 2004;Yang et al., 2010), antioxidant (Casamenti et al., 2015), antiaging (Ahmad, S., Campos, M. G., Fratini, F., Altaye, S. Z., & Li, J., 2020), and immunomodulatory (Kohno et al., 2004;Okamoto et al., 2003) activities, and promotes cell proliferation (Kamakura, M., Suenobu, N., & Fukushima, M. 2001;Kawano et al., 2019;Lin et al., 2019). ...
... However, in osteoporosis, another age-related disease, QBA interacts directly with FFAR4 on osteoclasts, suppressing osteoclast genesis by inhibiting the Nuclear factor kappa B (NF-κB) signaling pathway (Tsuchiya et al., 2020). QBA improves rheumatoid arthritis by blocking the p38 kinase and c-Jun N-terminal kinase (JNK)-AP-1 signaling pathways (Yang et al., 2010); moreover, Tumor necrosis factor (TNF)-α and IL-6 levels are decreased and inhibit articular cartilage degeneration by preventing extracellular matrix degradation and cartilage cell damage (Hong, S. H., Hwang, S. W., Son, Y. K., Lee, N. Y., & Kim, O., 2020). This receptor might also be involved in the regulation of adipogenesis (Horrocks and Farooqui, 2004), inflammation, insulin resistance (Honda et al., 2015;Takikawa et al., 2013) QBA decreases muscle mass in female mice but increases bone density (Fan et al., 2020;Weiser, M. J., Grimshaw, V., Wynalda, K. M., Mohajeri, M. H., & Butt, C. M., 2018) in a sex-dependent manner. ...
Royal jelly (RJ) is one of the most valued natural products and is considered beneficial to human health, mainly due to its many biological and pharmacological properties. 10-Hydroxy-2-decenoic acid (10H2DA), also known as queen bee acid (QBA), is exclusive to RJ and represents the main lipid component of this food. Most in vitro studies using QBA have reported its beneficial health properties but only a few in vivo studies have focused on these benefits. Therefore, the focus of the present systematic review (SR) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was to analyze the properties of QBA in different diseases such as cardiovascular, age-related or neurodegenerative diseases and cancer, employing in vivo and in vitro models and summarize the beneficial and protective effect of QBA that were observed in most of the studies.
... Royal jelly (RJ) is a secretion provided by the nurse worker's honey bee glands (Karadeniz et al., 2011). An analysis of its composition indicated that RJ has various combinations mainly water, proteins, sugars, free amino acids, different types of vitamins, minerals, and large quantities of unsaturated fatty acid such as 10-hydroxy-trans-2-decenoic acid (10-H2DA), which singly accounts for about 50% of RJ fatty acid content (Yang et al., 2010;Takikawa et al., 2013). RJ has further been described to have a variety of pharmacological actions in mammals, such as antimicrobial (Fujiwara et al., 1990), antitumor (Kamakura et al., 2001), anti-inflammatory (FUJII et al., 1990, and immunomodulatory effects (Okamoto et al., 2003). ...
... As most fatty acids component in RJ is 10-H2DA (Lercker et al., 1982), so it seems that this bee product plays a significant role in the physiological application. 10-H2DA and its saturated equivalent form are known as (10HDA) have many pharmacological effects such as antitumor activity (Townsend et al., 1961), increase collagen production (Koya-Miyata et al., 2004), anti-biotic activity (Blum et al., 1959), immunomodulatory (Mihajlovic et al., 2013), and anti-inflammatory effects (Yang et al., 2010). ...
Multiple sclerosis (MS) is a chronic autoimmune disorder indicated by central nervous system (CNS) inflammation, demyelination, and axonal damage, which is earned to the attitude of autoreactive T cells with their own myelin proteins, contributing to physical ailment and paralysis. Royal jelly (RJ) and its main ingredient fatty acids 10-hydroxy-2-decenoic acid (10-H2DA), which is the unique diet of queen honeybees. The broad range of pharmacological properties RJ and 10-H2DA have been reported, although the immunomodulatory effects are crudely understood. Female C57/BL6 mice were inoculated with the synthetic MOG35–55, clinical scores were observed daily for the 25 days. Mice sacrificed and their brains and splenocytes collected and then brain demyelination and lymphocyte infiltration, proliferation, profiles of cytokine and gene expression were determined respectively by H&E, LFB, BrdU, ELISA, and Real-time PCR tests. Our data demonstrated that RJ and 10-H2DA prohibited the development of EAE. Histological investigations revealed that in reduction leukocyte infiltration and demyelination in the CNS of treated groups. 10-H2DA and RJ had dose-dependent inhibitory effects on the release of the inflammatory mediators in comparison to the control group and deferred the onset of EAE, by suppressing the immune response primarily through altering Th17 and Th1 cell polarization. In summary, we demonstrated that RJ and 10-H2DA treatment have been able to effectively promote the clinical manifestations and prevent the disease onset in EAE. Overall, these results provide new evidence for using RJ against inflammatory disorders and support the potential therapeutic effect of RJ and 10-H2DA for MS.
... 16 It has been demonstrated that Royal jelly which is the main source of food for the bee queen, has different pharmacological activities such as antioxidant activity, anti-inflammatory activity, antihypercholesterolemic and immunosuppressive effect. [19][20][21] 10-HDA is a major unsaturated fatty acid compound, with immunosuppressive properties, in Royal jelly. 21 Yang et al. inhibited the activity of metalloproteins in rheumatoid arthritis by using 10-HDA. ...
... Therefore, they have identified 10-HDA as a potent therapeutic agent with anti-inflammatory effect in rheumatoid arthritis. 20 10-HDA also decreased the release of IL-6, an inflammatory cytokine, in Macrophages activated by lipopolysaccharide (LPS) and consequently inflammation. 22 Therefore, the objective of this study was to assess the inhibitory effect of 10-HDA on the maturation of cultured DCs on commonly used polymeric scaffolds; chitosan and Alg-PEI used in bone tissue engineering and gene delivery, respectively. ...
Dendritic cells (DCs), in response to the biomaterials, utilize toll‐like receptors (TLRs) to become mature or tolerogenic through TLRs‐dependent signaling pathways, especially TLR4. Regarding the physicochemical properties of biomaterials, some of such signaling pathways are activated. Unsaturated fatty acids have been explored as an antagonist for TLRs and lead to the tolerogenic phenotype of DCs. Here we showed that, although cultured DCs on both chitosan and Alginate‐polyethyleneimine (Alg‐PEI) films became fully mature, 10‐hydroxy‐2‐decanoic acid (10‐HDA), an unsaturated fatty acid found in royal jelly, led to the tolerogenic immunophenotype of DCs on both films. The cultured cells on the films possessed iDCs‐like morphology in the presence of 10‐HDA. Moreover, 10‐HDA expressed lower levels of CD80, CD83, CD86, and HLA‐DR, a higher level of IL‐10, and lower level of IL‐12 in the cultured DCs on both films. Furthermore, HEK293T cells expressing only TLR4 (HEK‐TLR4 cells) were co‐cultured with LPS, a specific agonist for TLR4, and 10‐HDA. The 10‐HDA significantly reduced the expression of tumor necrosis factor‐a (TNF‐α) in the HEK‐TLR4 cells compared to treated only with LPS. These findings indicate that the 10‐HDA acts as an antagonist of TLR4; therefore, potentially can be used in autoimmune diseases and preventing the rejection of biomaterials implantation and allograft transplantation.
... www.ajbls.com DOI: 10.5530/ajbls.2020. 9.41 folic acid, biotin and pyridoxine and smaller quantities of Vitamins C, D, A and E. [5] In addition, the major minerals in RJ are calcium, sodium, potassium, copper, iron, zinc and manganese. ...
... [6] One of the key bioactive compounds of RJ is 10-hydroxy-trans-2-decenoic acid (10HDA), an unsaturated fatty acid found in natural source, especially in RJ. [7] Generally in RJ, different biological activities depend on the type of cells; [8,9] for example, its 10HDA has important anticancer activity. [10] Shakhoon (queen cell), a frame made of waxed bees and filled with RJ, is the honey bee larva's spot. RJ plays a key role in the feeding and growth of larvae into a long-term, fertile mature queen of honey bee ( Figure 1). ...
Royal Jelly (RJ) is most wanted healthy food supplement that makes lots of health benefits. One of the benefits include that it can act as potent supplement for healthy egg to help women with infertility. This review is focused on the recent developments in use of RJ in the treatment of infertility and boon for them to give a dream child. The healthy egg is very phenomenal key factor for the in vitro fertilization to be successful in sexing with sperm. RJ is traditionally used as health supplement for infertility treatment from the ancient time in Indian traditional system. The recent literature revealed that, scientific and traditional findings are proven it RJ is one of the therapeutic molecule and act as a food supplements that can be used it in to improve egg cell physiology. Although, there is no clinical research studies have been reported yet on RJ. Hence, in this review explored the comprehensive report on health benefits of RJ and its impact on reproductive aspects in particular in egg development of women during ovulation. This article will be the key step to the researchers and scientists who are involved in searching alternative, cost effective and without side effect for treating infertility in global scenario.
... Показано, что 10-гидрокси-2-деценовая кисло та способна ингибировать активность матриксных металлопротеиназ: коллагеназы 1 и стромелизина 1 [48]. Высказано мнение, что наблюдаемое ингиби рование может быть связанно со структурной схоже стью некоторых участков 10-гидрокси-2-деценовой кислоты с молекулами эстрогенов. ...
... It has been shown that 10-hydroxy-2-decenoic acid is able to inhibit the activity of matrix metalloproteinases: collagenase 1 and stromelysin 1 [48]. It has been suggested that the observed inhibition may be associated with the structural similarity of some sections of 10-hydroxy-2-decenoic acid with estrogen molecules. ...
Both bee products themselves and their combinations are widely represented in the domestic pharmaceutical market, however, modern experimental studies of the biological activity of these compounds are few, and in many of the existing publications the authors describe an extremely wide and controversial range of therapeutic effects. The aim of the study is to analyze the experimental works on the study of biological activity of bee products. Materials and methods. The study was conducted using search and information (eLibrary, PubMed, CyberLeninka, ResearchGate) and library databases (Russian State Library, Central Scientific Agricultural Library). In the designated databases, publications were searched by such terms as “biological activity”, “royal jelly”, etc. The depth of the search was not limited. Results and discussion. The analysis of the published works shows that such substances as bee venom and royal jelly have experimentally confirmed their biological activity. In both cases, the active substances have been described and a review of their detected biological activity has been carried out. Conclusion . The authors suggest that when developing the method of laboratory synthesis of decene acids, it can be possible to carry out their large-scale preclinical research, which may become the basis for the creation of a drug with a selective effect.
... Additionally, in chicken models of intestinal mucosal injury, royal jelly acid reduced the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), reversed the upregulation of TLR4 and NF-κB, and ameliorated intestinal mucosal injury (Han, et al., 2023). In rheumatoid arthritis synovial fibroblast cells, royal jelly acid modulated the p38 kinase and c-Jun N-terminal kinase (JNK)-AP-1 signaling pathways, thereby alleviating symptoms of rheumatoid arthritis (Yang, et al., 2010). Although royal jelly acid has demonstrated effective anti-inflammatory properties in vitro and in vivo, more studies are necessary to explore its potential mechanisms in different inflammatory and related conditions. ...
Royal jelly acid (10-HDA), an unsaturated fatty acid unique to royal jelly, exhibits a diverse range of biological activities, including hypoglycemic, anti-inflammatory, and anticancer properties. In recent years, the increasing demand for natural product supplements as health enhancers has led to a significant rise in the consumption of royal jelly products for daily wellness. Consequently, the market for royal jelly supplements has expanded considerably. Understanding the mechanisms underlying the biological activities of royal jelly acid is crucial for optimizing its therapeutic applications and guiding the development of innovative royal jelly-based products. This review consolidates current research on the preparation, metabolism and potential pharmacological roles of royal jelly acid in managing cancer, inflammatory disorders, and glucolipid metabolic diseases and explores the molecular mechanisms driving these effects. Future research should leverage advanced analytical techniques to uncover the intricate mechanisms of royal jelly acid’s actions, paving the way for its broader integration into healthcare and clinical settings.
... Previous research has also found royal jelly to have anti-bacterial and immune regulatory effects [17,22]. Royal jelly has also exhibited anti-aging properties by inhibiting cellular degradation activities and enhancing collagen synthesis [23]. Therefore, the royal jelly ingredient in the face serum used in the present study may have had an additive effect on the skin health of the participants. ...
Objective: The purpose of this study was to investigate the efficacy of a commercially available manuka honey-based face serum that includes royal jelly and bee venom on various ingredients frequently associated with skin health benefits over an eight-week period.
Materials and methods: Forty female participants aged 40-55 with self-reported skin health concerns were recruited. Participants used the serum twice daily and completed questionnaires during Weeks 2, 4, and 8. Photos of the face were analyzed for dermatological skin grading and Optic Elite facial analysis at Week 8.
Results: There were significant improvements in fine lines, wrinkles, dark spots, hyperpigmentation, dryness, and overall skin health beginning at Week 2, with sustained enhancements observed until Week 8. Dermatologist skin grading results were mixed, with 20 (60.6%) of participants demonstrating improvements in skin brightness, but lower percentages of participants showed improvement in overall skin health, fine lines/wrinkles, roughness, pigmentation, and redness/erythema. Optic Elite analysis showed improvements in several skin health scores, providing further evidence for the serum’s effects on skin health. Participants self-reported high satisfaction with the effectiveness of the serum.
Conclusions: These findings suggest that the face serum may be an effective skincare product for improving skin health and mitigating signs of aging.
... Queen bee acid (10-hydroxy-2-decenoic acid or hda) and 10-hydroxydecanoic acid (hdaa) are the bioactive components of royal jelly and medical grade honey [1][2][3][4][5][6]. Medical grade honey (MGH) and royal jelly (RJ) are used to heal various wounds, especially infected wounds, pressure ulcers (bedsores), diabetic ulcers, and/or venous or arterial ulcers [1,[7][8][9][10][11][12][13][14][15][16]. ...
Royal jelly and medical grade honey are traditionally used in treating wounds and infections, although their effectiveness is often variable and insufficient. To overcome their limitations, we created novel amphiphiles by modifying the main reparative and antimicrobial components, queen bee acid (hda) and 10-hydroxyl-decanoic acid (hdaa), through peptide bonding with specific tripeptides. Our molecular design incorporated amphiphile targets as being biocompatible in wound healing, biodegradable, non-toxic, hydrogelable, prohealing, and antimicrobial. The amphiphilic molecules were designed in a hda(hdaa)-aa1-aa2-aa3 structural model with rational selection criteria for each moiety, prepared via Rink/Fmoc-tBu-based solid-phase peptide synthesis, and structurally verified by NMR and LC–MS/MS. We tested several amphiphiles among those containing moieties of hda or hdaa and isoleucine–leucine–aspartate (ILD-amidated) or IL-lysine (ILK-NH2). These tests were conducted to evaluate their prohealing and antimicrobial hydrogel properties. Our observation of their hydrogelation and hydrogel-rheology showed that they can form hydrogels with stable elastic moduli and injectable shear-thinning properties, which are suitable for cell and tissue repair and regeneration. Our disc-diffusion assay demonstrated that hdaa-ILK-NH2 markedly inhibited Staphylococcus aureus. Future research is needed to comprehensively evaluate the prohealing and antimicrobial properties of these novel molecules modified from hda and hdaa with tripeptides.
... Additionally, it contains trace elements with biological activities as well as several minerals (Ca, P, S, Mg, Zn, K, Na, Fe, Cu, and Mn) (Stocker et al. 2005). In RJ, 10-hydroxy-trans-2-decenoic acid (10-HDA) is the primary fatty acid (Yang et al. 2010), it is crucial for enhancing anticancer and immune system function. In addition, it has a trace quantity of vitamin C, numerous trace minerals, antibacterial and antibiotic components, enzymes, and a comparatively large amount of fatty acids (5%); yet, it lacks any fat-soluble vitamins (Botezan et al. 2023). ...
