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Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin
Abstract
Curcumin, a dietary pigment in curry, suppresses tumor initiation and tumor promotion. Curcumin is also a potent inhibitor for AP-1 and NF-kappaB activation. In this report, we show that curcumin inhibits JNK activation by various agonists including PMA plus ionomycin, anisomycin, UV-C, gamma radiation, TNF-alpha, and sodium orthovanadate. Although both JNK and ERK activation by phorbol 12-myristate 13-acetate (PMA) plus ionomycin were suppressed by curcumin, the JNK pathway was more sensitive. The IC50 (50% inhibition concentration) of curcumin was between 5-10 microM for JNK activation and was 20 microM for ERK activation. In transfection assays, curcumin moderately suppressed MEKK1-induced JNK activation; however, it effectively blocked JNK activation caused by co-transfection of TAK1, GCK, or HPK1. Curcumin did not directly inhibit JNK, SEK1, MEKK1 or HPK1 activity. Although curcumin suppressed TAK1 and GCK activities at high concentrations, this inhibition cannot fully account for the JNK inhibition by curcumin in vivo. Our data suggest that curcumin may affect the JNK pathway by interfering with the signaling molecule(s) at the same level or proximally upstream of the MAPKKK level. Taken together, the inhibition of the MEKK1-JNK pathway reveals a possible mechanism of suppression of AP-1 and NF-kappaB signaling by curcumin, and may explain the potent anti-inflammatory and anti-carcinogenic effects of this chemical.
... Curcumin is the most explored of the so called curcuminoids, a family of chemo-preventive substances present in the spice, which increasingly being mentioned in health journals and scientific papers as research on it grows (1,2,3). Recent studies suggest that it may help to ease digestive discomfort, reduce inflammation and hereby to increase resistance to disease (2). ...
... Researchers were found that the plant extracts have potential antimicrobial effects against microorganisms [6,7]. The increasing failure of chemotherapeutics and antibiotic resistance on pathogenic microbial growth has led to the screening of new tools that have a potential antimicrobial activity [7,1]. Indeed, plants are natural sources of antibacterial agents. ...
... Turmeric can be used in relief from pain and bleeding of gingival in gingivitis and periodontitis, as colorant in pit and fissure sealant or in dental-plaque detection system. Chemopreventive activity of curcumin is observed when it is administered prior to, during, and after carcinogen treatment as well as when it is given only during the promotion/progression phase of colon carcinogenesis [27,1]. In this study,curcumin showed a potential effect on oral gram positive bacteria. ...
Abstract: Oral pathogenic gram-positive bacteria, Streptococcus pyogenes (Strept.pyogenes) are caused severe human
diseases with complications, including rheumatic fever, sepsis, severe soft-tissue invasion, and toxic-shock-like syndrome
(TSLS). Whereas, Streptococcus mutants(Strept. mutans),described a key causative agent of caries and infective endocarditis.
Therefore, the aim of this study was to evaluate the inhibitory effect of Curcumin on Strept. mutans and Strept.pyogenes
growth in comparison with the antibiotic Ciprofloxacin using well diffusion method. Minimum Inhibitory Concentration
(MICs) showed that curcumin-mediated growth inhibition of Strept. mutans and, Strept. pyogenes. Results showed that
curcumin significantly inhibitedthe activity of Strept. mutans and Strept. pyogenes growth with inhibition zones, 9.7mm and
10.2 mm, respectively while the inhibition zone of Ciprofloxacin 15.52mm to 13.4mm against Strept. mutans, Strept. pyogenes
respectively.The antimicrobial activity of curcumin on Strept. mutans and Strept. pyogenes growth suggests that the curcumin
may be useful for controlling dental biofilms, subsequently dental caries formation.This study provides significant insights into
the therapeutic effect of curcumin against pathogenic gram positive bacteria, suggesting its potential as an alternative therapy,
and opens the way for further studies on identification of novel antimicrobial targets of curcumin.
... Curcumin is the most explored of the so called curcuminoids, a family of chemo-preventive substances present in the spice, which increasingly being mentioned in health journals and scientific papers as research on it grows (1,2,3). Recent studies suggest that it may help to ease digestive discomfort, reduce inflammation and hereby to increase resistance to disease (2). ...
... Researchers were found that the plant extracts have potential antimicrobial effects against microorganisms [6,7]. The increasing failure of chemotherapeutics and antibiotic resistance on pathogenic microbial growth has led to the screening of new tools that have a potential antimicrobial activity [7,1]. Indeed, plants are natural sources of antibacterial agents. ...
... Turmeric can be used in relief from pain and bleeding of gingival in gingivitis and periodontitis, as colorant in pit and fissure sealant or in dental-plaque detection system. Chemopreventive activity of curcumin is observed when it is administered prior to, during, and after carcinogen treatment as well as when it is given only during the promotion/progression phase of colon carcinogenesis [27,1]. In this study,curcumin showed a potential effect on oral gram positive bacteria. ...
Abstract: Oral pathogenic gram-positive bacteria, Streptococcus pyogenes (Strept.pyogenes) are caused severe human
diseases with complications, including rheumatic fever, sepsis, severe soft-tissue invasion, and toxic-shock-like syndrome
(TSLS). Whereas, Streptococcus mutants(Strept. mutans),described a key causative agent of caries and infective endocarditis.
Therefore, the aim of this study was to evaluate the inhibitory effect of Curcumin on Strept. mutans and Strept.pyogenes
growth in comparison with the antibiotic Ciprofloxacin using well diffusion method. Minimum Inhibitory Concentration
(MICs) showed that curcumin-mediated growth inhibition of Strept. mutans and, Strept. pyogenes. Results showed that
curcumin significantly inhibitedthe activity of Strept. mutans and Strept. pyogenes growth with inhibition zones, 9.7mm and
10.2 mm, respectively while the inhibition zone of Ciprofloxacin 15.52mm to 13.4mm against Strept. mutans, Strept. pyogenes
respectively.The antimicrobial activity of curcumin on Strept. mutans and Strept. pyogenes growth suggests that the curcumin
may be useful for controlling dental biofilms, subsequently dental caries formation.This study provides significant insights into
the therapeutic effect of curcumin against pathogenic gram positive bacteria, suggesting its potential as an alternative therapy,
and opens the way for further studies on identification of novel antimicrobial targets of curcumin.
... In this context we found that both NF-κB translocation to the nucleus and JNK phosphorylation, which are crucial steps in the activation of the pathways involving these factors, were markedly reduced by curcumin pretreatment of IR cardiac cells. Other investigators, using different experimental models, have reported that curcumin inhibits NF-κB-and JNK-related pathways and protects cells experiencing oxidative stress or other stressing agents [30,31]. The novel finding arising from the present study is that these actions are also partly attributable to the antioxidant properties of curcumin, because the pretreatment of IR cells with this compound resulted in an inhibition of NF-κB nuclear translocation and of JNK phosphorylation that was quantitatively comparable to that observed, respectively, for Bay 11-7082 and SP600125 and significantly higher than that induced by Trolox. ...