Royal jelly renowned for its robust nutritional, functional, and biological properties, is a pivotal product derived from honeybees. The purpose of this investigation was to assess the theory that in ovo injection of freeze‐dried royal jelly (FDRJ) solutions at varying concentrations can influence the hatchability, blood properties and hatching characteristics of day‐old chicks. A total of 480 eggs (54.81 ± 0.187 g) were allocated into four experimental groups: negative control (NC), without injection, positive control (PC), administered with regular saline, a low FDRJ dose group (9 mg/egg), and a high FDRJ dose group (18 mg/egg). The in ovo injections were administered on Day 18 of incubation, and the experiment was subsequently continued until the incubation period concluded at 21 days. Results revealed that the lower FDRJ dose (9 mg/egg) significantly improved hatchability percentages compared to other treatments. Conversely, the higher FDRJ dose (18 mg/egg) and control groups (NC and PC) resulted in significantly higher chick yield percentages than the lower FDRJ and PC groups. The NC group showed the supreme yolk sac (YS) percentage, whereas the yolk‐free body mass (YFBM) percentages displayed an inverse trend. Furthermore, the in ovo FDRJ injection did not affect haematological values or the relative organ weight of day‐old chicks. In conclusion, in ovo FDRJ injection demonstrated beneficial effects on hatchability and chick weight, as evidenced by the studied parameters.
... However, it is still unknown which compounds and mechanisms exert cardioprotective effects. Yang et al. showed that the lipid composition of RJ may be responsible for its biological activity [18]. Queen bee acid (QBA), which is exclusively found in RJ, accounts for up to 40 % of all fatty acids in this substance and is frequently utilized as a quality indicator of RJ [19]. ...
Queen bee acid (QBA), which is exclusively found in royal jelly, has anti-inflammatory, antihypercholesterolemic, and antiangiogenic effects. A recent study demonstrated that QBA enhances autophagic flux in the heart. Considering the significant role of autophagy in the development of myocardial ischemia/reperfusion (I/R) injury, we investigated the effect of pretreatment with QBA on myocardial damage. In an in vivo model, left coronary artery blockage for 30 min and reperfusion for 2 h were used to induce myocardial I/R. In an in vitro model, neonatal rat cardiomyocytes (NRCs) were exposed to 3 h of hypoxia and 3 h of reoxygenation (H/R). Our results showed that pretreatment with QBA increased the cell viability of cardiomyocytes exposed to H/R in a dose-dependent manner, and the best protective concentration of QBA was 100 μM. Next, we noted that QBA pretreatment (24h before H/R) enhanced autophagic flux and attenuated mitochondrial damage, cardiac oxidative stress and apoptosis in NRCs exposed to H/R injury, and these effects were weakened by cotreatment with the autophagy inhibitor bafilomycin A1 (Baf). In addition, similar results were observed when QBA (10 mg/kg) was injected intraperitoneally into I/R mice 30 min before ischemia. Compared to mice subjected to I/R alone, those treated with QBA had decreased myocardial infarct area and increased cardiac function, whereas, these effects were partly reversed by Baf. Notably, in NRCs exposed to H/R, tandem fluorescent mRFP-GFP-LC3 assays indicated increased autophagosome degradation due to the increase in autophagic flux upon QBA treatment, but coinjection of Baf blocked autophagic flux. In this investigation, no notable adverse effects of QBA were detected in either cellular or animal models. Our findings suggest that QBA pretreatment mitigates myocardial I/R injury by eliminating dysfunctional mitochondria and reducing reactive oxygen species via promoting autophagic flux.
... RJ's ability to prolong life may be due to its anti-inflammatory and antioxidant characteristics, which can also stop the development of some crippling metabolic illnesses (Bianco, 2022). According to a study, 10-HDAA (0.5-2.0 mM) separated from RJ inhibits matrix metallopeptidase-1 and matrix metallopeptidase-3 activity in synovial fibroblasts, which mediate joint degradation in rheumatoid arthritis, possibly through inhibiting the p38 and c-Jun N-terminal kinase-activator protein-1 signaling pathways (Yang et al., 2010). Meanwhile, an in vitro investigation suggested that 10-HDAA may be a secure rheumatoid arthritis treatment for preventing joint destruction (You et al., 2020). ...
The popularity of royal jelly (RJ) as a functional food has attracted attention from various industries, especially nutraceuticals, due to the increasing demand from health enthusiasts. Sebacic acid, 10‐hydroxy decanoic acid, and trans‐10‐hydroxy‐2‐decanoic acid are the primary medium‐chain fatty acids (MCFAs) within RJ responsible for their health benefits. This review aims to consolidate information on these MCFAs’ metabolic relationship and health functionalities in nutraceutical applications. We also investigated the natural characteristics mediated by these MCFAs and their metabolism in organisms. Finally, the production of these MCFAs using conventional (from castor oil) and alternative (from RJ) pathways was also discussed. This review can be a reference for using them as functional ingredients in nutraceutical industries.
... RJ, a traditional cure for various skin injuries [87], has not been extensively utilized in clinical practice or studied for wound management, principally due to the lack of knowledge on the RJ bioactive molecules and on the precise mechanisms boosting the wound repairing ability [88]. ...
There is a long and interesting history between honeybees and humans. From the beginning, honey has been utilized not only as a sweetener, but also as an ointment and a drug to treat several diseases. Until the discovery of antibiotics, honey was a very popular product used to protect and preserve skin and promote wound healing, to counteract gastrointestinal pains and disorders of the oral cavity, and for other diseases. After the development of antibiotic resistance, honey again gained interest for its use in wound management. Subsequently, more recently, in vitro and in vivo studies have displayed antimicrobial, antioxidant, and other effects of honey and honeybee products, as well as protection of cardiovascular, respiratory, nervous, and gastrointestinal systems. Moreover, recent studies have demonstrated that beehive products are also able to influence the phenotype of skin cells, such as keratinocytes, fibroblasts, and endothelial cells, involved in correct wound healing. This review will characterize the great potential of honeybee products in the field of health and skin care, considering that honey is a virtually inexhaustible natural resource which people, as bees have been domesticated over the centuries, can freely access.
... Nowadays, pharmacologic treatments for RA symptoms include non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and diseasemodifying anti-rheumatic drugs (DMARDs), although these treatments come with certain adverse effects. As a result, complementary therapies, particularly nutritional supplements, have gained more attention [46]. ...
Royal jelly (RJ), a highly nutritious natural product, has gained recognition for its remarkable health-promoting properties, leading to its widespread use in the pharmaceutical, food, and cosmetic industries. Extensive investigations have revealed that RJ possesses a broad spectrum of therapeutic effects, including anti-inflammatory, antioxidant, antitumor, anti-aging, and antibacterial activities. Distinctive among bee products, RJ exhibits a significantly higher water and relatively lower sugar content. It is characterized by its substantial protein content, making it a valuable source of this essential macronutrient. Moreover, RJ contains a diverse array of bioactive substances, such as lipids, phenolic compounds, flavonoids, organic acids, minerals, vitamins, enzymes, and hormones. This review aims to provide an overview of current research on the bioactive components present in RJ and their associated health-promoting qualities. According to existing literature, these bioactive substances hold great potential as alternative approaches to enhancing human health. Notably, this review emphasizes the anti-inflammatory properties of RJ, particularly in relation to inflammatory diseases, such as multiple sclerosis (MS), rheumatoid arthritis (RA), and inflammatory bowel diseases (IBD). Furthermore, we delve into the antitumor and antioxidant activities of RJ, aiming to deepen our understanding of its biological functions. By shedding light on the multifaceted benefits of RJ, this review seeks to encourage its utilization and inspire further investigation in this field.
... RJ is distinguished from other bee products by the presence of an unsaturated fatty acid termed 10-hydroxy-2-decenoic acid (Table 3 and Figure 1C). This compound has anti-inflammatory and bactericidal effects on human colon cancer cells [39] and could be a potential medicine for rheumatoid arthritis [40]. The antibacterial compounds royalisin and jelleine II were found in RJ [41,42]. ...
Honeybee products, as multicomponent substances, have been a focus of great interest. The present work aimed to perform the nutritional and chemical profiling and biochemical characterization of bee pollen (BP), bee bread (BB), and royal jelly (RJ) and study their applications in the fortification of functional fermented dairy products. Their effects on starter cultures and the physicochemical and sensorial quality of products were monitored. A molecular networking analysis identified a total of 46 compounds in the three bee products that could be potential medicines, including flavonoids, fatty acids, and peptides. BB showed the highest protein and sugar contents (22.57 and 26.78 g/100 g), which cover 45.14 and 53.56% of their daily values (DVs), with considerable amounts of the essential amino acids threonine and lysine (59.50 and 42.03%). BP, BB, and RJ can be considered sources of iron, as 100 g can cover 141, 198.5, and 94.94% of DV%, respectively. BP was revealed to have the highest phenolic and flavonoid contents (105.68 and 43.91 µg/g) and showed a synergetic effect when mixed with RJ, resulting in increased antioxidant activity, while BB showed a synergetic effect when mixed with RJ in terms of both antioxidant and proteolytic powers (IC50 7.54, 11.55, 12.15, 12.50, and 12.65 cP compared to the control (10.55 cP)), reflecting their organoleptic properties and highlighting these health-oriented products as promising natural products for human health care.
... 10-Hydroxy-2-decenoic acid (10-HDA), also known as royal jelly acid, is the major fatty acid component of royal jelly. 10-HDA has been reported to possess a variety of activities beneficial to human health, including anti-inflammatory [19,20], antitumor [21][22][23], immunomodulatory [24,25], and lifespan-extending activities [26]. We have previously reported that 10-HDA has an antibacterial activity against planktonic S. aureus by destroying the integrity of the cell membrane [27]. ...
Persistent infections caused by Staphylococcus aureus biofilms pose a major threat to global public health. 10-Hydroxy-2-decenoic acid (10-HDA), a main fatty acid in royal jelly, has been shown to possess various biological activities. The purpose of this study was to explore the effects of 10-HDA on the biofilms and virulence of S. aureus and its potential molecular mechanism. Quantitative crystal violet staining indicated that 10-HDA significantly reduced the biofilm biomass at sub-minimum inhibitory concentration (MIC) levels (1/32MIC to 1/2MIC). Scanning electron microscope (SEM) observations demonstrated that 10-HDA inhibited the secretion of extracellular polymeric substances, decreased bacterial adhesion and aggregation, and disrupted biofilm architecture. Moreover, 10-HDA could significantly decrease the biofilm viability and effectively eradicated the mature biofilms. It was also found that the hemolytic activity of S. aureus was significantly inhibited by 10-HDA. qRT-PCR analyses revealed that the expressions of global regulators sarA, agrA, and α-hemolysin gene hla were downregulated by 10-HDA. These results indicate that 10-HDA could be used as a potential natural antimicrobial agent to control the biofilm formation and virulence of S. aureus.
... 10-HDA promote collagen synthesis and production of the collagen promoting factor, transforming growth factor β1, in human skin fibroblasts make royal jelly to protect skin against UVB induced photoaging ( Koya-Miyata et al., 2004;Park et al., 2011). In addition to promoting collagen synthesis, 10-HDA has been found to inhibit the release of the MMP-1 and MMP-3 from rheumatoid arthritis synovial fibroblasts (Yang et al., 2010;Wang et al., 2012). 10-HDA also prevented UVAinduced JNK/p38 activation and MMP-1 and MMP-3 upregulation in fibroblasts capable of skin dermal protection and antirheumatoid activity . ...
There has been an increasing demand for natural products, particularly the bee products in the Covid-19 pandemic situation. Honeybees produce honey, royal jelly, propolis, bee venom, bee pollen, and beeswax, which potentially benefit to humans. Bee bread and pollen are widely used for apitherapeutic purposes due to the nutritional and medicinal properties. These include about 200 different substances, especially enzymes, free amino acids and vitamins. Clinical standardization of these products is usually hindered due to chemical variability and inconsistency of bee products depending on honeybee and botanical sources. The major bioactive compounds in honeybee products include phenolics, methylglyoxal, royal jelly proteins (MRJPs), and oligosaccharides. Royal jelly consist of antimicrobial jelleins and royalisin peptides, MRJPs, and hydroxy-decenoic acid derivatives, notably 10-hydroxy-2-decenoic acid (10-HDA), which has potent antimicrobial, anti-inflammatory, immunomodulatory, neuromodulatory, metabolic syndrome preventing, and anti-aging activities. Caffeic acid phenethyl ester and artepillin C found in propolis shows good antiviral, immunomodulatory, anti-inflammatory and anticancer effects. The major components of bee venom consists of toxic peptides like melittin (pain-inducing), apamin (SK channel blocking), and phospholipase A2 (allergenic). Bee pollen rich in vitamins, antioxidant and anti-inflammatory plant phenolics. Bee pollen also contains antiatherosclerotic, antidiabetic, and hypoglycemic flavonoids, unsaturated fatty acids, and sterols. Beeswax is pharmaceutical as well as widely used in cosmetics and makeup. Given the importance of drug discovery from natural sources and present Covid-19 pandemic situation, this review is aimed at providing an exhaustive screening of the bioactive compounds detected in honeybee products and of their curative or adverse biological effects.
... RJ and its derived compounds possess biological activities that improve health and enhance longevity in several animal models (Honda et al. 2011;Inoue et al. 2003;Kunugi and Mohammed Ali 2019;Qiu et al. 2020;Wan et al. 2018;Xin et al. 2016). It has been reported that the lipid fraction of RJ, including 10-hydroxy-2-decenoic acid (10-H 2 DA, namely, queen bee acid (QBA)) and 10-hydroxydecanoic acid (10-HDA), may be responsible for its bioactive properties (Yang et al. 2010). QBA is the exclusive fatty acid of RJ, representing 40% of total fatty acid composition, and it is used as a quality marker of RJ (Li et al. 2013). ...
Autophagy is a conserved intracellular catabolic pathway that removes cytoplasmic components to contribute to neuronal homeostasis. Accumulating evidence has increasingly shown that the induction of autophagy improves neuronal health and extends longevity in several animal models. Therefore, there is a great interest in the identification of effective autophagy enhancers with potential nutraceutical or pharmaceutical properties to ameliorate age-related diseases, such as neurodegenerative disorders, and/or promote longevity. Queen bee acid (QBA, 10-hydroxy-2-decenoic acid) is the major fatty acid component of, and is found exclusively in, royal jelly, which has beneficial properties for human health. It is reported that QBA has antitumor, anti-inflammatory, and antibacterial activities and promotes neurogenesis and neuronal health; however, the mechanism by which QBA exerts these effects has not been fully elucidated. The present study investigated the role of the autophagic process in the protective effect of QBA. We found that QBA is a novel autophagy inducer that triggers autophagy in various neuronal cell lines and mouse and fly models. The beclin-1 (BECN1) and mTOR pathways participate in the regulation of QBA-induced autophagy. Moreover, our results showed that QBA stimulates sirtuin 1 (SIRT1), which promotes autophagy by the deacetylation of critical ATG proteins. Finally, QBA-mediated autophagy promotes neuroprotection in Parkinson’s disease in vitro and in a mouse model and extends the lifespan of Drosophila melanogaster. This study provides detailed evidences showing that autophagy induction plays a critical role in the beneficial health effects of QBA.
... 10-HDA, also known as royal jelly acid, is an organic acid compound extracted from royal jelly and is one of the main active ingredients [17,18]. It has a variety of physiological functions such as antibacterial, anti-inflammatory, blood lipid lowering, immunity enhancing, and anticancer effects [19][20][21][22][23][24]. However, its pharmacodynamic effect and pharmacological mechanism of action in cancer remain unknown. ...