... Indeed, it has been reported that curcumin can inhibit IKK [32][33][34], an essential enzyme for NF-κB activation, and can induce covalent modifications affecting NF-κB binding to DNA [35,36]. As for JNK, it has been found that curcumin may interfere at the proximal upstream portion of this pathway, in particular at the MAPK kinase kinase level [31]. Moreover, in light of recent findings indicating a cross talk between NF-κB and JNK [37], the above-mentioned effects might be independent or reciprocally related. ...
... The authors demonstrated that curcumininduced THP-1 cell apoptosis through the activation of c-Jun NH2-terminal kinase/extracellular signalregulated kinase/activator protein 1 (JNK/ERK/AP1) pathways [63]. Yi-Rong Chen et al. reported that curcumin affects the mitogen-activated protein kinase kinase kinase 1/JNK (MAPKKK1-JNK) pathway by interfering with the signaling molecule(s) like AP-1 and NF-κB as a possible mechanism of action [64]. They speculated that curcumin may affect the JNK pathway by interfering with the signaling molecule(s) at the same level or proximally upstream of the MAPK kinase kinases (MAPKKKs) level. ...
... kB, JNK/ERK/AP1, JAK/STAT, MAPKKK1-JNK, Bcl-2, p38-MAPK[63,64,66,69] kB, c-Jun/activator protein 1 (AP-1), cyclin D1, CDK-4, PI3K/mTOR/ETS2[76][77][78][79] 6.Gastric cancer, colon cancer, liver cancer and fibrosarcoma Bcl-2, PARP, Caspase-3, NF-kB, Caspase-9, HSP70-TLR4, IL-6, and IL-11[81][82][83]85] ...
Cancer is a devastating disease condition and is the second most common etiology of death globally. After decades of research in the field of hematological malignancies and cellular therapeutics, we are still looking for therapeutic agents with the most efficacies and least toxicities. Curcumin is one of the cancer therapeutic agents that is derived from the Curcuma longa (turmeric) plant, and still in vitro and in vivo research is going on to find its beneficial effects on various cancers. Due to its potency to affect multiple targets of different cellular pathways, it is considered a promising agent to tackle various cancers alone or in combination with the existing chemotherapies. This review covers basic properties, mechanism of action, potential targets (molecules and cell-signaling pathways) of curcumin, as well as its effect on various solid and hematological malignancies.
... In our studies, while JNK and ERK 1/2 inhibition significantly attenuated PXR-mediated CYP3A4 luciferase activity, p-38 inhibition showed no significant change. Curcumin, which can inhibit both JNK (IC50: 5 µM) and ERK (IC50: 20 µM) (Chen and Tan, 1998), also attenuated PXR-mediated CYP3A4 luciferase activity. ...
... al. reported that the induction of CYP3A4 mRNA and promoter activity by the VDR ligand, 1,25(OH)2D3 was attenuated in the presence of a JNK inhibitor, while ERK or p-38 inhibition had no effect (Yasunami et al, 2004). SP is one of the most widely used and extensively studied ATP-competitive JNK inhibitors (Zhang et al, 2012;Davies et al, 2012;Bogoyevitch et al, 2011;Feng et al, 2013;Koch et al, 2014), and curcumin has been shown to inhibit JNK signaling pathways (Suh et al, 2007;Chen et al, 1998); however, these compounds can target additional pathways to affect CYP3A4 expression. For example, both SP and curcumin can activate aryl hydrocarbon receptor (AHR) Bachelda et al, 2008;Ciolino et al, 1998;Mohammadi-Bardbori et al, 2012); recent studies have shown that AHR activation decreases basal and RIF-induced CYP3A4 expression in HepaRG cells (Rasmussen et al, 2017). ...
Cytochrome P450 (CYP) 3A4 is the most abundant drug metabolizing enzyme and is responsible for the metabolism of ~50% of clinically available drugs. Induction of CYP3A4 impacts the disposition of its substrates and leads to harmful clinical consequences such as failure of therapy. In order to prevent such undesirable consequences, molecular mechanisms of regulation of CYP3A4 need to be fully understood. CYP3A4 induction is primarily regulated by the xenobiotic nuclear receptor, pregnane-X-receptor (PXR). After ligand binding, PXR is transported to the nucleus, where it binds to the CYP3A4 promoter and induces its gene expression. It is known that PXR function is modulated by phosphorylation(s) by multiple kinases. In this study, we determined the role of the c-Jun-N-terminal kinase (JNK) in PXR-mediated induction of CYP3A4 enzyme in vitro. HepG2 cells were transfected with CYP3A4 luciferase and PXR plasmids, followed by treatment with JNK inhibitor (SP600125; SP) and PXR activators, rifampicin (RIF) or hyperforin. Our results indicate that SP treatment significantly attenuated PXR-mediated induction of CYP3A4 reporter activity, as well as gene expression and enzyme activity. JNK knockdown by siRNA (targeting both JNK 1 and 2) also attenuated CYP3A4 induction by RIF. Interestingly, SP treatment attenuated JNK activation by RIF. Furthermore, treatment with RIF increased PXR nuclear levels and binding to the CYP3A4 promoter; SP attenuated these effects. This study shows that JNK is a novel mechanistic regulator of CYP3A4 induction by PXR.
... Copyright© Raut V and Bhandari S. demonstrated to block IL-1stimulated gene expression of a neutrophil chemotactic peptide, interleukin-8 (IL-8), as well as lipopolysaccharide-induced IL-1 and TNF production by a human monocyte protein macrophage cell line [61,62]. In addition, curcumin has been shown to inhibit the proinflammatory l Th1 cytokine profile, and NF-kappaB activation pathway [63][64][65]. Curcumin also suppresses MMP overexpression, presumably due to its ability to inhibit protein kinase C [66]. ...
Many natural medicinal plants have been utilised to cure a range of disorders since ancient times and are regarded as a possible source of phytochemicals for the creation of new medications. One of these is curcumin, a bioactive molecule that is easily available, affordable, and harmless. It is a vital, naturally occurring, highly lipophilic and phenolic chemical. Curcumin (diferuloylmethane), a low-molecular-weight chemical derived from the roots of Curcuma longa L. (family Zingiberaceae), is mostly used as a curry spice, flavouring agent, insect repellant, food colouring agent, traditional medication, and cosmetic component. Curcumin is a tautomeric molecule that exists in organic solvents as an enolic form and in water as a keto form. Though inconclusive, epidemiological findings show that turmeric intake may lessen the incidence of some malignancies and provide other beneficial biological benefits in people. Turmeric’s biological benefits have been linked to its ingredient curcumin, which has been extensively researched for its anti-inflammatory, anti-ulcer, anti-diabetic, anti-viral, antioxidant, wound healing, and anti-cancer properties. Curcumin is a low-toxicity nutraceutical that has been utilised successfully in a variety of medical ailments, as discussed in this article.
... [2] In addition to this problem, antibiotics are sometimes associated with adverse effects on the host including hypersensitivity, immune-suppression and allergic reactions. [3] Keeping in mind the basic concept of Ayurveda, Ari Healthcare Pvt. Ltd., has developed "AHPL/AYTAB/1514" tablet i.e. marketed as Amarantha CurQmint Tablet for effective management of halitosis, cough, common cold and sore throat. ...
In modern medicine, adverse effects, resistance and expensiveness associated with the use of antibiotics are of a great concern. There is an urge for development of prevention and treatment options that are natural, safe, effective and economical. Ari Healthcare Pvt. Ltd. has conceptualized and developed a formulation called "Amarantha CurQmint Tablet" for treatment of halitosis, cough, common cold and sore throat. In the present study, Amarantha CurQmint Tablet was tested for anti-microbial activity against oral cavity pathogens such as E. coli, Staph. auerus and Candida albicans in comparison with marketed product, methanol and standard drug i.e. Chlorhexidine. Various concentrations of Amarantha CurQmint Tablet i.e. 2%, 3% and 4% showed more zone of inhibition (of 25 mm each) against Staph. auerus than Methanol (11 mm) and Chlorhexidine (19 mm). Also, 3% and 4% concentrations of Amarantha CurQmint Tablet showed more zone of inhibition (of 23 mm and 25 mm respectively) against E. coli than Methanol (11 mm) and Chlorhexidine (19 mm). All concentrations of Amarantha CurQmint Tablet i.e. concentration of 1%, 2%, 3% and 4% showed more zone of inhibition (of 20 mm, 25 mm, 25 mm, and 25 mm, respectively) against Candida albicans than Methanol (11 mm) and standard drug Chlorhexidine (19 mm). The zones of inhibitions of Marketed Product
... Apoptosis is intimately linked to the phosphorylation of c-Jun, which is predominantly activated by the active JNK. According to several types of research, Curcumin may be able to prevent cytokine and phorbol ester-induced JNK activation, cjun phosphorylation, and AP-1 transcriptional activity [117,118]. This pathway can be inhibited by curcumin and substituted curcumin moiety in cancer cells (Fig. 12). ...
The uncontrolled growth and spread of aberrant cells characterize the group of disorders known as cancer. According to GLOBOCAN 2022 analysis of cancer patients in either developed countries or developing countries the main concern cancers are breast cancer, lung cancer, and liver cancer which may rise eventually. Natural substances with dietary origins have gained interest for their low toxicity, anti-inflammatory, and antioxidant effects. The evaluation of dietary natural products as chemopreventive and therapeutic agents, the identification, characterization, and synthesis of their active components, as well as the enhancement of their delivery and bioavailability, have all received significant attention. Thus, the treatment strategy for concerning cancers must be significantly evaluated and may include the use of phytochemicals in daily lifestyle. In the present perspective, we discussed one of the potent phytochemicals, that has been used over the past few decades known as curcumin as a panacea drug of the "Cure-all" therapy concept. In our review firstly we included exhausted data from in-vivo and in-vitro studies on breast cancer, lung cancer, and liver cancer which act through various cancer-targeting pathways at the molecular level. Now, the second is the active constituent of turmeric known as curcumin and its derivatives are enlisted with their targeted protein in the molecular docking studies, which help the researchers design and synthesize new curcumin derivatives with respective implicated molecular and cellular activity. However, curcumin and its substituted derivatives still need to be investigated with unknown targeting mechanism studies in depth.
... c-Jun N-terminal kinases) oraz czynników transkrypcyjnych AP-1 (ang. activator protein 1) odpowiedzialnych za regulację aktywności białek prozapalnych [58]. Hamowanie kaspaz w odpowiedzi na kurkuminę obserwowane jest również w obrębie uszkodzonego rdzenia kręgowego poprzez zahamowanie utraty neuronów i poprawę funkcji lokomotorycznych zwierzęcia [57]. ...
The development of methods used in molecular biology has allowed a milestone in medical and pharmaceutical sciences. Progress has also been made in the field of pharmacognosy, which places substances of natural origin contained in plant raw materials at the center of attention. The beneficial effects of some of them have been known for years, while scientific evidence of their health-promoting properties was lacking for a long time. This was also the case with curcumin and the long road from its isolation in pure form in 1842 to the knowledge of its chemical structure in 1910. Due to the chemical properties of the molecule, curcumin is attributed with many health-promoting properties. These affect many organ systems including the skin, visual pathway, respiratory system, circulatory system, digestive system and nervous system. One of the complications that follow nerve damage is the loss of locomotor function in the animal and the development of inflammation within it. Curcumin has anti-inflammatory properties. This is confirmed by its inhibition of nuclear factor κB, a mediator in inflammatory processes. In addition, a very important field associated with neuronal dysfunction is the aging process. This is caused, among other things, by the presence of reactive oxygen species. The neuroprotective effect of curcumin allows to reduce their concentration caused by the accumulation of mutations within the mitochondrial DNA. The beneficial effect on the nervous system is due to the penetration of curcumin across the blood-brain barrier. However, its poor solubility significantly limits the therapeutic properties resulting from curcumin supplementation. Methods are currently being developed to increase its bioavailability using nanoparticles.
... Curcumin, derived from Curcuma longa, has been shown to have anticancer effects. Different pathways such as nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), epidermal growth factor (EGF), and glycogen synthase kinase 3 beta (GSK-3β) have been shown to be targeted by curcumin [267][268][269][270][271][272][273]. Curcumin treatment significantly abolished the nucleolar localization of TP53INP2 in the cells and prevented the activation of the mechanistic target of rapamycin complex 1 (mTORC1) by inhibiting mTOR lysosomal localization [56]; and by impairing the assembly of RNA Pol I preinitiation complex at rDNA promoters by inhibiting the binding of UBF and Pol R1A to the promoter regions of rDNA, thereby leading to a decrease in the activity of the rDNA promoter [56]. ...
Introduction:
The ribosome is a ribonucleoprotein organelle responsible for protein synthesis, and its biogenesis is a highly coordinated process that involves many macromolecular components. Any acquired or inherited impairment in ribosome biogenesis or ribosomopathies is associated with the development of different cancers and rare genetic diseases. Interference with multiple steps of protein synthesis has been shown to promote tumor cell death.
Areas covered:
We discuss the current insights about impaired ribosome biogenesis and their secondary consequences on protein synthesis, transcriptional and translational responses, proteotoxic stress, and other metabolic pathways associated with cancer and rare diseases. Studies investigating the modulation of different therapeutic chemical entities targeting cancer in in vitro and in vivo models have also been detailed.
Expert opinion:
Despite the association between inherited mutations affecting ribosome biogenesis and cancer biology, the development of therapeutics targeting the essential cellular machinery has only started to emerge. New chemical entities should be designed to modulate different checkpoints (translating oncoproteins, dysregulation of specific ribosome-assembly machinery, ribosomal stress, and rewiring ribosomal functions). Although safe and effective therapies are lacking, consideration should also be given to using existing drugs alone or in combination for long-term safety, with known risks for feasibility in clinical trials and synergistic effects.
... We previously engineered Arabidopsis to incorporate the alternative monomer curcumin into the lignin polymer (Oyarce et al., 2019). Curcumin, a metabolite naturally occurring in Curcuma longa (turmeric), has two phenolic rings linked by a seven carbon chain containing two conjugated carbonyl functionalities ( Figure 1A; Chen and Tan, 1998). The conjugated 9-carbonyl function at the para-position of the two phenolic hydroxyl functions eases the cleavage of 8-O-4 inter-unit linkages under alkaline conditions (Oyarce et al., 2019). ...