10-Hydroxy-2-decenoic acid (10-HDA), also known as royal jelly acid, has a variety of physiological functions, and recent studies have shown that it also has anticancer effects. However, its anticancer mechanisms have not been clearly defined. In this study, we investigated the underlying mechanisms of 10-HDA in A549 human lung cancer cells. We used Cell Counting Kit-8 assay, scratch wound healing assay, flow cytometry, and western blot analysis to investigate its apoptotic effects and underlying mechanism. Our results showed that 10-HDA inhibited the proliferation of three types of human lung cancer cells and had no significant toxic effects on normal cells. Accompanying reactive oxygen species (ROS), 10-HDA induced A549 cell apoptosis by regulating mitochondrial-associated apoptosis, and caused cell cycle arrest at the G0/G1 phase in a time-dependent manner. Meanwhile, 10-HDA also regulated mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) signaling pathways by increasing the expression levels of phosphorylated c-Jun N-terminal kinase, p-p38, and I-κB, and additionally, by decreasing the expression levels of phosphorylated extracellular signal-regulated kinase, p-STAT3, and NF-κB. These effects were blocked by MAPK inhibitors and N-acetyl-L-cysteine. Furthermore, 10-HDA inhibited cell migration by regulating transforming growth factor beta 1 (TGF-β1), SNAI1, GSK-3β, E-cadherin, N-cadherin, and vimentin. Taken together, the results of this study showed that 10-HDA induced cell cycle arrest and apoptosis in A549 human lung cancer cells through ROS-mediated MAPK, STAT3, NF-κB, and TGF-β1 signaling pathways. Therefore, 10-HDA may be a potential therapy for human lung cancer.
... Moreover, treating rheumatoid arthritis synovial fibroblasts with 10H2DA (0.5 mM, 1 mM, and 2 mM) for 2 h followed by stimulation with TNF-α (10 ng/ml) for 2 h had no effect on ERK activity, NF-κB DNA-binding activity and IκBα degradation. Meanwhile, 10H2DA caused blocking of p38 kinase and c-Jun Nterminal kinase-activator protein-1 (AP-1) signaling pathways [27]. ...
Cassava (Manihot esculenta), is a major source of carbohydrates after rice and maize providing a basic diet to over half a billion people. It is an annual crop belonging to the family Euphorbiaceae. It produces edible root tubers which form the staple food for inhabitants in the developing world mainly in the tropical and subtropical countries. It is a very drought tolerant crop which is classified as either bitter or sweet cassava. However, it produces Hydrogen Cyanide (HCN) which is toxic. This ant nutritional component can cause partial paralysis and have been known to kill and wipe out families in Africa. It is surprising that farmers seem to prefer the bitter varieties as they are starchier, deter pests and wild animals. There have not been adequate studies to evaluate the causes and molecular basis of the production of Hydrogen cyanide by cassava. Observations of feeding patterns of porcupines on cassava roots, defense mechanisms in cassava and macro level results on cassava metabolism were hereby used to explain the molecular epigenetic link of cyanogenesis of cassava. The results explain the exogenous release and its subsequent removal of HCN during cassava processing. It shall form the basis for the selection and improvement of cassava products for food security.
... Royal jelly, a traditional remedy for many kinds of cutaneous injuries, may have potential applications in the therapy of abnormal wounds. Limited previous studies have revealed that royal jelly, or its derivatives, have the effectiveness of promoting wound repair at both animal and cellular levels [10][11][12][19][20][21][22][23][24], yet the subjacent mechanisms of action are still unclear. Besides, it is wellknown that the compositions and bioactivities of royal jelly change with the honeybee species, environmental conditions, harvesting time and botanical sources [25]; however, there is no study investigating the woundhealing properties of royal jelly harvested in blossom seasons of different nectariferous plants, which may have hindered the application of specific royal jelly and the discovery of wound healing-promoting substances. ...
Background
Non-healing wounds have been a severe issue in the global healthcare system. Regrettably, royal jelly, a traditional remedy for various skin injuries, has not been widely applied in cutaneous wounds in clinical practice nowadays, which may be due to the confusion and the lack of knowledge about the efficacies of different types of royal jelly, the bioactive constituents, and the precise mechanisms underlying the wound repairing activity. Since the compositions and bioactivities of royal jelly are predominantly influenced by nectar plants, this study aims to explore the differences in the wound-healing properties of royal jelly produced by Apis mellifera L. during the blossom seasons of different floral sources, to provide guidelines for the future rational application of royal jelly in cutaneous wounds, and to promote the further discovery of wound repair-promoting substances.
Methods
Royal jelly samples were harvested during flowering seasons of Castanea mollissima Bl. (chestnut) and Brassica napus L. (rapeseed) in South China, from which hydrophilic and lipophilic fractions were extracted. The in vivo wound-healing potential was preliminarily assessed in Wistar rats’ excisional full-thickness wounds, followed by investigating the mechanisms of action through in vitro assays with human epidermal keratinocytes and LPS-stimulated inflammation in macrophages.
Results
The results indicated that different royal jelly samples exhibited distinct wound-healing potential, in which Castanea mollissima Bl. royal jelly was more potent. It sped up wound closure between day 2 and day 4 to 0.25 cm²/day (p < 0.05), and could accelerate wound repair by enhancing the proliferative and migratory capabilities of keratinocytes by 50.9% (p < 0.001) and 14.9% (p < 0.001), modulating inflammation through inhibiting nitric oxide production by 46.2% (p < 0.001), and promoting cell growth through increasing the secretion of transforming growth factor-β by 44.7% (p < 0.001). In contrast, Brassica napus L. royal jelly could regulate inflammation by reducing the amount of tumour necrosis factor-α by 21.3% (p < 0.001).
Conclusions
The present study improves the application of royal jelly for curing difficult-to-heal wounds, in which the hydrosoluble extract of Castanea mollissima Bl. royal jelly promises the greatest potential. It also provides clues which may lead towards the identification of substances derived from royal jelly to treat wounds.
... Honey is also used for the cure of many human diseases skin disorders, gastrointestinal disorders, neurological diseases, cardiovascular disorders, and diseases of the intestine [23][24][25][26][27][28]. Royal jelly, a larval food of honeybees, is also used to treat a wide variety of diseases, such as asthma, anorexia, gastrointestinal ulcers, arteriosclerosis, anemia, hypo-or hypertension, anti-cancer, wound healing, and neurasthenia or inhibit sexual libido [29][30][31][32][33]. Moreover, the venom of the honeybee has been employed to reduce the symptoms of and ameliorate inflammatory and autoimmune diseases, such as multiple sclerosis, arthritis, rheumatism, chronic pain, asthma, neurological diseases, and dermatological conditions [34][35][36][37][38][39][40]. ...
Background:
Mutations in the human Ubiquilin 2 gene are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD), the fatal neurodegenerative disease that progressively affected neuronal cells in both brain and spinal cord. There is currently no effective therapy for these diseases. Over the last decade, researchers have focused on the potential use of natural products especially in neurodegenerative studies. Insect products have been used as traditional medicines, however, scientific information is still lacking. Fruit fly is recently used as a model organism to investigate degenerative diseases related to the nervous system because it has a short life span and produces a large number of offspring.
Methods:
The present study investigated the effects of honeybee products and edible insect powders on the locomotive and learning abilities, neuromuscular junctions (NMJs) structure, and reactive oxygen species (ROS) in larval brains of Ubiquilin- knockdown Drosophila.
Results:
dUbqn knockdown flies showed defects in locomotive and learning abilities accompanied with structural defects in NMJs. The results obtained revealed that the recovery of locomotive defects was significantly greater in dUbqn knockdown flies fed with coffee honey from Apis cerana (1% v/v) or Apis dorsata melittin (0.5 μg/ml) or wasp powder (2 mg/ml) than that of in untreated dUbqn knockdown flies. Furthermore, dUbqn knockdown flies fed with coffee honey showed the partial rescue of structural defects in NMJs, improved learning ability, and reduced the accumulation of ROS caused by dUbqn depletion in the brain over the untreated group.
Conclusion:
These results suggest that coffee honey from Apis cerana contains a neuroprotective agent that will contribute to the development of a novel treatment for ALS/FTD.
... Schematical representation of the biological composition of royal jelly and the main functional activities of the compounds[37][38][39][40][41][42][43]. ...
Women’s life stages are based on their reproductive cycle. This cycle begins with menstruation and ends with menopause. Aging is a natural phenomenon that affects all humans, and it is associated with a decrease in the overall function of the organism. In women, aging is related with and starts with menopause. Also, during menopause and postmenopausal period, the risk of various age-related diseases and complaints is higher. For this reason, researchers were pushed to find effective remedies that could promote healthy aging and extended lifespan. Apitherapy is a type of alternative medicine that uses natural products from honeybees, such as honey, propolis, royal jelly, etc. Royal jelly is a natural yellowish-white substance, secreted by both hypopharyngeal and mandibular glands of nurse bees, usually used to feed the queen bees and young worker larvae. Over the centuries, this natural product was considered a gold mine for traditional and natural medicine, due to its miraculous effects. Royal jelly has been used for a long time in commercial medical products. It has been demonstrated to possess a wide range of functional properties, such as: antibacterial, anti-inflammatory, vasodilatative, hypotensive, anticancer, estrogen-like, antihypercholesterolemic, and antioxidant activities. This product is usually used to supplement various diseases such as cardiovascular disease, Alzheimer’s disease, sexual dysfunctions, diabetes or cancer. The main objective of this study is to highlight the effectiveness of royal jelly supplementation in relieving menopause symptoms and aging-related diseases. We also aimed to review the most recent research advances regarding the composition of royal jelly for a better understanding of the effects on human health promotion.
... Según algunos autores, aumenta la resistencia a la fatiga y es un importante estimulante del sistema inmunitario, lo que ayuda a reforzar las defensas del organismo, muy importante en deportistas 654 . También se le han adjudicado propiedades antibacterianas, antiinflamatorias, inmunomoduladoras y antioxidantes [655][656][657] . ...
... Moreover, treating rheumatoid arthritis synovial fibroblasts with 10H2DA (0.5 mM, 1 mM, and 2 mM) for 2 h followed by stimulation with TNF-α (10 ng/ml) for 2 h had no effect on ERK activity, NF-κB DNA-binding activity and IκBα degradation. Meanwhile, 10H2DA caused blocking of p38 kinase and c-Jun Nterminal kinase-activator protein-1 (AP-1) signaling pathways [27]. ...
10-hydroxy-trans-2-decenoic acid (10H2DA), also known as royal jelly acid, is the main lipid component of RJ. It possesses anti-tumor,
neurogenic, anti-inflammatory, antioxidant, bactericidal, nematocidal, and estrogen-like properties. A limited number of studies demonstrate the potentials of its main fatty acid, 10-H2DA, for alleviating anxiety and depressive-like behaviors as well as for enhancing neuronal functioning. However, the exact mechanism through which 10-H2DA produces its effect is not well-understood. This mini review gives examples of how 10H2DA might positively contribute to the treatment of psychiatric and neurological disorders. In addition, it surveys the available knowledge about the molecular mechanism through which it regulates transcriptional processes and gene expression in the brain.
... Due to anti-inflammatory properties ERJ has the potential to be developed as food to enhancing immune activities for the prevention of inflammatory disease [159]. As a unique compound in RJ, 10-HDA significantly inhibits the activities of matrix metalloproteinases (MMP-1, MMP-3), p38, and the c-Jun N-terminal kinases-activating protein-1 (JNK-AP-1) signaling pathway, which could serve as a protective tool against the therapy of rheumatoid arthritis [160]. Moreover, 10-HDA inhibits lipopolysaccharide (LPS)-induced inhibitor of kappa-B-zeta (IkB-z) and IL-6 productions, which contribute to autoimmune and inflammatory diseases [161]. ...
Royal jelly (RJ) is a yellowish-white and acidic secretion of hypopharyngeal and mandibular glands of nurse bees used to feed young worker larvae during the first three days and the entire life of queen bees. RJ is one of the most appreciated and valued natural product which has been mainly used in traditional medicines, health foods, and cosmetics for a long time in different parts of the world. It is also the most studied bee product, aimed at unravelling its bioactivities, such as antimicrobial, antioxidant, anti-aging, immunomodulatory, and general tonic action against laboratory animals, microbial organisms, farm animals, and clinical trials. It is commonly used to supplement various diseases, including cancer, diabetes, cardiovascular, and Alzheimer’s disease. Here, we highlight the recent research advances on the main bioactive compounds of RJ, such as proteins, peptides, fatty acids, and phenolics, for a comprehensive understanding of the biochemistry, biological, and pharmaceutical responses to human health promotion and life benefits. This is potentially important to gain novel insight into the biological and pharmaceutical properties of RJ.
... 2 It seems that RJ with its capability can inhibit the P38MAPK phosphorylation in activated LPS of microglia. 24 RJ can exert its antiinflammatory effects on NF-Kβ pathway. RJ can inhibit the NF-Kβ by reducing H2O2 production, inhibiting the IKβ kinase, phosphorylation of P65 and depleting of P65. 25 Silici et al. illustrated that RJ inhibits the induction of cisplatin-induced nephrotoxicity through the inhibition of oxidative stress, which is in line with the findings of the current study. ...
ABSTRACTBackground: Proteins play the most important role in the structure and function of liver. Royal Jelly (RJ) as a honey bee secretion has antioxidant activities. This study was designed to evaluate the effects of RJ against hepatic damage in rats induced by Low Protein Diet (LPD). Materials and Methods: Forty‑eight male rats were randomly assigned into 6 groups: sham and LPD (%8 protein) groups; RJ groups (200 mg/kg RJ for 5 months and 200 mg/kg RJ for 10 months, orally) and LPD + RJ groups (200 mg/kg RJ orally + LPD for 5 months and 200 mg/kg RJ orally and LPD for 10 months). Griess technique was hired for determination of serum Nitric Ox‑ide (NO) level. Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline Phosphatase (ALP) concentrations were determined for liver functional disturbances value. In addition, Thiobarbituric acid reactive species, antioxidant capacity, the diameter of hepatocytes and the Central Hepatic Vein (CHV) were investigated. Results: LPD significantly increased the liver Malondialdehyde (MDA) and NO levels, the mean diameter of CHV and hepatocyte, hepatic enzymes and decreased tissue Ferric Reducing
Ability of Plasma (FRAP) level compared to the sham group (P< 0.01). The RJ and RJ + LPD in all treatments significantly reduced the mean diameter of hepatocyte and CHV, hepatic enzymes, liver MDA and NO levels and increased tissue FRAP level compared to the LPD group (P< 0.01). Conclusion: RJ administration recovers the hepatic injury due to oxidative stress by LPD in rats. Key words: Low protein diet, Liver, Hepatoprotective, Royal jelly, Rats.
... [2] It seems that RJ with its capability can inhibit the P38MAPK phosphorylation in activated lipopolysaccharide of microglia. [24] RJ can exert its anti-inflammatory effects on nuclear factor kappa B pathway. RJ can inhibit the NF-Kβ by reducing H 2 O 2 production, inhibiting the inhibitor kappa β kinase, phosphorylation of P65, and depletion of P65. ...
... 10-Hydroxy-trans-2-decenoic acid (10H2DA), 3,10-dihydroxydecanoic acid, and sebacic acid are unique medium chain fatty acids in royal jelly (Lercker, Capella, Conte, Ruini, & Giordani, 1981). 10H2DA has been reported to exhibit various pharmacological activities such as antitumor (Townsend et al., 1960), antibiotic (Blum, Novak, & Taber, 1959), neuron proliferator (Hattori, Nomoto, Fukumitsu, Mishima, & Furukawa, 2007), immunomodulator , and anti-rheumatic effects (Yang et al., 2010). Some of the mechanisms by which 10H2DA exerts these effects were recently elucidated. ...