Lignocellulosic biomass is recalcitrant toward deconstruction into simple sugars mainly due to the presence of lignin. By engineering plants to partially replace traditional lignin monomers with alternative ones, lignin degradability and extractability can be enhanced. Previously, the alternative monomer curcumin has been successfully produced and incorporated into lignified cell walls of Arabidopsis by the heterologous expression of DIKETIDE-CoA SYNTHASE (DCS) and CURCUMIN SYNTHASE2 (CURS2). The resulting transgenic plants did not suffer from yield penalties and had an increased saccharification yield after alkaline pretreatment. Here, we translated this strategy into the bio-energy crop poplar. Via the heterologous expression of DCS and CURS2 under the control of the secondary cell wall CELLULOSE SYNTHASE A8-B promoter (ProCesA8-B), curcumin was also produced and incorporated into the lignified cell walls of poplar. ProCesA8-B:DCS_CURS2 transgenic poplars, however, suffered from shoot-tip necrosis and yield penalties. Compared to that of the wild-type (WT), the wood of transgenic poplars had 21% less cellulose, 28% more matrix polysaccharides, 23% more lignin and a significantly altered lignin composition. More specifically, ProCesA8-B:DCS_CURS2 lignin had a reduced syringyl/guaiacyl unit (S/G) ratio, an increased frequency of p-hydroxyphenyl (H) units, a decreased frequency of p-hydroxybenzoates and a higher fraction of phenylcoumaran units. Without, or with alkaline or hot water pretreatment, the saccharification efficiency of the transgenic lines was equal to that of the WT. These differences in (growth) phenotype illustrate that translational research in crops is essential to assess the value of an engineering strategy for applications. Further fine-tuning of this research strategy (e.g., by using more specific promoters or by translating this strategy to other crops such as maize) might lead to transgenic bio-energy crops with cell walls more amenable to deconstruction without settling in yield.
... Kurkumin merupakan salah satu senyawa aktif pada rimpang temu putih yang merupakan senyawa turunan fenolik (polifenol) yang termasuk ke dalam kelompok kurkuminoid, senyawa kurkumin ini berkhasiat sebagai antikanker (Chen dan Tan, 1998 Berdasarkan hasil pengujian nilai rata-rata angka kapang khamir pada bubuk temu putih dalam kantung teh celup berkisar antara 2,33 x 10 2 koloni/g sampai dengan 4,67 x 10 2 koloni/g (Tabel 4). Persyaratan maksimal total mikroba pada syarat mutu kategori teh kering dalam kemasan sesuai SNI 3836:2013adalah 5 x 10 2 koloni/g sehingga sampel bubuk temu putih dalam kantung teh celup memenuhi syarat mutu kategori teh kering dalam kemasan persyaratan mutu minuman tradisional dengan nilai total mikroba yang tertinggi yaitu pada hari ke-28 sebesar 4,67 x 10 2 koloni/g dan nilai total mikroba yang terendah yaitu pada hari ke-0 sebesar 2,33 x 10 2 koloni/g. ...
The zedoary rizome (Curcuma Zedoaria (Berg) Roscoe) has a curcumin compound, which is one of the active compounds in the rhizome. Fresh zedoary rizome is easily damaged so it is often preserved by drying it. This research was aimed to determine the microbial contamination of the zedoary rizome packed in tea bags during storage in a room temperature. This research used Completely Randomized Design with storage at room temperature as a treatments, which consisted of 5 levels: 0 days, 7 days, 14 days, 21 days and 28 days. With 3 replication to obtain 15 units of sample. Data were analyzed by Analysis of Variance (ANOVA) and followed by multiple comparison test of Duncan Multiple Range Test (DMRT). The result showed that during storage, there were carasteristics changes in zedoary rizome powder such as increased of total plate count, total mold and yeast count, coliform and water content, but there was no E. coli growth. The zedoary rizome powder in tea bags during storage on days 0 to 28 fulfilled the requirements for food safety because microbial growth is below the maximum limit of Indonesian National Standard (SNI), but the water content on days 14 to 28 does not meet the SNI requirements.
... JNK/c-Jun activation and Tau protein level were reduced by curcumin treatment, while ERK activity was significantly increased as already reported in different models of retinopathies [52,55,56]. Ten micromolar of curcumin was able to prevent the JNK activation probably for its direct antagonist effect on this kinase [57] especially reducing the JNK3 pro-apoptotic isoform, which can also explain the prevention of the autophagy pathway activation [58]. Unexpectedly, an increased JNK activity was observed after 5 μM of curcumin treatment leading us to hypothesize that curcumin lower concentration is not able to act on JNK pathway, but it may induce the upstream ERK cascade activation. ...
Retinal ganglion cell (RGC) loss is a pathologic feature common to several retinopathies associated to optic nerve damage, leading to visual loss and blindness. Although several scientific efforts have been spent to understand the molecular and cellular changes occurring in retinal degeneration, an effective therapy to counteract the retinal damage is still not available. Here we show that eyeballs, enucleated with the concomitant optic nerve cut (ONC), when kept in PBS for 24 h showed retinal and optic nerve degeneration. Examining retinas and optic nerves at different time points in a temporal window of 24 h, we found a thinning of some retinal layers especially RGC’s layer, observing a powerful RGC loss after 24 h correlated with an apoptotic, MAPKs and degradative pathways dysfunctions. Specifically, we detected a time-dependent increase of Caspase-3, -9 and pro-apoptotic marker levels, associated with a strong reduction of BRN3A and NeuN levels. Importantly, a powerful activation of JNK, c-Jun, and ERK signaling (MAPKs) were observed, correlated with a significant augmented SUMO-1 and UBC9 protein levels. The degradation signaling pathways was also altered, causing a significant decrease of ubiquitination level and an increased LC3B activation. Notably, it was also detected an augmented Tau protein level. Curcumin, a powerful antioxidant natural compound, prevented the alterations of apoptotic cascade, MAPKs, and SUMO-1 pathways and the degradation system, preserving the RGC survival and the retinal layer thickness. This ex vivo retinal degeneration model could be a useful method to study, in a short time window, the effect of neuroprotective tools like curcumin that could represent a potential treatment to contrast retinal cell death.
... The following references appear in the Supplemental Information: Bondeva et al. (2002); Chatila et al. (1989); Chen and Tan (1998); Elzi et al. (2001) with a pair of barcoding proteins and one biosensor, using a total of 0.75 mg plasmid per well. The next day, cells were harvested from each well with Accutase (Corning, 25-058-CI) and mixed together. ...
Genetically encoded fluorescent biosensors are powerful tools for monitoring biochemical activities in live cells, but their multiplexing capacity is limited by the available spectral space. We overcome this problem by developing a set of barcoding proteins that can generate over 100 barcodes and are spectrally separable from commonly used biosensors. Mixtures of barcoded cells expressing different biosensors are simultaneously imaged and analyzed by deep learning models to achieve massively multiplexed tracking of signaling events. Importantly, different biosensors in cell mixtures show highly coordinated activities, thus facilitating the delineation of their temporal relationship. Simultaneous tracking of multiple biosensors in the receptor tyrosine kinase signaling network reveals distinct mechanisms of effector adaptation, cell autonomous and non-autonomous effects of KRAS mutations, as well as complex interactions in the network. Biosensor barcoding presents a scalable method to expand multiplexing capabilities for deciphering the complexity of signaling networks and their interactions between cells.
... Studies have found that JNK1 mediates cell survival while JNK2 contributes to apoptosis however, the opposite has also been observed (Arbour et al., 2002;Liu et al., 2004). Hence, through inhibition of VEGF, curcumin may have indirectly upregulated the pro-apoptotic JNK protein levels since JNK is not a direct target of curcumin (Chen and Tan, 1998;Lin et al., 2009). Lastly, the effects of curcumin was examined in an in vivo cancer model involving transgenic mice expressing VEGF-A (Tung et al., 2011). ...
Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo . This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.
... Curcumin, a natural ingredient derived from Curcuma longa, has a potent anticancer effect on various types of cancers, including multiple myeloma, breast cancer, colon cancer, and pancreatic cancer [22][23][24][25][26][27]. Many different pathways, such as nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), epidermal growth factor receptor (EGFR) and glycogen synthase kinase 3 beta (GSK-3β), have been reported to be targeted by curcumin to combat cancer cells [22,[25][26][27][28][29][30]. Despite the broad interest of curcumin for the anticancer potential, the controversial and complicated effects seem to restrict the use of curcumin as an anticancer drug. ...
Ribosomal DNA (rDNA) transcription drives cell growth and cell proliferation via the product ribosomal RNA (rRNA), the essential component of ribosome. Given the fundamental role of rRNA in ribosome biogenesis, rDNA transcription has emerged as one of the effective targets for a number of human diseases including various types of cancers. In this study, we identify curcumin, an ancient drug, as a novel natural inhibitor of rDNA transcription. Curcumin treatment impairs the assembly of the RNA polymerase I preinitiation complex at rDNA promoters and represses rDNA promoter activity, which leads to the decrease of rRNA synthesis. In addition, curcumin treatment stimulates autophagosome formation and promotes autophagic degradation in cells. Mechanistically, curcumin inactivates the mechanistic target of rapamycin complex 1 (mTORC1), the upstream regulator of rDNA transcription and autophagy induction, by inhibiting mTOR lysosomal localization. Functionally, curcumin treatment inhibits protein synthesis, cell growth and cell proliferation. Taken together, these findings identify curcumin as an effective inhibitor of rDNA transcription and provide novel mechanisms for the anticancer properties of curcumin.
Abbreviations:
Atg: autophagy-related; GFP: green fluorescent protein; LAMP2: lysosomal associated membrane protein 2; LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; mTORC1: mechanistic target of rapamycin complex 1; rDNA: ribosomal DNA; rRNA: ribosomal RNA; TP53INP2: tumor protein p53 inducible nuclear protein 2.
... The anti-cancer activities of this compound are exerted through affecting several pro-cancerous factors (Tomeh et al., 2019). These include downregulation of transcription factors like NF-κB, AP-1; pro-metastatic factors like uPA, MMPs; growth factor receptors like EGFR, HER2; cell signaling components like protein tyrosine kinases, protein serine/threonine kinases (Aggarwal et al., 2003) including c-Jun N-terminal kinase (Chen and Tan, 1998). Apart from these, curcumin has been found to protect DNA damage by carcinogens, promote "mild but yet significant activation of apoptosis", and inhibit angiogenesis, invasion and metastasis. ...
... 61 Esta inhibición es mediada por la vía de señalización de las proteínas cinasas activadas por mitógenos (MAP cinasas), lo que suspende, a su vez, la expresión de citocinas proinflamatorias. 9, 55,62,63 El potencial farmacológico como antiinflamatorio de la curcumina ha despertado el interés en varias áreas de investigación con el fin desarrollar terapias conjuntas que puedan incrementar su efectividad; por ejemplo, el preparado comercial de curcumina contiene, además de la curcumina (Cur), demetoxicurcumina (DMC) y bisdemetoxicurcumina (BDMC); se encontró que estos compuestos en conjunto son más potentes que cada uno por separado. 64 Por otro lado, el uso de las nanopartículas de curcumina para tratar la inflamación redujo significativamente la secreción de TNF-α activado por macrófagos J774 in vitro, y en tejidos inflamados. ...
Curcumin is a substance derived from the plant Curcuma longa and
one that has been attributed a range of therapeutic eff ects. In dental
practice, curcumin has not only been found to help with pain control, but
has also been eff ective against periodontitis, stomatitis, and pediatric
mucositis. Controlling pain and infl ammation are both very important
aspects of most dental treatments. The search for more effi cient and
eff ective analgesic and anti-infl ammatory alternatives with fewer
side eff ects compared to those currently used is one of the greatest
challenges for biomedical science. This review presents some of the
scientifi c evidence of the eff ects of curcumin, both as an analgesic and
an anti-infl ammatory agent, in order to establish the foundations for
further clinical and basic science studies that will provide a greater
understanding of the cellular, biochemical, molecular, physiological,
and pharmacological processe
... Curcumin is a potent anti-inflammatory and anti-cancer agent ( Figure 1) [36]. Molecular studies have shown that the antiinflammatory effects of curcumin result from inhibition of the AP-1 and NF-κB pathways: these signalling pathways are activated in response to IL-1β stimulation and activate Cox-2, a key inflammatory mediator involved in downstream activation and release of matrix-degrading MMPs [37][38][39][40][41]. Resveratrol (trans-3,4' -trihydroxystilbene) is a polyphenolic phytoalexin ( Figure 1) that demonstrates anti-inflammatory, anti-tumour, immunomodulatory, cardioprotective, anti-oxidative and chemopreventive capabilities [13,[42][43][44][45][46][47]. ...
Introduction Currently available treatments for osteoarthritis (OA) are restricted to nonsteroidal anti-inflammatory drugs, which exhibit numerous side effects and are only temporarily effective. Thus novel, safe and more efficacious anti-inflammatory agents are needed for OA. Naturally occurring polyphenolic compounds, such as curcumin and resveratrol, are potent agents for modulating inflammation. Both compounds mediate their effects by targeting the NF-κB signalling pathway.
... As shown in Figure 4(c), curcumin inhibits the activation of AP-1 via a direct interaction with AP-1 DNA-binding motif [195,196]. Curcumin also inhibits the activation of AP-1 as well as JNK which was induced by tumour promoters and carcinogens [197,198]. Curcumin suppresses tumour progression of AP-1 in both ADPC (PC-3) and AIPC (LNCaP) cells, which indicated by the reduced colony forming ability in soft agar [93,104]. Other studies reported that curcumin exhibits its anti-cancer effects by significantly impeding AP-1 protein in AIPC (PC-3) cells [109]. ...