10‐Hydroxy‐trans‐2‐decenoic acid (10H2DA) is a unique lipid component of royal jelly produced by worker honeybees that exerts insulin‐like effects. We herein investigated the effects of 10H2DA on the gene expression of aquaporin 9 (AQP9), which functions as a glycerol transporter in the liver, to clarify whether 10H2DA modulates energy metabolism. 10H2DA suppressed AQP9 gene expression in HepG2 cells by promoting the phosphorylation of Akt and AMP‐activated protein kinase (AMPK). This suppression was partially recovered by the treatment of cells with inhibitors for Akt and AMPK. Based on the result showing that leptomycin B partially recovered the suppression of AQP9 gene expression, 10H2DA inhibited the expression of Foxa2, a transcription factor for the AQP9 gene, and also induced its nuclear exclusion. Although 10H2DA up‐regulated phosphoenolpyruvate carboxykinase and glucose‐6‐phosphatase gene expression, this was suppressed through the modulation of Foxa2 by insulin. These results suggest that 10H2DA suppresses AQP9 gene expression through the phosphorylation of Akt and AMPK and down‐regulation of Foxa2 expression. 10H2DA suppressed AQP9 gene expression in HepG2 cells by promoting the phosphorylation of Akt and AMP‐activated protein kinase (AMPK). 10H2DA inhibited the expression of Foxa2, a transcription factor for the AQP9 gene, a transcription factor for the AQP9 gene, and also induced its nuclear exclusion. 10H2DA suppresses AQP9 gene expression through the phosphorylation of Akt and AMPK and down‐regulated expression of Foxa2.
... On the other hand, a relatively large number of in vitro studies indicate that 10-HDA can be a safe treatment of RA. The 10-HDA is likely to prevent joint destruction by inhibiting MMP production from rheumatoid arthritis synovial fibroblasts through blockage of p38 kinase and c-Jun N-terminal kinase-AP-1 signaling pathways [34,76]. The 10-HDA also prevents cell proliferation of fibroblast-like synoviocytes by inhibiting target genes of PI3K-AKT pathway and genes of cytokine-cytokine receptor interaction [77]. ...
Aging is a natural phenomenon that occurs in all living organisms. In humans, aging is associated with lowered overall functioning and increased mortality out of the risk for various age-related diseases. Hence, researchers are pushed to find effective natural interventions that can promote healthy aging and extend lifespan. Royal jelly (RJ) is a natural product that is fed to bee queens throughout their entire life. Thanks to RJ, bee queens enjoy an excellent reproductive function and lengthened lifespan compared with bee workers, despite the fact that they have the same genome. This review aimed to investigate the effect of RJ and/or its components on lifespan/healthspan in various species by evaluating the most relevant studies. Moreover, we briefly discussed the positive effects of RJ on health maintenance and age-related disorders in humans. Whenever possible, we explored the metabolic, molecular, and cellular mechanisms through which RJ can modulate age-related mechanisms to extend lifespan. RJ and its ingredients—proteins and their derivatives e.g., royalactin; lipids e.g., 10-hydroxydecenoic acid; and vitamins e.g., pantothenic acid—improved healthspan and extended lifespan in worker honeybees Apis mellifera, Drosophila Melanogaster flies, Gryllus bimaculatus crickets, silkworms, Caenorhabditis elegans nematodes, and mice. The longevity effect was attained via various mechanisms: downregulation of insulin-like growth factors and targeting of rapamycin, upregulation of the epidermal growth factor signaling, dietary restriction, and enhancement of antioxidative capacity. RJ and its protein and lipid ingredients have the potential to extend lifespan in various creatures and prevent senescence of human tissues in cell cultures. These findings pave the way to inventing specific RJ anti-aging drugs. However, much work is needed to understand the effect of RJ interactions with microbiome, diet, activity level, gender, and other genetic variation factors that affect healthspan and longevity.
... [31]. Several studies have reported the beneficial effects of queen bee acid in vitro, including antitumor activity, anti-inflammatory activity and antiangiogenic activity [32][33][34], although a clear mechanism of action has yet to be described. It has been shown that queen bee acid is an inhibitor of histone deacetylase, which is known to play a key role in epigenetic switch for the queen bee larvae phenotype, and stimulates neurogenesis from stem cells [35,36]. ...
... 2 It seems that RJ with its capability can inhibit the P38MAPK phosphorylation in activated LPS of microglia. 24 RJ can exert its antiinflammatory effects on NF-Kβ pathway. RJ can inhibit the NF-Kβ by reducing H2O2 production, inhibiting the IKβ kinase, phosphorylation of P65 and depleting of P65. 25 Silici et al. illustrated that RJ inhibits the induction of cisplatin-induced nephrotoxicity through the inhibition of oxidative stress, which is in line with the findings of the current study. ...
INTRODUCTION Increased production of Reactive Oxygen Species (ROS) induces the secretion of inflammatory cytokines and lipid peroxidation and elevates the production of NO in different tissues. 1 Lipid peroxidation is an important factor involved in inducing oxidative damage in the cell membrane, lipoproteins and other lipid structures. 2 Lipid peroxidation leads to the generation of peroxides and hydroxides, which causes toxicity in the body and a decline in antioxidant enzymes activity. 3 This is a fact that liver has a life cycle for anatomical, biochemical and physiological evolution. It is not surprising that nutrition factors are considered to be effective in function and structure of liver. 4 Nearly two third of metabolic items of the body are comprised of proteins. 5 Roshankhah et al. showed that administration of LPD significantly had harmful effects of structure and function of brain in rats. 6 LPD impairs the cells, cell membrane and DNA which leads to cell necrosis. 7 Some factors such as the increased level of ROS production, inflammatory cytokines and NO are believed to be involved in LPD in different tissues. 8 LPD in long time causes oxidative stress, which is followed by the production of ROS such as superoxide radical and hydroxyl radical, induction of cell damage by biomembrane lipids destruction and disruption of cellular metabolism. 9 The oxidative stress induced by lipid peroxidase production causes the hepatic cell membrane damage and triggers the activity of some hepatic enzymes. 10 Presentation of antioxidant compounds can be an appropriate strategy to decrease the oxidative stress-induced damage. 11 RJ plays key roles in neonatal growth, completion of special sexual features and long life of the queen. Hypopharyngeal glands of honeybees by production of royal jelly play a crucial role in beehive development, especially queen. 12 The bees feed by RJ in the first three days and their diet is changed afterward, while the queen always feeds by RJ. 13 RJ contains a wide range of chemical compounds such as Royalism (with potent antibacterial properties), Apisimin (stimulating the proliferation of monocytes in human), Jelleines (with antimicrobial activity) and lipids, fatty acids, carbohydrates, vitamins (B-group vitamins, thiamine, riboflavin, pentatonic acid, niacin, folic acid and biotin). 14 The antioxidant activity of RJ inhibits the effects of oxidative stress and lipid peroxidation and protects DNA against oxidative stress. 15 Kanbur et al. reported that mice fed with RJ had a higher level of 8-hydroxy-2-decenoic acid (oxidative stress marker) in their liver and blood serum, with increased average longevity. 16 Further, Karadeniz et al. showed that the administration of RJ decreased liver toxicity and oxidative stress induced by cisplatin compounds. 17 LPD has toxic effects and RJ has numerous beneficial properties, especially antioxidant features. Further, no study has ever investigated the effects of RJ on the LPD-induced disorders of the liver. Hence, the present study was carried out to explore the effects of RJ on LPD-induced impairments of the liver of male rats. MATERIALS AND METHODS Animals Animals were treated according to the guidelines of animal care and handling developed by the Iran`s Ministry of Health. Forty eight male Wistar rats (weighing 220-250 g) were purchased from Pastor Institute of Iran. The average age of the animals was two months (8 weeks). The animals were housed in standard cages (three per cage) with control ABSTRACT Background: Proteins play the most important role in the structure and function of liver. Royal Jelly (RJ) as a honey bee secretion has antioxidant activities. This study was designed to evaluate the effects of RJ against hepatic damage in rats induced by Low Protein Diet (LPD). Materials and Methods: Forty-eight male rats were randomly assigned into 6 groups: sham and LPD (%8 protein) groups; RJ groups (200 mg/kg RJ for 5 months and 200 mg/kg RJ for 10 months, orally) and LPD + RJ groups (200 mg/kg RJ orally + LPD for 5 months and 200 mg/kg RJ orally and LPD for 10 months). Griess technique was hired for determination of serum Nitric Oxide (NO) level. Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline Phosphatase (ALP) concentrations were determined for liver functional disturbances value. In addition, Thiobarbituric acid reactive species, antioxidant capacity, the diameter of hepatocytes and the Central Hepatic Vein (CHV) were investigated. Results: LPD significantly increased the liver Malondialdehyde (MDA) and NO levels, the mean diameter of CHV and hepatocyte, hepatic enzymes and decreased tissue Ferric Reducing
... Although some studies have indicated that topical application of royal jelly can shorten the period of infected or uninfected wound healing in animal models and even diabetic foot ulcers [16][17][18], the substances and precise mechanisms associated with wound healing are still poorly investigated. Previous studies merely reported that royal jelly components, especially 10-hydroxy-2-decenoic acid (10-HDA) and defensin-1, might accelerate wound healing through anti-inflammation, promoting synthesis of growth factors, or migration of skin fibroblasts or keratinocytes [15,[19][20][21][22]; MRJPs could induce proliferation of several human cell lines [23]. ...
Background:
Skin injury is inevitable in daily life. In recent years, with the increasing morbidity of diseases such as diabetes and metabolic disorders, chronic wounds have become a considerable challenge in clinical practice. Royal jelly, reported to have multifarious biological and physiological properties, has been used as a remedy for a variety of wounds since ancient times. However, the active components and mechanisms underlying the wound-healing properties of royal jelly are still largely unknown.
Methods:
Water-soluble proteins of royal jelly were fractionated and investigated for the proliferative and migratory effects on human epidermal keratinocytes (HaCaT) in an in vitro wound healing model. The proteins present in bioactive fractions were characterised and quantified using Label-free protein quantification method. The potential functions of these proteins in biological systems were further analysed using bioinformatic tools.
Results:
A protein fraction, mainly containing major royal jelly proteins 2 (MRJP2), MRJP3 and MRJP7, stimulated proliferative and migratory activities in HaCaT cells without visible cytotoxicity. It exerted the greatest effects on the growth of HaCaT cells in the first 48 h. Furthermore, when treated with this protein fraction, the closure rates of the in vitro scratch wound were significantly increased. Functional analysis indicated that MRJP2, MRJP3 and MRJP7 were associated with carbohydrate transport and metabolism.
Conclusions:
We fractionated the water-soluble proteins of royal jelly and identified one fraction (Fraction 2) that induced both proliferative and migratory effects on a human epidermal keratinocyte cell line. Major royal jelly proteins (MRJP2, MRJP3 and/or MRJP7) were speculated to possess potential wound-healing bioactivity. This is the first report that royal jelly may improve wound closure via MRJP-induced cellular proliferation and migration. These proteins may be valuable lead compounds for the development of novel wound healing medications. Our findings would facilitate better understanding of the wound repair mechanisms of royal jelly.
... ling period of desquamated skin lesions, and by decreasing exudation, it increases the wound healing capacity and collagen formation in granulation tissue formation (Galaly et al., 2014). It enables wound healing by inhibiting capillary permeability and may effectively treat diabetic foot ulcers besides the standard treatments (Mannoor et al., 2009). Yang et al. (2010 administered RJ orally to reduce oral mucositis. Because of its vasodilation effects around the affected wound, it can help to dilate the blood vessels to enhance blood flow (Siavash et al., 2015;Pasupuleti et al., 2017). 10H2DA has a therapeutic value in inhibiting joint destruction in rheumatoid arthritis. It was found that RJ has ant ...
Royal jelly (RJ) has been known for centuries, but in the last 5-6 decades its systematic production and consumption has increased. RJ is secreted by the hypopharyngeal and mandibular glands of worker honeybees ( Apis mellifera ). This thick and milky substance contains water, proteins, carbohydrates, lipids, minerals, vitamins and such bio-active compounds as acetylcholine, peptides, the hormones testosterone, progesterone, prolactin, estradiol, (hydroxydecanoic acid) (HAD), adenosine monophosphate (AMP)-N1Oxide, polyphenols, flavonoids and adenosine. Because of its bioactive compounds, RJ can be considered as a functional and nutraceutical food. The main goal of this review is to summarize and update its physicochemical properties, bio-active ingredients, storage stability and shelf life. The functional properties are antioxidative activity, insulin-like action, improvement against diabetes, liver protection, antitumoral action, neurotrophic action, antibiotic effect, anti-inflammatory action and wound healing, hypotensive effect and blood regulatory actions, anti-aging effect and skin protection, effects on the reproductive system and fertility and also fortifying, tonic action and immunomodulating and anti-alergic activity. RJ may cause allergic reactions, asthma and even fatal anaphylaxis in some humans. Therefore, RJ should be orally ingested as nutreaceutical agent or food-ingredient only after an allergy test.
... The data obtained were similar with Nabas et al. [38] who mentioned that the amino acids: valine, leucine, and lysine were recorded 0.734%, 0.965%, and 0.986%, respectively, while the fatty acids were recorded 10-hydroxy-2-decenoic acid and tetracosanoic acid reached 3.158% and 0.298%, respectively. The main fatty acid present in RJ is 10-hydroxy-trans-2-decenoic acid (10-HDA); it plays an important role in boosting the immune system, anticancer activity [39]. ...
Data obtained showed that significant differences with all hematological and biochemical parameters in arthritic rats cured by royal jelly, honey and venom in RBC, Hg and RF respectively, whereas WBC, HCT and CRP showed more effecting arthritic rats treated with honey, venom and royal jelly, respectively. In the serum level of sodium and potassium, the superior effects on arthritic rats were caused by honey, followed by venom and royal jelly, respectively. Serum level of calcium was recorded high level in arthritic rats caused by venom, honey and royal jelly, respectively.
... This little difference could be due to the difference in geographical location and floral sources of the samples. 10-HDA is reported to have antioxidant, antibiotic and oestrogenic properties (Hattori et al., 2007;Jamnik et al., 2007;Suzuki et al., 2008) while HDAA has oestrogenic (Suzuki et al., 2008), immunomodulatory (Mihajlovic et al., 2013) and anti-inflammatory properties (Yang et al., 2010). Furthermore, 2-Furancarboxaldehyde, 5-hydroxymethyl has antimicrobial and preservative properties (Revathi et al., 2014;Ramalakshmi & Muthuchelian 2011). ...
Royal jelly (RJ) is rich with phytochemical compounds and nutritional contents with various biological properties. However, no study has been reported on these compositions for RJ that is originated from Malaysia. Hence, the objective of this study
was to determine and compare the phytochemical composition and gas chromatography-mass spectrometry (GC-MS) analysis of RJ of honey bee (Apis mellifera) from Penang (north region) and Johor (south region) of Malaysia. Both samples from Penang and Johor consist of protein (14.71 vs. 14.02%), lipid (0.48 vs. 0.53%), carbohydrate (16.11 vs. 14.39%), ash (1.02 vs. 0.97%), moisture (67.70 vs. 70.10%), and energy (127.5 vs. 118.5 Kcal/100 g). A total of twenty-four and twenty-one volatile compounds were identified, and major compounds were trans-10-Hydroxy-2-decanoic acid (25.19 vs. 29.71%),
10-Hydroxydecanoic acid (16.30 vs. 14.44%) and 2-Furancarboxaldehyde, 5-hydroxymethyl (6.07 vs. 5.52%) in RJ from Penang and Johor, respectively. In conclusion, RJ from Penang, which was harvested during dry season, had higher percentages
of protein, carbohydrate, ash and energy as well as had more volatile phytochemical compounds than RJ from Johor, suggesting the variation in the composition that may be related to the geographical location and floral sources. Our data suggest that
Malaysian RJ is enriched with nutritional contents and phytochemical compounds with good biological properties that can be a potential source of nutraceutical ingredients.
... This little difference could be due to the difference in geographical location and floral sources of the samples. 10-HDA is reported to have antioxidant, antibiotic and oestrogenic properties (Hattori et al., 2007;Jamnik et al., 2007;Suzuki et al., 2008) while HDAA has oestrogenic (Suzuki et al., 2008), immunomodulatory (Mihajlovic et al., 2013) and anti-inflammatory properties (Yang et al., 2010). Furthermore, 2-Furancarboxaldehyde, 5-hydroxymethyl has antimicrobial and preservative properties (Revathi et al., 2014;Ramalakshmi & Muthuchelian 2011). ...