Prostate cancer (PCa) is a heterogeneous disease and ranked as the second leading cause of cancer-related deaths in males worldwide. The global burden of PCa keeps rising regardless of the emerging cutting-edge technologies for treatment and drug designation. There are a number of treatment options which are effectively treating localised and androgen-dependent PCa (ADPC) through hormonal and surgery treatments. However, over time, these cancerous cells progress to androgen-independent PCa (AIPC) which continuously grow despite hormone depletion. At this particular stage, androgen depletion therapy (ADT) is no longer effective as these cancerous cells are rendered hormone-insensitive and capable of growing in the absence of androgen. AIPC is a lethal type of disease which leads to poor prognosis and is a major contributor to PCa death rates. A natural product-derived compound, curcumin has been identified as a pleiotropic compound which capable of influencing and modulating a diverse range of molecular targets and signalling pathways in order to exhibit its medicinal properties. Due to such multi-targeted behaviour, its benefits are paramount in combating a wide range of diseases including inflammation and cancer disease. Curcumin exhibits anti-cancer properties by suppressing cancer cells growth and survival, inflammation, invasion, cell proliferation as well as possesses the ability to induce apoptosis in malignant cells. In this review, we investigate the mechanism of curcumin by modulating multiple signalling pathways such as androgen receptor (AR) signalling, activating protein-1 (AP-1), phosphatidylinositol 3-kinases/the serine/threonine kinase (PI3K/Akt/mTOR), wingless (Wnt)/ß-catenin signalling, and molecular targets including nuclear factor kappa-B (NF-κB), B-cell lymphoma 2 (Bcl-2) and cyclin D1 which are implicated in the development and progression of both types of PCa, ADPC and AIPC. In addition, the role of microRNAs and clinical trials on the anti-cancer effects of curcumin in PCa patients were also reviewed.
... 312 Curcumin suppresses AP-1, ATF2, c-Jun, p-JNK, and MAPK, further inhibiting NF-κB activation. 313,314 Resveratrol alone and combination with curcumin blocked the TNF-α-dependent NF-κB pathway in adipocytes that further reduce cytokine expression. [315][316][317] Curcumin also blocks NF-κB and Wnt/β-catenin signaling pathways in cervical cancer. ...
Most chronic diseases, caused by lifestyle factors, appear to be linked to inflammation. Inflammation is activated mechanistically, and nuclear factor-κB (NF-κB) is a significant mediator. NF-κB, one of the most studied transcription factors, was first identified in the nucleus of B lymphocytes almost three decades ago. This protein has a key function in regulating the human immune system, and its dysregulation has been linked to many chronic diseases including asthma, cancer, diabetes, rheumatoid arthritis, inflammation, and neurological disorders. Physiologically, many cytokines have been discovered that activate NF-κB. Pathologically, environmental carcinogens such as cigarette smoke, radiation, bacteria, and viruses can also activate this transcription factor. NF-κB activation controls expression of more than 500 genes, and most are deleterious to the human body when dysregulated. More than 70,000 articles have been published regarding NF-κB. This review emphasizes the upside and downside of NF-κB in normal and disease conditions and the ways in which we can control this critical transcription factor in patients.
... The dietary pigment curcumin is a potent inhibitor of JNK activation by various agonists, including PMA plus ionomycin, anysomycin, UV-C, and TNF␣. 78 To test whether curcumin could also inhibit JNK activation in response to MNNG, C2C12 cells were pretreated with curcumin before their stimulation with MNNG, and cell extracts were immunoprecipitated with an antibody against JNK1, and the enzymatic activity assessed using GST-cJun as the substrate. As shown in Figure 4, activation of JNK activity after a 1-hour treatment with MNNG was completely abrogated by curcumin pretreatment, thus providing a useful tool for blocking JNK activation by this alkylating agent. ...
The monofunctional alkylating agent N-methyl-N-nitro-N-nitrosoguanidine (MNNG) is a widespread environmental carcinogen that causes DNA lesions, leading to cell death. However, MNNG can also trigger a cell-protective response by inducing the expression of DNA repair/transcription-related genes. We demonstrate that the urokinase-type plasminogen activator (uPA) gene product, a broad spectrum extracellular protease to which no DNA repair function has been assigned, is transcriptionally induced by MNNG in C2C12 and NIH3T3 cells. This induction required an AP1-enhancer element located at −2.4 kilobase (kb), because it was abrogated by deletion of this site. MNNG was found to induce the activation of JNK/SAPK and p38 mitogen-activated protein kinases (MAPKs). Accordingly, we attempted to assess the contribution of each of these MNNG-inducible MAPKs to uPA gene induction by this alkylating agent. Coexpression of dominant negative versions of kinases of the JNK pathway, such as catalytically inactive forms of MEKK1, MKK7, and JNKK, and of cytoplasmic JNK-inhibitor JIP-1, as well as treatment of cells with curcumin (which blocks JNK activation by MNNG), inhibited MNNG-induced uPA transcriptional activity. In contrast, neither dominant negative MKK6 nor SB203580, which specifically inhibit p38 MAP kinase activation, abrogated the MNNG-induced effect. Taken together, our results show that the JNK signaling pathway links external MNNG stimulation and AP1-dependent uPA gene expression, providing the first functional dissection of a transcription-coupled signal transduction pathway for MNNG.
... The extracellular matrix is another factor that plays an essential role in regulating the behavior of neuronal progenitors. Changes in the membrane composition and the deletion of several genes cause corneal abnormalities and defects in cell (3). Therefore, exogenous compounds can be used to study changes in the behavioral patterns of neuronal progenitor cells as well as in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Multiple Sclerosis (MS), and in congenital defects of CNS development (4,5). ...
Background: Oxidative stress and neuroinflammation have found to be implicated in several neurodegenerative disorders (ND). Neuroprotection against oxidative agents has been proposed as a therapy on the basis that it might prevent neuroinflammation. Curcumin is an anti-oxidant with anti-inflammatory properties which has been proposed to be used as a therapeutic agent in ND.
Aim: In this study, we examined the neuroprotective effect of curcumin on neural stem cells (NSCs) exposed to H2O2 as an oxidative injury model.
Methods: After culturing NSCs, they were co-treated with curcumin and H2O2, after which their effects were tested on cell viability using MTT assay.
Results: Our results indicated that the high concentration of H2O2 significantly promoted cell death. Specifically, after using 250 µM of H2O2, the mortality increased dramatically in comparison with the control groups. On the other hand, the presence of curcumin encouraged cell survival of NSCs treated with H2O2.
Conclusion: Our result showed that curcumin has a protective effect on NSCs against H2O2 and it may ameliorate the mortality rate induced by H2O2.
... This agent modulate various molecular targets such as growth factors, transcription factors and their receptors, enzymes, cytokines, apoptosis and genes regulating cell proliferation [226]. Curcumin prevents the activation of transcriptional factors, NF-kB signaling [227], pancreatic cancer [228], STAT signaling [229], AP-1 signaling [230], Notch-1 signaling [231], Wnt/beta-catenin signaling [232,233], CBP signaling [234,235], Egr-1 [236,237], inflammatory cytokines [238][239][240], the activity of interleukins [241][242][243][244][245][246], the activity of multiple protein kinases [247,248], FPTase [249], the appearance of vas-cular endothelial growth factor [250,251] and anti-apoptotic proteins [252]. Besides, it suppresses the activity of tyrosine protein kinases, serine-threonine [253] and expression of matrix metalloproteinase (MMP)-9 and inducible nitric oxide synthase (iNOS) [254], EGFR1 activity [230], HER-2 activity [255], FGF-mediated cell [256], DGF-mediated cell signaling [257,258], androgen receptors (AR), AR-related co-factors [259], expression of estrogen receptor (ER) [260], expression of adhesion molecules [261,262] and expression of cyclin D1 [226,230]. ...