Royal jelly (RJ) is rich with phytochemical compounds and nutritional contents with various biological properties. However, no study has been reported on these compositions for RJ that is originated from Malaysia. Hence, the objective of this study was to determine and compare the phytochemical composition and gas chromatography-mass spectrometry (GC-MS) analysis of RJ of honey bee (Apis mellifera) from Penang (north region) and Johor (south region) of Malaysia. Both samples from Penang and Johor consist of protein (14.71 vs. 14.02%), lipid (0.48 vs. 0.53%), carbohydrate (16.11 vs. 14.39%), ash (1.02 vs. 0.97%), moisture (67.70 vs. 70.10%), and energy (127.5 vs. 118.5 Kcal/100 g). A total of twenty-four and twenty-one volatile compounds were identified, and major compounds were trans-10-Hydroxy-2-decanoic acid (25.19 vs. 29.71%), 10-Hydroxydecanoic acid (16.30 vs. 14.44%) and 2-Furancarboxaldehyde, 5-hydroxymethyl (6.07 vs. 5.52%) in RJ from Penang and Johor, respectively. In conclusion, RJ from Penang, which was harvested during dry season, had higher percentages of protein, carbohydrate, ash and energy as well as had more volatile phytochemical compounds than RJ from Johor, suggesting the variation in the composition that may be related to the geographical location and floral sources. Our data suggest that Malaysian RJ is enriched with nutritional contents and phytochemical compounds with good biological properties that can be a potential source of nutraceutical ingredients. © 2018, Malaysian Society of Applied Biology. All rights reserved.
... 10-HDA was reported to have pharmacological functions potentially due to its anti-tumor [28][29][30], angiogenesis-inhibition [22], and immunomodulatory activities [31]. The pro-inflammatory cytokines such as TNF-a, IL-1β, IL-8 and TGF-β may trigger inflammatory diseases.10-HDA ...
Background:
Royal jelly (RJ), the exclusive food for the larva of queen honeybee, is regarded as the novel supplement to promote human health. The function of RJ may be attributed to its major and unique fatty acid, 10-hydroxy-2-decenoic acid (10-HDA). The current study investigated the anti-inflammory function of 10-HDA on human colon cancer cells, WiDr, as well as its effect on the growth of pathogenic bacterium.
Methods:
The pro-inflammatory cytokines, receptor antagonist cytokine (IL-1ra) and nuclear factor-kappa B (NF-κB) in WiDr cells was analyzed by Enzyme-linked immunosorbent assay (ELISA) or western blot. The growth inhibition of 10-HDA on bacterium was evaluated by determination of minimal inhibitory concentrations (MIC) and minimal bactericide concentrations (MBC).
Results:
The production of pro-inflammatory cytokines, Interleukin (IL)-8, IL-1β and tumor necrosis factor-alpha (TNF-α) in WiDr cells was modulated by 10-HDA. IL-8 were dramatically declined by 10-HDA at 3 mM, while IL-1β and TNF-α were significantly decreased. 10-HDA increased IL-1ra in a dose manner. NF-κB pathway is primarily in response to prototypical pro-inflammatory cytokines, and NF-κB was reduced after 10-HDA treatment. 10-HDA acted as potent bactericide against animal- or human-specific pathogens, including Staphylococcus aureus, Streptococcus alactolyticus, Staphylococcus intermedius B, Staphylococcus xylosus, Salmonella cholearasuis, Vibro parahaemolyticus and Escherichia coli (hemolytic).
Conclusions:
The current study showed that in vitro 10-HDA from RJ exhibited anti-inflammatory activity in WiDr cells, as well as anti-bacterial activity against animal pathogens. 10-HDA showed its potential as anti-imflammtory agent and bactericide to benefit human gastrointestinal tract.
Royal jelly (RJ), a honeybee product, is used as a cosmetic and food ingredient to improve skin condition. However, the influences of RJ on hair growth remain unclear. In this study, we investigated whether RJ regulates hair follicle development, hair shaft formation, and proliferation of hair follicle stem cells (HFSCs) using a gentle anagen induction model by shaving the back skin and a forced anagen induction model by depilating the back skin in mice. The results showed that topical application of RJ on depilated skin induced thinning of the hair shaft and smaller hair bulb formation during the anagen phase. In addition, RJ suppressed the proliferation of CK15-positive HFSCs in hair follicles at the early and middle anagen stages of shaved back skin. RJ suppressed the proliferation of cultured HFSCs in vitro. These findings suggested that RJ induces the formation of thin hair shafts by suppressing the HFSC proliferation.
Royal jelly is a yellowish-white substance with a gel texture that is secreted from the hypopharyngeal and mandibular glands of young worker bees. It consists mainly of water (50–56%), proteins (18%), carbohydrates (15%), lipids (3–6%), minerals (1.5%), and vitamins, and has many beneficial properties such as antimicrobial, anti-inflammatory, anticancer, antioxidant, antidiabetic, immunomodulatory, and anti-aging. Royal jelly has been used since ancient times in traditional medicine, cosmetics and as a functional food due to its high nutritional value. The main bioactive substances are royalactin, and 10-hydroxy-2-decenoic acid (10-HDA). Other important bioactive molecules with antioxidant and photoprotective skin activity are polyphenols. However, they present difficulties in extraction and in use as they are unstable physicochemically, and a higher temperature causes color change and component degradation. In the present study, a new encapsulation and delivery system consisting of liposomes and cyclodextrins incorporating royal jelly has been developed. The new delivery system aims to the elimination of the stability disadvantages of royal jelly’s sensitive component 10-HDA, but also to the controlled release of its ingredients and, more particularly, 10-HDA, for an enhanced bioactivity in cosmeceutical applications.
Toll-like receptor 4 (TLR4) is actively involved in many health-related problems, including transplantation rejection and autoimmune diseases. Therefore, it is important to identify an antagonist to inhibit the TLR4-induced immune cell activation. In our previous study, 10-hydroxy-2-decanoic acid (10-HDA) was introduced as a potential antagonist for TLR4; however, possible interaction between 10-HDA and TLR4 needed to be detected. Due to the ability of surface plasmon resonance (SPR) biosensor to confirm the specific interactions between receptors and ligands, a new configuration of SPR biosensor proposed to detect the possible interaction between 10-HDA and TLR4. Hence, 10-HDA was immobilized using the (3-aminopropyl) triethoxysilane (APTES) polymer as a crosslinking agent on the Ag-MgF2 surface. Besides, genetically modified HEK293T cells with high TLR4 expression were used to study the possible interaction between 10-HDA and TLR4. Surprisingly, the SPR angle was significantly reduced in the presence of HEK cells expressing TLR4, while HEK cells without TLR4 did not affect the SPR angle. So, the proposed SPR biosensor successfully detected the interaction betweenTLR4 and 10-HDA. The sensitivity and detection limit of the biosensor were achieved at 0.05 and 0.5 million cells expressing TLR4, respectively, with a two-fold dynamic range.
Royal jelly as a functional food has great potential to promote human health. As a unique ingredient in royal jelly, 10-hydroxy-2-decenoic acid (10-HDA) is a vital criterion to evaluate the quality of royal jelly. Current approaches for 10-HDA detection mainly rely on high-performance liquid chromatographic (HPLC), but it requires large-scale equipment and skilled laborers that are costly and time-consuming. Herein, we report a colorimetric sensing strategy for 10-HDA detection based on Ag(I) and tetramethylbenzidine (TMB), a widely used chromogenic reagent. Ag(I) can oxidize TMB to generate oxidized TMB (oxTMB) showing a light-blue color. Due to the chelation with Ag (I), the introduction of 10-HDA can prevent the generation of oxTMB that results in a color fading and a decrease in absorbance. This colorimetric sensing strategy enables highly sensitive detection of 10- HDA with a linear range from 1μM to 10 μM and a limit of detection of 0.13 μM. More importantly, this 10-HDA assay allows for a visual readout either by a smartphone or the naked eye with low cost, convenience, and rapid response that has been successfully applied for evaluating the quality of royal jelly in actual samples. The sensing strategy developed in this work provides a new colorimetric approach that holds great promise as a point-of-care platform for the food industry.
1. Giriş
Yara; cerrahi işlemler, travmalar, fiziksel hasar ve diabetes mellitus
gibi kronik hastalık sonucu canlı dokunun yapı ve fonksiyonel işlevinin
bozulması olarak tanımlanmaktadır. Yara tedavisi hem bireysel olarak
hastalarda hem de sağlık hizmetleri ekonomisi üzerinde önemli etkiye
sahiptir. Yalnızca Amerika Birleşik Devletlerinde, iyileşmeyen yaralar
yaklaşık 50 milyar doları, cerrahi kesik ve travmalardan kaynaklanan
yara izleri yaklaşık 12 milyar doları, yanıklar ise her yıl 7,5 milyar
dolarlık sağlık bakımı maliyetini oluşturmaktadır (Rodrigues ve ark.,
2019). Diyabetli hastalar, yaşlılar ve orak hücre hastalığı gibi genetik
bozuklukları olan hastalar özellikle uzun vadeli sekele yol açan anormal
yara iyileşmesine yatkındır. Yara tedavisinde süreç yaraların oluşumuna
bağlı olarak değişim göstermektedir. Altta yatan hastalık (diyabet veya
kardiyovasküler hastalık gibi), enfeksiyonlar ve ilaçlar (steroidler)
nedeniyle yara iyileşme süreçlerinin kesintiye uğraması sonucu anatomik
ve işlevsel bütünlük sağlanamamaktadır. Yara bakımında amaç en
kısa sürede bozulmuş olan dokunun fonksiyonel durumu düzeltmek,
enfeksiyonu önlemek, ödemi, ağrıyı azaltmak ve yara formasyonunu
minimize etmektir (Schultz ve ark., 2011).
Yara iyileşmesi için birkaç tedavi mevcut olmasına rağmen, anti�enflamatuar ajan olan ilaçların çoğu, kapsamlı yan etkilere sahiptir ve
klinik kullanımı sınırlıdır. Antiinflamatuar özelliklere sahip güvenli ve
etkili ilaçlara olan talep, dermatolojik ve yara iyileştirici bakımın geleceği
için çok önemlidir (Ghuman ve ark., 2019).Günümüzde arı ürünlerinden
elde edilen doğal biyolojik olarak aktif maddelerin tıbbi kullanımı yani
apiterapi giderek daha fazla ilgi görmektedir. özel aktif maddelere sahip
Arı ürünleri bal, propolis, arı poleni, arı sütü, arı zehiri ve balmumu
yara iyileşmesinde ve deri üzerindeki tıbbi etkisi çok sayıda çalışma ile
kanıtlanmıştır. Arı ürünleri sadece tedavide değil, aynı zamanda kozmetik
ürünlerin içeriği olarak cilt bakımı için de kullanılmıştır (Kurek-Górecka
ve ark., 2020).
Biodiversity strengthens the productivity of any ecosystem (agricultural land, forest, lake, etc.). The loss of biodiversity contributes to food and energy insecurity; increases vulnerability to natural disasters, such as floods or tropical storms; and decreases the quality of both life and health. Wild and managed bees play a key role in maintaining the biodiversity and in the recovery and restoration of degraded habitats. The novelty character of this perspective is to give an updated representation of bee products’ biodiversity, sustainability, and health relationship. The role of bees as bioindicators, their importance in the conservation of biodiversity, their ecosystem services, and the variety of the bee products are described herein. An overview of the main components of bee products, their biological potentials, and health is highlighted and detailed as follows: (i) nutritional value of bee products, (ii) bioactive profile of bee products and the related beneficial properties; (iii) focus on honey and health through a literature quantitative analysis, and (iv) bee products explored through databases. Moreover, as an example of the interconnection between health, biodiversity, and sustainability, a case study, namely the “Cellulose Park”, realized in Rome (Italy), is presented here. This case study highlights how bee activities can be used to assess and track changes in the quality of agricultural ecosystems—hive products could be valid indicators of the quality and health of the surrounding environment, as well as the changes induced by the biotic and abiotic factors that impact the sustainability of agricultural production and biodiversity conservation in peri-urban areas.
Royal jelly (RJ) demand is growing every year and so is the market for functional foods in general. RJ is formed by different substances, mainly carbohydrates, proteins, and lipids, but also vitamins, minerals, and phenolic or volatile compounds in lower proportion. Major royal jelly proteins (MRJP) are, together with 10-hydroxy-2-decenoic acid (10-HDA), key substances of RJ due to their different biological properties. In particular, 10-HDA is a unique substance in this product. RJ has been historically employed as health enhancer and is still very relevant in China due to the traditional medicine and the apitherapy. Nowadays, it is mainly consumed as a functional food or is found in supplements and other formulations for its health-beneficial properties. Within these properites, anti-lipidemic, antioxidant, antiproliferative, antimicrobial, neuroprotective, anti-in-flammatory, immunomodulatory, antiaging, and estrogenic activities have been reported for RJ or its specific components. This manuscript is aimed at reviewing the current knowledge on RJ components , their assessment in terms of authenticity, their biological activities, and related health applications .
Insects are the most diverse group of organisms with one million species that account for 80% of the world's species. Particularly in East Asia, edible insects serve as a source of nutrients. Among these, silkworms and honeybees are well-known sources of food and have been used for the treatment of a large number of human disorders. This review focuses on the utilization of insects as food (entomophagy) as well as for their pharmacological properties (entomotherapy) that have been tested in vitro as well as in vivo.
Background:
Consumption of a high-fat diet (HFD) in aged rats is associated with several metabolic disorders. The mechanism of skeletal muscle lipotoxicity and insulin resistance (IR) is multi-factorial, but the exact mechanism of how aging affects these processes unknown. Royal jelly (RJ) is a dietary supplement with many physiological and pharmacological properties. No previous studies have demonstrated the protective effects and mechanism of RJ in aged obese rats.
Objectives:
The study was carried to investigate the effects of aging and HFD on skeletal muscles, and adipose tissue metabolism and inflammation, in aged rats, and whether RJ could combat such adverse effects.
Methodology:
A total of 40 male rats were divided into5 groups; young rats fed a standard diet, aged rats fed a standard diet, aged rats fed RJ, aged rats fed a HFD, and aged rats fed both a HFD and RJ for 8 weeks. We investigated changes in body weights (BW), abdominal fat weights, total cholesterol, triglycerides (TG), low density lipoprotein-cholesterol (LDL-c), high density lipoprotein-cholesterol (HDL-c), muscle TG, and IR levels. Also, concentrations of TNF-α receptor 1(TNFR1) were estimated in the serum and adipose tissues.
Results:
Aged, obese rats showed increased BW, adipose weights, IR, and disturbed serum and muscle lipids. Also, TNFR1 was increased. Rats fed RJ showed decreased adiposity, improved lipids' profiles, improved IR, and decreased TNFR1.
Conclusion:
Aging and HFD were associated with disturbed metabolism, and muscle lipotoxicity and inflammation, while RJ could counteract muscle lipotoxicity in rats and reduce IR, most likely due to an anti-inflammatory effect.
Royal jelly was fractionated by ion-exchange chromatography and a protein (DIII protein) that had growth stimulating activity to the U-937 human myeloid cell line was obtained. The molecular weight of the DIII protein was 58 kDa on SDS-PAGE. The growth stimulating activity of the DIII protein was shown to be relatively heat and pH stable.
Rheumatoid arthritis (RA) is a sexually dimorphic, autoimmune inflammatory disorder affecting the joints. Joint disability in RA results primarily from loss of matrix components (collagen and glycosoaminoglycan) in the cartilage and synovium. This study was carried out to understand the effect of physiological levels of testosterone, estrogen, and progesterone on oxidative stress-induced changes in matrix composition in rat synovium in arthritis. Arthritis induction in castrated and ovariectomized rats resulted in enhanced oxidative stress and this was assessed by lipid peroxidation levels and depletion of antioxidants. This, in turn, led to significantly (p < 0.01) increased levels of TNF-alpha and matrix metalloproteinase-2 (MMP-2), subsequently resulting in loss of collagen, elastin, and glycosoaminoglycan (GAG) and disorganization of reticulin as evidenced by biochemical quantitation and also by staining for collagen, reticulin, and elastin. Treatment with physiological doses of dihydrotestosterone (25 mg topically) and estrogen (5 microg/0.1 ml subcutaneously) restored the antioxidant levels significantly (p < 0.05) and reduced the levels of TNF-alpha and MMP-2, with estrogen exhibiting a higher potency. This, in turn, attenuated the damage to reticulin organization as well as the loss of collagen and GAG in the articular tissues. However, elastin loss could not be attenuated by either treatment. Progesterone (2 mg/0.1 ml subcutaneously) was not shown to have any significance in disease modification, and on the contrary, it inhibited the protective effects of estrogen. However, progesterone contributed to increased collagen levels in the tissues.