... Curcumin, a component of Curcuma longa, has been shown to inhibit phosphorylation of EGF receptor in NIH3T3 cells. Curcumin has also been shown to inhibit JNK activity in MCF-7 and Jurkat cells (Chen and Tan, 1998 (2008) have reported that curcumin causes a significant increase in the production of reactive oxygen species, which further led to sustained extracellular signal-regulated kinase (ERK) 1/2 activation. ...
... The activator proteins play a key role in the process of tumorigenesis owing to their ability to transform cancer cells (Karin et al., 1997). The inhibition of tumorigenic factors that can activate AP-1 and JNK has been observed in response to curcumin treatment (Huang et al., 1991;Chen and Tan, 1998). Curcumin induced inhibition of AP-1 was a result of its direct interface with AP-1 DNA binding motif (Bierhaus et al., 1997). ...
Curcumin (a polyphenolic compound in turmeric) is famous for its potent anti-inflammatory, anti-oxidant, and anti-cancer properties, and has a great potential to act as an epigenetic modulator. The epigenetic regulatory roles of curcumin include the inhibition of DNA methyltransferases (DNMTs), regulation of histone modifications via the regulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs), regulation of microRNAs (miRNA), action as a DNA binding agent and interaction with transcription factors. These mechanisms are interconnected and play a vital role in tumor progression. The recent research has demonstrated the role of epigenetic inactivation of pivotal genes that regulate human pathologies such as cancers. Epigenetics helps to understand the mechanism of chemoprevention of cancer through different therapeutic agents. In this regard, dietary phytochemicals, such as curcumin, have emerged as a potential source to reverse epigenetic modifications and efficiently regulate the expression of genes and molecular targets that are involved in the promotion of tumorigenesis. The curcumin may also act as an epigenetic regulator in neurological disorders, inflammation, and diabetes. Moreover, curcumin can induce the modifications of histones (acetylation/deacetylation), which are among the most important epigenetic changes responsible for altered expression of genes leading to modulating the risks of cancers. Curcumin is an effective medicinal agent, as it regulates several important molecular signaling pathways that modulate survival, govern anti-oxidative properties like nuclear factor E2-related factor 2 (Nrf2) and inflammation pathways, e.g., nuclear factor kappa B (NF-κB). Curcumin is a potent proteasome inhibitor that increases p-53 level and induces apoptosis through caspase activation. Moreover, the disruption of 26S proteasome activity induced by curcumin through inhibiting DYRK2 in different cancerous cells resulting in the inhibition of cell proliferation opens up a new horizon for using curcumin as a potential preventive and treatment approach in proteasome-linked cancers. This review presents a brief summary of knowledge about the mechanism of epigenetic changes induced by curcumin and the potential effects of curcumin such as anti-oxidant activity, enhancement of wound healing, modulation of angiogenesis and its interaction with inflammatory cytokines. The development of curcumin as a clinical molecule for successful chemo-prevention and alternate therapeutic approach needs further mechanistic insights.
... which increasingly being mentioned in health journals and scientific papers as research on it grows. [1,2] Recent studies suggest that it may help to ease digestive discomfort, reduce inflammation and hereby to increase resistance to disease. [2] Oral pathogenic bacteria are involved in periodontal, vascular diseases [4] , and respiratory infections. ...
Oral pathogenic gram-positive bacteria, Streptococcus oralis, Streptococcus sanguis, are caused severe human diseases with complications, including rheumatic fever, sepsis, severe soft-tissue invasion, and toxic-shock-like syndrome (TSLS). Whereas, Streptococcus mutants (Strept. mutans), described a key causative agent of caries and infective endocarditis. Therefore, the aim of this study was to evaluate the inhibitory effect of Curcumin on Strept. mutans and Streptococcus oralis, Streptococcus sanguis growth in comparison with the antibiotic Ciprofloxacin using well diffusion method. Minimum Inhibitory Concentration (MICs) showed that curcumin-mediated growth inhibition of Strept. mutans and, Streptococcus oralis, Streptococcus sanguis. Results showed that curcumin significantly inhibited the activity of Strept. mutans and Strept. pyogenes growth with inhibition zones, 9.7mm and 10.2 mm, respectively while the inhibition zone of Ciprofloxacin 15.52mm to 13.4mm against Strept. mutans, Streptococcus oralis, Streptococcus sanguis respectively. The antibacterial activity of curcumin on Strept. Mutans, Streptococcus oralis, and Streptococcus sanguis growth suggests that the curcumin may be useful for controlling dental biofilms, subsequently dental caries formation. This study provides significant insights into the therapeutic effect of curcumin against pathogenic gram positive bacteria, suggesting its potential as an alternative therapy, and opens the way for further studies on identification of novel antimicrobial targets of Curcumin.
Keywords: Curcumin, Curcuma longa, Antibacterial Activity, Minimum Inhibitory Concentration (MIC), Zone of Inhibition (ZOI).
... Recent studies have shown that curcumin, the active compound of turmeric possesses potent antioxidant and anti-inflammatory activities, have been investigated in several systems [12][13][14][15]. Curcumin can modulate several transcriptional factors [16][17][18][19][20][21][22], cytokines [23][24][25][26][27], growth factors (28)(29)(30), kinases (31)(32)(33), and other enzymes [34][35][36]. ...
Background: Diabetes has a significant impact on the impaired function of the reproductive system in the testis.
Objective: The aim of this study was to investigate the effects of curcumin from turmeric on structural changes of testicular tissues and microvasculature in STZ-induced diabetic rats.
Methods: Rats were injected with a single dose of streptozotocin (60 mg/kg BW) to induce a diabetic condition. Three days after the injection, rats with a blood sugar level > 250 mg/dl were considered diabetic. Rats were allocated to one of three groups, diabetic (DM), diabetic rats receiving curcumin (DMC) (200 mg/kg BW), and control (C). Testicular tissues were studied eight weeks after the treatment using the histological technique. Testicular microvasculature was examined using the vascular corrosion cast technique under a scanning electron microscope (SEM).
Results: The testicular tissue of DM group showed damaged seminiferous tubules, spermatocytes, and spermatids with necrosis and germ cells degeneration. Destruction of testicular arteries and veins in pampiniform plexus were demonstrated. The destroyed capillaries, arterioles, and venules demonstrated stenosis and shrinkage. The vessel diameter in all DM groups decreased. In the DMC group which received curcumin, the appearance of all seminiferous tubules, spermatogenic, and sertoli cell was normal. The reconstruction and restoration of testicular artery, pampiniform plexus, capillary network, arterioles, and venules were clear. As a result of curcumin supplementation, the standard and healthy testis microvasculature was restored. The DMC vessels diameter increased back to a quasi normal condition, particularly at the artery, arteriole, and capillary levels.