Primary and passaged human synovial fibroblasts isolated from rheumatoid pannus were treated with recombinant interleukin-1 (IL-1) alpha or beta, tumor necrosis factor-alpha (TNF), or phorbol myristate acetate (PMA) to determine the effects of these stimuli on the relative expression of stromelysin, collagenase, and tissue inhibitor of metalloproteinases (TIMP). The steady-state mRNA levels for these genes and glyceraldehyde-3-phosphate dehydrogenase were determined on Northern blots. Immunoblot analyses of the conditioned media using monoclonal antibodies generated against recombinant human stromelysin, collagenase, or TIMP showed that protein levels reflected the corresponding steady-state mRNA levels. The results revealed that 1) stromelysin and collagenase were not always coordinately expressed; 2) IL-1 was more potent than TNF or PMA in the induction of stromelysin expression; 3) neither IL-1 nor TNF significantly affected TIMP expression; 4) PMA induced both metalloproteinase and TIMP expression; and 5) the combination of IL-1 plus TNF had a synergistic effect on stromelysin expression. Dose response and time course experiments demonstrated that the synergistic effect of IL-1 plus TNF occurred at saturating concentrations of each cytokine and lasted for 7 days. In summary, the ability of IL-1 and TNF to preferentially induce stromelysin and collagenase expression, versus TIMP, may define a pivotal role for these cytokines in the pathogenesis of rheumatoid arthritis.
A new potent antibacterial protein, for which we propose the name royalisin, was found in royal jelly of the honeybee Apis mellifera L. and purified to homogeneity for the first time by acid extraction, gel filtration, and reverse-phase high pressure liquid chromatography. The primary structure of royalisin was determined to consist of 51 residues, with three intramolecular disulfide linkages, having a calculated molecular mass of 5523 Da. Royalisin is an amphipathic protein, with the C-terminal half of the molecule being rich in charged amino acids; and it showed extensive sequence homology to two other antibacterial proteins, sapecin from embryonic Sarcophaga peregrina cells and phormicins from Phormia terranovae larvae. Royalisin was found to have potent antibacterial activity against Gram-positive bacteria at low concentrations, but not against Gram-negative bacteria. Royalisin may be involved in a defense system active against bacterial invasion of the honeybee.
Matrix metalloproteinases (MMPs) are expressed in joint tissues of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The objective of this study was to define the steady state levels of seven different MMPs and two tissue inhibitors of metalloproteinases (TIMPs) as well as the potential metalloproteinase activity in the synovial fluid (SF) to provide more insight into the role of MMPs in cartilage destruction in RA and OA.
Levels of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, TIMP-1, and TIMP-2 in SF aspirated from knee joints of 97 patients with RA and 103 patients with OA were measured by the corresponding one step sandwich enzyme immunoassays. Proteolytic activity of MMPs in these SFs was examined in an assay using [(3)H]carboxymethylated transferrin substrate in the presence of inhibitors of serine and cysteine proteinases after activation with p-aminophenylmercuric acetate (APMA). Destruction of RA knee joints was radiographically evaluated.
Levels of MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 were significantly higher in RA SF than in OA SF. MMP-7 and MMP-13 were detectable in more than 45% of RA SFs and in less than 20% of OA SFs, respectively. Among the MMPs examined, MMP-3 levels were extremely high compared with those of other MMPs. Direct correlations were seen between the levels of MMP-1 and MMP-3 and between those of MMP-8 and MMP-9 in RA SF. Although the levels of MMP-1 and MMP-3 increased even in the early stage of RA, those of MMP-8 and MMP-9 were low in the early stage and increased with the progression of RA. Molar ratios of the total amounts of the MMPs to those of the TIMPs were 5.2-fold higher in patients with RA than in OA, which was significant. APMA-activated metalloproteinase activity in SF showed a similar result, and a direct correlation was seen between the molar ratios and the activity in RA SF.
Our results show that high levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and TIMP-1 are present in RA SF and suggest that once these MMPs are fully activated, they have an imbalance against TIMPs, which may contribute to the cartilage destruction in RA.
Mitogen-activated protein kinase (MAPK) cascades are involved in inflammation and tissue destruction in rheumatoid arthritis (RA). In particular, c-Jun N-terminal kinase (JNK) is highly activated in RA fibroblast-like synoviocytes and synovium. However, defining the precise function of this kinase has been difficult because a selective JNK inhibitor has not been available. We now report the use of a novel selective JNK inhibitor and JNK knockout mice to determine the function of JNK in synoviocyte biology and inflammatory arthritis. The novel JNK inhibitor SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one) completely blocked IL-1--induced accumulation of phospho-Jun and induction of c-Jun transcription in synoviocytes. Furthermore, AP-1 binding and collagenase mRNA accumulation were completely suppressed by SP600125. In contrast, complete inhibition of p38 had no effect, and ERK inhibition had only a modest effect. The essential role of JNK was confirmed in cultured synoviocytes from JNK1 knockout mice and JNK2 knockout mice, each of which had a partial defect in IL-1--induced AP-1 activation and collagenase-3 expression. Administration of SP600125 modestly decreased the rat paw swelling in rat adjuvant-induced arthritis. More striking was the near-complete inhibition of radiographic damage that was associated with decreased AP-1 activity and collagenase-3 gene expression. Therefore, JNK is a critical MAPK pathway for IL-1--induced collagenase gene expression in synoviocytes and in joint arthritis, indicating that JNK is an important therapeutic target for RA.
Expression and activation of matrix metalloproteinases such as MMP-3 (stromelysin-1) and MMP-1 (collagenase-1) are increased in patients with rheumatoid arthritis (RA). Previous negative reports of their value as predictors of joint damage may be due to the lack of a large longitudinal study of early RA patients. This study evaluated their use in assessing early untreated patients with RA and predicting subsequent joint damage.
Ninety-eight patients with early untreated RA of less than 12 months duration and 20 normal controls had baseline serum samples tested with a double-antibody enzyme-linked immunosorbent assay for each of MMP-1 and MMP-3. The subsequent changes in Larsen score (DeltaLarsen) and Health Assessment Questionnaire (DeltaHAQ) over the first 12 months were recorded.
Baseline serum levels of MMP-3 and MMP-1 correlated significantly with baseline C-reactive protein (CRP) (r=0.42 and 0.49, P<0.001), DeltaHAQ (r=0.32 and 0.30, P<0.01) and DeltaLarsen (r=0.23 and 0.32, P<0.05) respectively. Analysis of the group of patients with a normal CRP at presentation (n=21) showed correlation of the baseline MMP-3 and MMP-1 with the presence of erosive disease during the first 12 months (r=0.52 and 0.65 respectively, P<0.05). Logistic regression analysis, in the patients who were non-erosive at presentation, showed that the strongest correlation with progression in Larsen score was the baseline MMP-3 level (r=0.30, P=0.01).
Baseline serum MMP-1 and MMP-3 levels correlate with disease activity and predict functional and radiographic outcome in early untreated RA. They may have a particular value in predicting the progression of erosive disease in patients who are not erosive at presentation.
To explore the potential applicability of recombinant adeno-associated virus (rAAV) vectors in the treatment of rheumatoid arthritis (RA), primary human fibroblast-like synoviocytes (FLS) derived from patients with RA were infected with rAAV encoding mouse IL-10 under the control of the CMV promoter. Addition of the proteasome inhibitor carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (zLLL) to the cultures dramatically enhanced expression of the IL-10 transgene, in a dose-dependent manner. The increased expression was transient, peaking at 3 days and returning to near baseline by 7 days. The enhancement was observed even when zLLL was added 13 days after infection with rAAV. The effect of zLLL was not specific to either the mIL-10 transgene or the CMV promoter, as similar findings were observed using an rAAV construct encoding alpha1-anti-trypsin under the control of the chick beta-actin promoter or GFP, driven by the CMV promoter. Transgene expression could be repeatedly induced by reexposure to zLLL. Transgene mRNA levels increased in parallel with protein levels. Transgene expression could also be repeatedly induced in vivo by administering zLLL to SCID mice previously injected with rAAV-infected FLS. These data demonstrate that proteasome inhibition can dramatically enhance transgene expression in human RA FLS following infection with rAAV and suggest a possible approach to regulating synovial transgene expression in vivo.
Objective
To examine the cellular mechanisms by which the proinflammatory cytokine interleukin‐17 (IL‐17) induces the synthesis of 92‐kd gelatinase (matrix metalloproteinase 9 [MMP‐9]) by human monocyte/macrophages in primary culture.
Methods
IL‐17–stimulated human monocytes isolated from the peripheral blood of healthy donors were cultured in the presence of antiinflammatory cytokines, neutralizing antibodies against IL‐1β, tumor necrosis factor α (TNFα), or IL‐1 receptor antagonist, and with protein kinase inhibitors of diverse specificity. MMP measurements were performed using specific enzyme‐linked immunosorbent assays, while the expression of specific messenger RNA was determined by Northern blotting. Detection of phosphorylated proteins and specific transcriptional factors was performed by Western blotting and by gel retardation experiments, respectively.
Results
Biologically active IL‐17 was detected in the synovial fluid of patients with rheumatoid arthritis. IL‐17–induced MMP‐9 production in human monocyte/macrophages was dependent on endogenous prostaglandin E2 synthesis and related to autocrine stimulation by TNFα, but was IL‐1β independent. This activation involves both p42/44 and p38 kinases and nuclear factor κB. IL‐17–inducible activator protein 1 and signal transducer and activator of transcription 1/3 may transactivate the MMP‐9 promoter.
Conclusion
IL‐17 may contribute to an unbalanced production of proinflammatory cytokines and MMP‐9 in diseased articular joint tissues by interacting with the macrophages in the rheumatoid synovium.
The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a “classification tree” schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91–94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
Objective
To determine how interleukin-1 (IL-1), through activation of collagenase 1 (matrix metalloproteinase 1 [MMP-1]) transcription in synovial fibroblasts, contributes to cartilage degradation in rheumatoid arthritis.Methods
Primary rabbit synovial fibroblasts were transiently transfected with MMP-1 promoter/luciferase constructs, and promoter activity in response to IL-1 was assessed. A minimal IL-1-response element was defined and used to evaluate DNA binding proteins by electrophoretic mobility shift assay and in situ ultraviolet crosslinking assay.ResultsTranscriptional activation of the MMP-1 gene by IL-1 in rabbit synovial fibroblasts required a dorsal-like element, which was located at nucleotide (nt) -3,029, as well as an activator protein 1 site at nt -77. Importantly, an IL-1-induced DNA binding activity that was specific for the dorsal-like element contained the p50 subunit of nuclear factor κB (NF-κB).Conclusion
These studies demonstrate, for the first time, a role for NF-κB in the induction of MMP-1, and suggest a mechanism of NF-κB-mediated cartilage degradation in rheumatoid arthritis.
Objective. To quantify stromelysin and collagenase in synovial fluid (SF) from patients with rheumatoid arthritis (RA) or traumatic knee injury.
Methods. Stromelysin and collagenase were measured in the SF of 33 patients with RA or posttraumatic knee injury, using specific double-antibody sandwich enzyme-linked immunosorbent assays. Stromelysin was fractionated from representative SF, and the molecular form was identified by immunoblot analysis.
Results. The stromelysin concentration was ˜20-fold higher than the collagenase concentration in the fluids from patients with RA and ˜8-fold higher in the fluids from patients with traumatic injury. For both metalloproteinases, there was a higher enzyme concentration in RA SF than in the SF from patients with trauma (stromelysin 40.1 ± 26 μ/ml [mean ± SD] in RA SF, 8.5 ± 15 μ/ml in trauma SF; collagenase 2.2 ± 3.3 μ/ml in RA SF, 1.1 ± 2.3 μ/ml in trauma SF). The majority of the stromelysin within the SF bound to reactive red—agarose and was identified as prostromelysin based on electrophoretic mobility and immunoblotting with monospecific antibodies.
Conclusion. The finding of high levels of stromelysin in SF from patients with RA supports the proposal that this enzyme may play a role in the connective tissue degradation observed in this disease.
Objective
To examine the cellular mechanisms by which the proinflammatory cytokine interleukin-17 (IL-17) induces the synthesis of 92-kd gelatinase (matrix metalloproteinase 9 [MMP-9]) by human monocyte/macrophages in primary culture.MethodsIL-17–stimulated human monocytes isolated from the peripheral blood of healthy donors were cultured in the presence of antiinflammatory cytokines, neutralizing antibodies against IL-1β, tumor necrosis factor α (TNFα), or IL-1 receptor antagonist, and with protein kinase inhibitors of diverse specificity. MMP measurements were performed using specific enzyme-linked immunosorbent assays, while the expression of specific messenger RNA was determined by Northern blotting. Detection of phosphorylated proteins and specific transcriptional factors was performed by Western blotting and by gel retardation experiments, respectively.ResultsBiologically active IL-17 was detected in the synovial fluid of patients with rheumatoid arthritis. IL-17–induced MMP-9 production in human monocyte/macrophages was dependent on endogenous prostaglandin E2 synthesis and related to autocrine stimulation by TNFα, but was IL-1β independent. This activation involves both p42/44 and p38 kinases and nuclear factor κB. IL-17–inducible activator protein 1 and signal transducer and activator of transcription 1/3 may transactivate the MMP-9 promoter.ConclusionIL-17 may contribute to an unbalanced production of proinflammatory cytokines and MMP-9 in diseased articular joint tissues by interacting with the macrophages in the rheumatoid synovium.
The growth stimulating effects of a royal jelly protein (DIII protein) were studied. The DIII protein stimulated the growth of five human lymphocytic cell lines in serum-free conditions. Cell cycle analysis showed that U-937 cells cultured with the DIII protein did not arrest to the G1 phase. Furthermore, a binding assay using europium-labeled DIII protein showed U-937 cells had a large number of low affinity receptors on the cell surface.
Mitogen-activated protein kinases (MAPKs) are components of a three kinase regulatory cascade. There are multiple members of each component family of kinases in the MAPK module. Specificity of regulation is achieved by organization of MAPK modules, in part, by use of scaffolding and anchoring proteins. Scaffold proteins bring together specific kinases for selective activation, sequestration and localization of signaling complexes. The recent elucidation of scaffolding mechanisms for MAPK pathways has begun to solve the puzzle of how specificity in signaling can be achieved for each MAPK pathway in different cell types and in response to different stimuli. As new MAPK members are defined, determining their organization in kinase modules will be critical in understanding their select role in cellular regulation.
In inflammatory conditions, chondrocytes produce large amounts of matrix metalloproteases (MMP) and nitric oxide (NO) thought to contribute to joint degradation. We tested the ability of all-trans retinoic acid (ATRA, a retinoic acid receptor (RAR) agonist) to modulate these inflammatory genes in chondrocytes from humans or rats, chosen as representative of animal models of arthritis. All RAR subtypes and RXR-alpha or -beta were expressed at the mRNA level in both species, although IL-1beta (10 ng/ml) inhibited RAR subtypes more markedly in rat than in human cells. ATRA (300 or 1000 nM) inhibited IL-1-induced expression of iNOS and nitrites level in both species, although the NO pathway was induced maximally in rat cells. ATRA displayed controversial effects on MMPs between rat and human chondrocytes, especially for MMP-9 expression. The effects of ATRA were irrelevant to the nuclear translocation of AP-1. The present data underlines that retinoids have a species-dependent impact on IL-1-induced responses in chondrocytes, suggesting that extrapolation of their pharmacological properties from animal cells has a poor relevance to clinical situation.
The primary objective of this review was to assess the size and consistency of Royal Jelly (RJ) effect on serum lipids in experimental animals and humans. The data from animal studies were pooled, where possible, and statistically evaluated by Student's t-test. Meta-analysis was used for the evaluation of human trials. It was found that RJ significantly decreased serum and liver total lipids and cholesterol levels in rats and rabbits and also retarded the formation of atheromas in the aorta of rabbits fed a hyperlipemic diet. Meta-analysis of the controlled human trials of RJ to reduce hyperlipidemia showed a significant reduction in total serum lipids and cholesterol levels and normalization of HDL and LDL as determined from decrease in beta/alpha lipoproteins. The best available evidence suggests that RJ at approximately 50 to 100 mg per day, decreased total serum cholesterol levels by about 14%, and total serum lipids by about 10% in the group of patients studied.
The transmission of extracellular signals into their intracellular targets is mediated by a network of interacting proteins that regulate a large number of cellular processes. Cumulative efforts from many laboratories over the past decade have allowed the elucidation of one such signaling mechanism, which involves activations of several membranal signaling molecules followed by a sequential stimulation of several cytoplasmic protein kinases collectively known as mitogen-activated protein kinase (MAPK) signaling cascade. Up to six tiers in this cascade contribute to the amplification and specificity of the transmitted signals that eventually activate several regulatory molecules in the cytoplasm and in the nucleus to initiate cellular processes such as proliferation, differentiation, and development. Moreover, because many oncogenes have been shown to encode proteins that transmit mitogenic signals upstream of this cascade, the MAPK pathway provides a simple unifying explanation for the mechanism of action of most, if not all, nonnuclear oncogenes. The pattern of MAPK cascade is not restricted to growth factor signaling and it is now known that signaling pathways initiated by phorbol esters, ionophors, heat shock, and ligands for seven transmembrane receptors use distinct MAPK cascades with little or no cross-reactivity between them. In this review we emphasize primarily the first MAPK cascade to be discovered that uses the MEK and ERK isoforms and describe their involvement in different cellular processes.
The transcription factor NF-kappa B has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-kappa B is through interactions with an inhibitor protein called I kappa B. Recent evidence confirms the existence of multiple forms of I kappa B that appear to regulate NF-kappa B by distinct mechanisms. NF-kappa B can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-kappa B to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of I kappa B. Exciting new research has elaborated several important and unexpected findings that explain mechanisms involved in the activation of NF-kappa B. In the nucleus, NF-kappa B dimers bind to target DNA elements and activate transcription of genes encoding proteins involved with immune or inflammation responses and with cell growth control. Recent data provide evidence that NF-kappa B is constitutively active in several cell types, potentially playing unexpected roles in regulation of gene expression. In addition to advances in describing the mechanisms of NF-kappa B activation, excitement in NF-kappa B research has been generated by the first report of a crystal structure for one form of NF-kappa B, the first gene knockout studies for different forms of NF-kB and of I kappa B, and the implications for therapies of diseases thought to involve the inappropriate activation of NF-kappa B.
The degradation of fibrillar type II collagen is a major feature of cartilage destruction in rheumatoid arthritis (RA). Since collagenase 3 is produced by chondrocytes and preferentially degrades type II cartilage collagen, it seemed likely that this enzyme would have a prominent role in the destruction of rheumatoid joints. Using immunolocalization techniques, we have examined and compared the production and distributions of collagenase 1 and collagenase 3 in cells and tissues derived from rheumatoid knee arthroplasties. Primary cultures of chondrocytes stimulated with interleukin-1 beta showed that most of the cells produced collagenase 1, whereas only a minority (approximately 5-10%) produced collagenase 3; a few chondrocytes demonstrated the co-ordinate production of both enzymes. Primary cultures of rheumatoid synoviocytes produced collagenase 1, but not collagenase 3. Both enzymes were demonstrated in the rheumatoid lesion. Collagenase 1 was more commonly observed in both synovium and cartilage (22 of the 28 specimens), was especially prominent at cartilage erosion sites, and most of the positive specimens demonstrated extracellular enzyme. By contrast, collagenase 3 was observed less frequently (7/28 specimens) and was produced by relatively few chondrocytes and synovial cells, this usually being much less than that observed for chondrocytes of osteoarthritic cartilage. These observations suggest different regulatory mechanisms for the production of collagenases 1 and 3 in the rheumatoid lesion, and demonstrate that the distribution and production of collagenase 1 are far more prevalent than those for collagenase 3.
To determine how interleukin-1 (IL-1), through activation of collagenase 1 (matrix metalloproteinase 1 [MMP-1]) transcription in synovial fibroblasts, contributes to cartilage degradation in rheumatoid arthritis.
Primary rabbit synovial fibroblasts were transiently transfected with MMP-1 promoter/ luciferase constructs, and promoter activity in response to IL-1 was assessed. A minimal IL-1-response element was defined and used to evaluate DNA binding proteins by electrophoretic mobility shift assay and in situ ultraviolet crosslinking assay.
Transcriptional activation of the MMP-1 gene by IL-1 in rabbit synovial fibroblasts required a dorsal-like element, which was located at nucleotide (nt) -3,029, as well as an activator protein 1 site at nt -77. Importantly, an IL-1-induced DNA binding activity that was specific for the dorsal-like element contained the p50 subunit of nuclear factor kappaB (NF-kappaB).
These studies demonstrate, for the first time, a role for NF-kappaB in the induction of MMP-1, and suggest a mechanism of NF-kappaB-mediated cartilage degradation in rheumatoid arthritis.
To investigate whether plasma levels of matrix metalloproteinases 3 (MMP-3, stromelysin), MMP-1 (collagenase), tissue inhibitor of metalloproteinases 1 (TIMP-1), and MMP1/TIMP-1 complex (MT complex) are specifically elevated in erosive joint diseases compared to nonerosive rheumatic diseases, and to assess how these markers reflect the clinical activity of rheumatoid arthritis (RA) compared to circulating cytokines and markers of connective tissue turnover as well as established variables [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor titer].
Plasma levels of MMP-3, MMP-1, TIMP- 1, and MT complex were determined by ELISA. One hundred fifteen patients with RA, 20 with osteoarthritis (OA), 28 with psoriasis arthritis (PsA), 24 with ankylosing spondylitis (AS), 3 groups with systemic autoimmune diseases, and 30 healthy controls were analyzed. In patients with RA routine laboratory variables, circulating inflammatory cytokines [interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and IL-6], collagen degradation products, and markers of bone formation were determined in parallel and were correlated to 4 variables of clinical activity.
MMP-3 levels were markedly elevated in RA compared to controls and OA, but also in all other groups, including 26 patients with systemic lupus erythematosus (SLE). MMP-1 levels were significantly elevated in RA, but also in OA, PsA, SLE, and mixed connective tissue disease. In contrast, MT complex was elevated in RA only. TIMP-1 was not different from controls. CRP levels, MMP-3, and ESR correlated best with clinical activity of RA. In contrast, there was no correlation of IL-1 and TNF-alpha and only a weak correlation of IL-6 with clinical measures. Among variables of connective tissue turnover, only pyridinoline and deoxypyridinoline crosslinks were weakly correlated with disease activity.
Elevated MMP-3 and MMP-1 levels are not specific for RA or for erosive joint diseases in general. In contrast, elevated MT complex levels were observed in patients with RA. However, the correlation of MT-1 with clinical data was weaker than that of MMP-3. Elevated MMP-3 levels reflected disease activity of RA better than cytokine levels or markers of connective tissue turnover. However, MMP-3 levels do not exceed the association of CRP with clinical activity.
To examine the mechanism of interleukin-1 (IL-1)-induced collagenase 3 (matrix metalloproteinase 13 [MMP-13]) gene expression in cultured chondrocytes for the purpose of better understanding how the gene is induced in these cells, and how it contributes to cartilage degradation in osteoarthritis.
The transcriptional and posttranscriptional responses of the MMP-13 gene to IL-1 were assessed first. Then, direct inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways and a constitutive repressor of nuclear factor kappaB (NF-kappaB) were used to assess the role of each pathway in IL-1-mediated induction of MMP-13.
We found that IL-1 induction of MMP-13 requires p38 activity, c-Jun N-terminal kinase (JNK) activity and NF-kappaB translocation. These results suggest that both NF-kappaB and activator protein 1 transcription factors are necessary for IL-1 induction of MMP-13. We also compared the signaling pathways necessary for IL-1 to stimulate collagenase 1 (MMP-1) in articular chondrocytes and chondrosarcoma cells and found that IL-1 induction of MMP-1 requires different pathways from those required by MMP-13. In chondrosarcoma cells, MMP-1 induction depends on p38 and MEK (an MAPK kinase of the extracellular signal-regulated kinase pathway) and does not require JNK or NF-kappaB. In articular chondrocytes, inhibition of MEK had no effect, while inhibition of p38 gave variable results.
These studies demonstrate, for the first time, that p38, JNK, and NF-kappaB are required for IL-1 induction of MMP-13. The results also highlight the differential requirements for signaling pathways in the induction of MMP-1 and MMP-13. Additionally, they demonstrate that induction of MMP-1 by IL-1 in chondrocytic cells depends on unique combinations of signaling pathways that are cell type-specific.
Despite increasing evidence regarding the significance of sex hormones in rheumatoid arthritis (RA), their etiopathological role and potential longterm effect on joint destruction remain unclear. We hypothesized that estrogen receptors (ER-alpha) are present in fibroblast-like synoviocytes, and 17beta-estradiol can modulate the production and activity of matrix degrading enzymes produced by these cells. Thus, depending on the endocrine balance, fibroblast-like synoviocyte activity can be suppressed or enhanced, leading to amelioration or exacerbation of the disease process, respectively.
By utilizing an in vitro cartilage invasion model, in combination with the molecular analyses of hormone receptors, matrix metalloproteinases (MMP) and their respective inhibitors, we investigated the effect of hormones (i.e., estrogen and progesterone) on fibroblast-like synoviocyte phenotypic changes, with particular emphasis on their functional interactions with cartilage.
Our studies reveal the presence of functional ER-alpha in fibroblast-like synoviocytes. The findings indicate that estrogen exerts a stimulatory effect, while progesterone has an inhibitory effect on the expression of MMP, their tissue inhibitors (TIMP), and enzymatic activity of MMP produced by these cells. Furthermore, transfection of fibroblast-like synoviocytes with the ER-alpha gene resulted in the increased degradation and invasion of cartilage.
We identified the presence of functional ER-alpha in fibroblast-like synoviocytes. This renders fibroblast-like synoviocytes as target cells for hormonal regulation. The regulatory effect of estrogen is partly targeted to the MMP and their respective inhibitors associated with fibroblast-like synoviocytes. Such studies provide a link between hormonal status and disease activity in RA and open new venues for future therapeutic intervention to combat this debilitating disease.
To determine the role of chondrocytes and factors released from chondrocytes in cartilage destruction by fibroblast-like synoviocytes (FLS) derived from patients with rheumatoid arthritis (RA).
RA FLS from 2 patients were implanted into SCID mice, together with fresh articular cartilage or with cartilage that had been stored for 24 hours at 4 degrees C or at 37 degrees C. The invasion of the same RA FLS into the fresh and stored cartilage was compared histologically using a semiquantitative scoring system. In addition, we investigated whether protein synthesis in chondrocytes affects the invasion of RA FLS in vitro. A 3-dimensional cartilage-like matrix formed by cultured chondrocytes was labeled with 35S. After formation of the cartilage-like matrix, protein synthesis was blocked with cycloheximide. The invasion of RA FLS from 6 patients into cycloheximide-treated and untreated matrix was assessed by measuring the released radioactivity in coculture with and without interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha).
The SCID mouse experiments showed a significant invasion of RA FLS into the cartilage (overall mean score 3.2) but revealed significant differences when the invasion of the same RA FLS into fresh and stored cartilage was compared. RA FLS that were implanted with fresh articular cartilage showed a significantly higher invasiveness than those implanted with pieces of cartilage that had been stored for 24 hours (overall mean score 2.3). Storage at 37 degrees C and 4 degrees C resulted in the same reduction of invasion (35% and 37%, respectively). In the in vitro experiments, RA FLS rapidly destroyed the cartilage-like matrix. Blocking of chondrocyte protein biosynthesis significantly decreased the invasion of RA FLS, as shown by a decreased release of radioactivity. Addition of IL-1beta, but not TNFalpha, to the cocultures partially restored the invasiveness of RA FLS.
These data underline the value of the SCID mouse in vivo model of rheumatoid cartilage destruction and demonstrate that chondrocytes contribute significantly to the degradation of cartilage by releasing factors that stimulate RA FLS. Among those, IL-1beta-mediated mechanisms might be of particular importance.
To investigate whether stress- and mitogen-activated protein kinases (SAPK/MAPK), such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, are significantly activated in rheumatoid arthritis (RA) synovial tissue compared with their activation in degenerative joint disease; to assess the localization of SAPK/MAPK activation in rheumatoid synovial tissue; and to search for the factors leading to stress kinase activation in human synovial cells.
Immunoblotting and immunohistology by antibodies specific for the activated forms of SAPK/MAPK were performed on synovial tissue samples from patients with RA and osteoarthritis (OA). In addition, untreated and cytokine-treated human synovial cells were assessed for SAPK/MAPK activation and downstream signaling by various techniques.
ERK, JNK, and p38 MAPK activation were almost exclusively found in synovial tissue from RA, but not OA, patients. ERK activation was localized around synovial microvessels, JNK activation was localized around and within mononuclear cell infiltrates, and p38 MAPK activation was observed in the synovial lining layer and in synovial endothelial cells. Tumor necrosis factor alpha, interleukin-1 (IL-1), and IL-6 were the major inducers of ERK, JNK, and p38 MAPK activation in cultured human synovial cells.
Signaling through SAPK/MAPK pathways is a typical feature of chronic synovitis in RA, but not in degenerative joint disease. SAPK/MAPK signaling is found at distinct sites in the synovial tissue, is induced by proinflammatory cytokines, and could lead to the design of highly targeted therapies.
In order to clarify the potential physiological function of royal jelly (RJ), we report here the gastrointestinal enzyme production of antihypertensive peptides from RJ. Intact RJ and its protein fraction did not retard the action of angiotensin I-converting enzyme (ACE) activity at all. However, development of ACE inhibition power of RJ was newly observed by pepsin hydrolysis (IC(50)=0.358 mg protein/mL), and the subsequent trypsin and chymotrypsin hydrolyses (IC(50)=0.099 mg protein/mL). Single oral administration of this gastrointestinal RJ hydrolysate (1 g/kg dose) in 10-week spontaneously hypertensive rat resulted in a significant reduction of systolic blood pressure of 22.7 plus minus 3.6 mmHg at 2 hr (P<0.05 vs. 0 hr by one-way ANOVA, n=7). Then, the RJ hydrolysate was fractionated with gel permeation chromatography to obtain the di- and tri-peptides (DTP) fraction. As a result of isolation from the DTP fraction by reversed phase-high performance liquid chromatography, eleven ACE inhibitory peptides were isolated from the DTP-RJ hydrolysate. Some of the ACE inhibitors were derived from the RJ-glycoprotein; eight peptides with the IC(50) value of <10 &mgr;M were identified from natural resources for the first time. Consequently, RJ protein was thought to be a good resource of ACE inhibitory peptides produced by the gastrointestinal enzyme hydrolyses.
The present overview summarizes important knowledge having accumulated during the last years. The liver maintains a steady mass which is basically controlled by a delicate balance between cell gain and cell loss. However, reconstitution of the organ after tissue loss does not only involve replacement of target cells, but also complex remodeling processes resulting in the reconstruction of the typical tissue architecture. Most information in liver regeneration refers to hepatocytes. It is important to note that hepatocytes are not terminally differentiated cells, but cells situated in the G0 phase that can undergo proliferation upon appropriate stimulation. In most situations, hepatic stem cells are not significantly involved in this response. Hepatocyte regeneration is accomplished by a sequence of distinct phases: an initiation phase, rendering cells in a state of replicative competence; a proliferation phase, where expansion of the cell population occurs; and a termination phase, where cell growth is suppressed to terminate regeneration at a set point. These three phases are regulated by a whole group of factors, mainly cytokines, the significance of which has in part been defined by use of animal models with target gene deletions (gene knockouts). It seems that several mechanisms are capable to sense the critical cell mass which has to be achieved. Hepatocyte regeneration is accompanied by a complex remodeling of hepatic tissue, with a transient breakdown of the lobular architecture. In contrast to hepatocytes, less is known for the the regenerative replacement of bile ducts, blood vessels and hepatic stellate cells.
We investigated the antifatigue effect of royal jelly (RJ), which had been stored at -20 degrees C from immediately after collection, in male Std ddY mice. The mice were accustomed to swimming in an adjustable-current swimming pool, then subjected to forced swimming five times during 2 wk, and the total swimming period until exhaustion was measured. They were separated into three groups with equal swimming capacity, which were administered RJ, RJ stored at 40 degrees C for 7 d (40-7d RJ), or the control solution including casein, cornstarch, and soybean oil before swimming. All mice were forced to swim for 15 min once; then the maximum swimming time to fatigue was measured after a rest period. The swimming endurance of the RJ group significantly increased compared with those of the other groups. The mice in the RJ group showed significantly decreased accumulation of serum lactate and serum ammonia and decreased depletion of muscle glycogen after swimming compared with the other groups, whereas there was no significant difference between the 40-7d RJ group and the control group in these parameters after swimming. A quantitative analysis of constituents in RJ showed that 5 7-kDa protein, which we previously identified as a possible freshness marker of RJ, was specifically degraded in RJ stored at 40 degrees C for 7 d, whereas the contents of various vitamins, 10-hydroxy-2-decenoic acid, and other fatty acids in RJ were unchanged. These findings suggest that RJ can ameliorate the physical fatigue after exercise, and this antifatigue effect of RJ in mice seems to be associated with the freshness of RJ, possibly with the content of 5 7-kDa protein.
Here, we have examined the role of distinct MAPK pathways in the regulation of collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by human skin fibroblasts. Tumor necrosis factor-alpha rapidly and transiently activated ERK1/2 and JNK in fibroblasts, whereas the activation of p38 MAPK was more persistent. Inhibition of p38 activity by SB203580 markedly (by 80-90%) inhibited induction of MMP-1 and MMP-3 expression by tumor necrosis factor-alpha, whereas blocking the activation of ERK1/2 by PD98059 had no effect. Activation of endogenous ERK1/2 by adenovirus-mediated transfer of constitutively active MEK1 resulted in potent induction of MMP-1 and MMP-3 expression. Activation of endogenous or adenovirally expressed p38 alpha by adenovirally delivered constitutively active MKK3b and MKK6b also enhanced MMP-1 and MMP-3 expression and augmented the up-regulatory effect of ERK1/2 activation on the expression of these MMPs. Activation of ERK1/2 resulted in induction of c-jun, junB, and c-fos expression, whereas activation of p38 alone had no effect. In contrast, activation of p38 alpha resulted in marked stabilization of MMP-1 and MMP-3 mRNAs. These results identify two distinct and complementary signaling mechanisms mediating induction of MMP-1 and MMP-3 expression in dermal fibroblasts: AP-1-dependent transcriptional activation via the ERK1/2 pathway and AP-1-independent enhancement via p38 alpha MAPK by mRNA stabilization. It is conceivable that both modes of action play an important role in controlling the proteolytic phenotype of fibroblasts, e.g. in wound repair and tumor invasion.
We have recently shown that royal jelly has potent antiallergic properties in a mouse model of immediate hypersensitivity. However, it is still unclear which components of royal jelly exhibit antiallergic activity. In this study, we have screened for antiallergic factors in royal jelly based on inhibition of IL-4 production by anti-CD3 stimulated spleen cells derived from OVA/alum-immunized mice. Using a series of column chromatographies, we purified a 70 kDa glycoprotein, major royal jelly protein 3 (MRJP3), that suppresses IL-4 production. In in vitro experiments, MRJP3 suppressed the production of not only IL-4 but also that of IL-2 and IFN-gamma by T cells concomitant with inhibition of proliferation. The MRJP3-mediated suppression of IL-4 production was also evident when lymph node cells from OVA/alum-immunized mice were stimulated with OVA plus antigen presenting cells. We next examined the purified suppressive factor on OVA/alum-induced allergic responses in mice. Interestingly, in spite of the antigenicity of MRJP3 itself as an extraneous foreign protein, intraperitoneal administration of MRJP3 inhibited serum anti-OVA IgE and IgG1 levels in immunized mice. In addition, heat-treated soluble MRJP3 treatment reduced its antigenicity while maintaining its inhibitory effects on antibody responses to OVA. These results indicate that MRJP3 can exhibit potent immunoregulatory effects in vitro and in vivo. Furthermore, considering the intriguing immunomodulatory effects of MRJP3, it may be of clinical significance to design MRJP3-derived antiallergic peptides by identifying the associated polypeptide regions.
DESPITE many investigations of royal jelly1, its chemistry and pharmacological activity have not been completely established. As part of a long-term study on the chemistry and biological activity of royal jelly2 we have recently investigated its possible anti-tumour properties. In this communication we wish to report that admixture of royal jelly with tumour cells before inoculation completely suppresses the development of a transplantable mouse leukæmia and the formation of ascitic tumours in mice. Fractionation studies have established that this anti-tumour activity resides in the main fatty acid of the royal jelly—10-hydroxydecenoic acid.
10-Hydroxy-Delta(2)-decenoic acid, the major component of the lipide fraction of royal jelly, exhibits antibiotic activity against many bacteria and fungi. This fatty acid is less than one-fourth as active as penicillin against Micrococcus pyogenes and less than one-fifth as active as chlortetracycline against Escherichia coli. It also slows the growth rate of Neurospora sitophila and some unidentified molds. The salt of this compound is considerably less active than the free acid.
Previous studies have shown that whole royal jelly, a fraction from royal jelly (10-hydroxy-2-decenoic acid), and certain closely related dicarboxylic acids, some of which are also found in royal jelly, will inhibit the development of transplantable AKR leukemia when the pH is below 5.6.The ester of 10-hydroxy-2-decenoic acid from royal jelly was found to be just as effective against AKR leukemic cells as the acid itself, with the added advantage that it could be used at neutrality.Through the testing of a series of mono- and di-carboxylic acids, as well as other closely related compounds, the activity has been shown to be associated mainly with 9- and 10-carbon straight chain monocarboxylic acids either saturated or unsaturated. Slight variations in the structure either reduce or destroy the activity.
To examine the expression, regulation, and potential roles of bone morphogenetic proteins (BMPs) in arthritic synovium.
Expression of BMPs in arthritic synovium from patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA) and in noninflamed synovium from patients undergoing diagnostic or therapeutic arthroscopies was studied by reverse transcription–polymerase chain reaction (RT-PCR), Western blot, immunohistochemistry, and 2-color immunofluorescence. In vitro regulation of gene expression in fibroblast-like synoviocytes (FLS) was determined by real-time quantitative RT-PCR and immunohistochemistry. We used 3H-thymidine incorporation after serum deprivation–induced growth arrest to examine effects on FLS proliferation. FLS apoptosis was evaluated by flow cytometry cell cycle analysis. Apoptotic cells in synovial tissue were detected by TUNEL staining.
Transcripts of different BMPs, most strikingly BMP-2 and BMP-6, were detected in synovial tissues. By Western blot, BMP-2 and BMP-6 precursor protein was found in RA and SpA synovial tissue extracts, but not in extracts of noninflamed synovial tissue. By immunohistochemistry, BMP-2 and BMP-6 were detected in the hyperplastic lining and the sublining layer of synovium from RA and SpA patients, both in CD90+ cells (FLS) and in some CD68+ cells (macrophages). Proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor α, but not interferon-γ, enhanced the expression of BMP-2 and BMP-6 transcripts in FLS in vitro. Neither BMP-2 nor BMP-6 affected FLS proliferation. BMP-2 promoted FLS apoptosis, whereas BMP-6 protected against nitric oxide–induced FLS apoptosis. BMP-2–positive apoptotic cells were found in arthritic synovium.
BMP-2 and BMP-6 are expressed in arthritic synovium and are strongly up-regulated by proinflammatory cytokines. Although BMP signaling has been proposed to be involved in cartilage and bone repair in arthritis, this pathway may be equally important in modulating FLS cell populations in inflamed synovium.
In this study, we have examined the anti-inflammatory actions of royal jelly (RJ) at a cytokine level. When supernatants of RJ suspensions were added to a culture of mouse peritoneal macrophages stimulated with lipopolysaccharide and IFN-gamma, the production of proinflammatory cytokines, such as TNF-alpha, IL-6, and IL-1, was efficiently inhibited in a dose-dependent manner without having cytotoxic effects on macrophages. This suggests that RJ contains factor(s) responsible for the suppression of proinflammatory cytokine secretion. We named the factor for honeybees RJ-derived anti-inflammatory factor (HBRJ-AIF), and further investigated the molecular aspects of it. Size fractionation study showed that HBRJ-AIF is composed of substances of low (< 5 kDa) and high (> 30 kDa) molecular weights, with the former being a major component. Chromatographic analysis showed that MRJP3 is one candidate for the HBRJ-AIF with high molecular weights. Thus, our results suggest that RJ has anti-inflammatory actions through inhibiting proinflammatory cytokine production by activated macrophages.
We have previously shown that royal jelly (RJ) promoted collagen production by skin fibroblasts in the presence of ascorbic acid-2-O-alpha-glucoside (AA-2G). In this study, we purified the honeybee RJ-derived collagen production-promoting factor (HBRJ-CPF) from an alkali-solubilized fraction of RJ by C18 reverse-phase column chromatography. The elution profile by the C18 column chromatography and the molecular mass of the purified HBRJ-CPF material coincided with those of 10-hydroxy-2-decenoic acid (10H2DA). We then examined the collagen production-promoting activities of several commercially available fatty acids contained in RJ. We found that 10H2DA and 10-hydroxydecanoic acid increased the collagen production in a dose-dependent manner. Furthermore, 10H2DA induced the fibroblast cell line, NHDF, to produce transforming growth factor-beta 1 (TGF-beta 1) which is an important factor for collagen production. As expected, the collagen production-promoting activity of 10H2DA was neutralized by the anti-TGF-beta 1 antibody. These result suggest that HBRJ-CPF identified as 10H2DA promoted the collagen production of AA-2G-treated fibroblasts by inducing TGF-beta 1 production.
The total oxidant scavenging capacity (TOSC) assay in a modified and automated version was applied for a comparative and detailed survey of the antioxidant capacities of 14 common European fruit and vegetable juices (ACE, apple, beetroot, blueberry, carrot, elderberry, lemon, lingonberry, multivitamin, orange, pink grapefruit, sauerkraut, and tomato juices as well as sour cherry nectar). The juices were ranked according to their scavenging capacity against the three reactive oxygen species (ROS) peroxyl and hydroxyl radicals and peroxynitrite. These ROS are of physiological and technological relevance and cover a broad range of reactivity. Nonlinear correlations between concentrations of all studied samples and antioxidant capacity were taken into account for the assessment of the results. Due to the more complex assay design, results are only partially in accordance with those of the literature. Because of its outstanding TOSC values against two of the three ROS, lingonberry juice deserves special attention.
Royal jelly (RJ) was shown to exhibit immunomodulatory properties, although its biological activity is still unclear. In order to elucidate the mechanism whereby RJ activates the immunological system, we examined the role of this substance on the haematopoietic response of Ehrlich ascites tumour (EAT)-bearing mice. Our results demonstrated that RJ prevented the myelosupression induced by the temporal evolution of the tumour and abrogated the splenic haematopoiesis observed in EAT-bearing mice. The stimulating effect of RJ was also observed in vitro on the multipotent bone marrow stem cells, evaluated by the long-term bone marrow cultures (LTBMCs). The study of survival clearly showed the antitumour activity of RJ. Treatment was given prophylactically for 20 days and therapeutically for 3, 8 and 13 days. Except for the treatment with the lower dose of 500 mg/kg, given for 23 days, all the other dose schedules were able to prolong survival. A more effective antitumoural response was observed with the more prolonged treatment regimen. In this regard, the administration of RJ for 33 days produced the highest protection reaching an extension of survival at about 38%, 71% and 85% for the doses of 500, 1000 and 1500 mg/kg, respectively, whereas with the 23 and 28 days treatment schedules, survival increased at a rate of 19% and 23%, respectively, and comparable results were found among the effective doses of RJ. Increased survival rate might be related to the decreased Prostaglandin E2 (PGE2) levels observed in EAT-bearing mice after RJ treatment. These results point to RJ as a promising modifier of biological response leading to myeloprotection and antitumour activity.
The development of osteoarthritis (OA) has recently been implicated as a result of immune-mediated damage of chondrocytes and their supporting matrixes. Pro-inflammatory cytokines like interleukin (IL)-1 and tumor necrosis factor alpha (TNF-alpha) play pivotal roles in immunopathogenesis of OA. Because vitamins preserving anti-oxidative effects are suggested to provide protection in OA patients from joint damage, in the present study, we examined the effects and mechanisms of all-trans retinoic acid (t-RA) in suppressing pro-inflammatory cytokine-induced matrix metalloproteinases (MMPs) production in human chondrocytes. Chondrocytes were prepared from cartilage specimens of OA patients receiving total hip or total knee replacement. The protein concentration was measured by ELISA, the mRNA expression by reverse transcriptase-polymerase chain reaction, the protein expression by Western blotting, the transcription factor DNA-binding activity by electrophoretic mobility shift assay and the protein kinase activity by kinase assay. We showed that both MMP-1 and MMP-13 mRNA expression, protein production and enzyme activity induced by either IL-1 or TNF-alpha were suppressed by t-RA or different retinoid derivatives. The molecular investigation revealed that the t-RA-mediated suppression was likely through blocking p38 kinase and c-Jun N-terminal kinase-activator protein-1 signaling pathways. In contrast, t-RA had no effect on extracellular signal-regulated kinase activity, nuclear factor (kappa)B (NF-(kappa)B) DNA-binding activity and I(kappa)B(alpha) degradation. Furthermore, we showed that t-RA could reduce IL-1-induced TNF-alpha production in chondrocytes. Our results suggest that vitamin A may protect OA patients from pro-inflammatory cytokine-mediated damage of chondrocytes and their supporting matrixes.
Rheumatoid arthritis (RA) is classically thought of as a Th1, T lymphocyte-driven disease of the adaptive immune system. However, cells of the innate immune system, including neutrophils, are prevalent within the diseased joint, and accumulate in large numbers. This study was undertaken to determine whether cells of the rheumatoid stromal microenvironment could establish an inflammatory environment in which endothelial cells are conditioned in a disease-specific manner to support neutrophil recruitment.
Human umbilical vein endothelial cells (ECs) and fibroblasts isolated from the synovium or skin of RA patients were established in coculture on opposite sides of porous transwell filters. After 24 hours of EC conditioning, the membranes were incorporated into a parallel-plate, flow-based adhesion assay and levels of neutrophil adhesion to ECs were measured.
ECs cocultured with synovial, but not skin, fibroblasts could recruit neutrophils in a manner that was dependent on the number of fibroblasts. Antibody blockade of P-selectin or E-selectin reduced neutrophil adhesion, and an antibody against CD18 (the beta2 integrin) abolished adhesion. Blockade of CXCR2, but not CXCR1, also greatly inhibited neutrophil recruitment. Interleukin-6 (IL-6) was detectable in coculture supernatants, and both IL-6 and neutrophil adhesion were reduced in a dose-dependent manner by hydrocortisone added to cocultures. Antibody blockade of IL-6 also effectively abolished neutrophil adhesion.
Synovial fibroblasts from the rheumatoid joint play an important role in regulating the recruitment of inflammatory leukocytes during active disease. This process may depend on a previously unsuspected route of IL-6-mediated crosstalk between fibroblasts and endothelial cells.