Conclusions: The results provided evident for effects of curcumin could be associated with recovering and improvement of the testicular tissues and microvasculatures in diabetic condition.
... Curcumin, a metabolite of Curcuma longa (turmeric), is characterized by two phenolic ring structures linked via a seven-carbon unsaturated aliphatic chain (Fig. 1a) 13 . The molecule has a β -diketone system, which is rapidly interconverted between its keto and enol tautomers in aqueous solution ( Fig. 1a and Supplementary Fig. 1). ...
Lignin is the main cause of lignocellulosic biomass recalcitrance to industrial enzymatic hydrolysis. By partially replacing the traditional lignin monomers by alternative ones, lignin extractability can be enhanced. To design a lignin that is easier to degrade under alkaline conditions, curcumin (diferuloylmethane) was produced in the model plant Arabidopsis thaliana via simultaneous expression of the turmeric (Curcuma longa) genes DIKETIDE-CoA SYNTHASE (DCS) and CURCUMIN SYNTHASE 2 (CURS2). The transgenic plants produced a plethora of curcumin- and phenylpentanoid-derived compounds with no negative impact on growth. Catalytic hydrogenolysis gave evidence that both curcumin and phenylpentanoids were incorporated into the lignifying cell wall, thereby significantly increasing saccharification efficiency after alkaline pretreatment of the transgenic lines by 14–24% as compared with the wild type. These results demonstrate that non-native monomers can be synthesized and incorporated into the lignin polymer in plants to enhance their biomass processing efficiency.
... These findings are underscored by another study showing the attenuating effect of curcumin on the expression and activity of TLR4 and downstream transducers in the inflammatory macrophages [101,102], as well as the expression of inflammatory cytokines in M1 macrophages, such as IL-6, IL-1b, MCP-1, and TNF-α, involved in atherosclerosis pathogenesis [87,99,103,104]. It is further supported by molecular studies which demonstrated curcumin as an antagonist that blocks the enzyme activity of TLR4, JNK, and NF-κB [90,91]. Based on the aforementioned evidence, TLR4/MAPK/NF-κB transducers are important determinants of macrophage polarization, in which inhibition of TLR4mediated pathways shifts macrophage polarization toward M2 phenotypes and suppresses M1 macrophages. ...
Accumulation of macrophages within the artery wall is an eminent feature of atherosclerotic plaques. Macrophages are influenced by various plaque microenvironmental stimuli, such as oxidized lipids, cytokines, and senescent erythrocytes, and thereby polarize into two main phenotypes called proinflammatory M1 and anti-inflammatory M2 macrophages. In the hemorrhagic zones of atheroma, upon exposure to iron, sequestration of iron by M1 macrophages results in an uncontrolled proinflammatory phenotype impairing wound healing, while M2 macrophages phagocytose both apoptotic cells and senescent erythrocytes. M1 macrophages are prominent phenotype in the unstable plaques, in which plaque shoulder contains macrophages mainly present markers of M1 phenotype, whereas the fibrous cap encompassing the necrotic lipid core content macrophages expressed markers of both M1 and M2 subtypes. The abovementioned findings suggest macrophage modulation as a potent approach for atherosclerosis therapy. Curcumin is a polyphenol dietary derived from turmeric with numerous pharmacological activities. Recent in vitro and in vivo studies have indicated that curcumin exerted lipid-lowering effects, and also can modulate function of different macrophage subsets in various macrophage-involved diseases. The current review aimed to present role of macrophage subtypes in atherosclerosis development and progression, and to understand effect of curcumin on macrophage polarization and foam cell formation in the atherosclerosis lesions. Overall, we would address important targets for macrophage modulation in atherosclerotic plaques.
... Воздействие фитонутриентов на другие каскады в составе MAPK-пути (JNK и p38) изучено в меньшей степени и характеризуется большей разнонаправленностью. Установлено, что кверцетин подавляет H 2 O 2 -индуцируемую активацию JNK-каскада, но не оказывает влияния на каскад тирозинкиназы p38 [127]. Куркумин ингибирует активацию JNK-сигнального пути, вызываемую различными стрессовыми факторами, канцерогенами и опухолевыми промоторами [128]. В клетках аденокарциномы молочной железы человека SK-BR-3 ресвератрол снижал содержание фосфорилированных форм киназ JNK и p38, таким образом подавляя сигнальные пути, активированные доцетакселом [114]. ...
... Conversely, blockage of p38 signaling had no effect. Whilst JNK has been implicated in both pro-and anti-apoptotic pathways, it appears that the duration of its activation is a critical factor in determining cell survival or apoptosis [10]. Curcumin inhibition of a consitutively activated NFkB-dependent luciferase reporter construct, accord with previous observations. ...
The leaves of Curcuma longa is commonly known as gummy gardenia/cambi gum tree. It is traditional medicinal plant grown in India, have many medicinal and therapeutic properties in diseases such as inflammatory bowel disease, pancreatitis, arthritis, and chronic anterior uveitis. This leaf extracts are found to have antioxidant, chemopreventive agents, anti-inflammatory and anti cancer activities. Curcumin is the active principle which is responsible for anticancer effects. This work was aimed to study the effect of Curcuma longa methanol extracts on HCT116 cell lines. It was found methanolic extracts of Curcuma longa leaves has phytochemical compounds having good inhibitory scavenging and anticancer activities.
... Phosphorylates AP-1 components c-Jun and ATF2 and thus regulates AP-1 transcriptional activity. Promotes β-catenin/CTNNB1 degradation and inhibits the Wnt signaling pathway [62,63]. ...
Research efforts are placing an ever increasing emphasis on identifying signal transduction pathways related to the chemopreventive activity of curcumin. Its anticarcinogenic effects are presumably mediated by the regulation of signaling cascades, including nuclear factor κB (NF-κB), activator protein 1 (AP-1), and mitogen-activated protein kinases (MAPK). By modulating signal transduction pathways, curcumin induces apoptosis in malignant cells, thus inhibiting cancer development and progression. Due to the lack of mechanistic insight in the scientific literature, we developed a novel inverse molecular docking protocol based on the CANDOCK algorithm. For the first time, we performed inverse molecular docking of curcumin into a collection of 13,553 available human protein structures from the Protein Data Bank resulting in prioritized target proteins of curcumin. Our predictions were in agreement with the scientific literature and confirmed that curcumin binds to folate receptor β, DNA (cytosine-5)-methyltransferase 3A, metalloproteinase-2, mitogen-activated protein kinase 9, epidermal growth factor receptor and apoptosis-inducing factor 1. We also identified new potential protein targets of curcumin, namely deoxycytidine kinase, NAD-dependent protein deacetylase sirtuin-1 and -2, ecto-5′-nucleotidase, core histone macro-H2A.1, tyrosine-protein phosphatase non-receptor type 11, macrophage colony-stimulating factor 1 receptor, GTPase HRas, aflatoxin B1 aldehyde reductase member 3, aldo-keto reductase family 1 member C3, amiloride-sensitive amine oxidase, death-associated protein kinase 2 and tryptophan-tRNA ligase, that may all play a crucial role in its observed anticancer effects. Moreover, our inverse docking results showed that curcumin potentially binds also to the proteins cAMP-specific 3′,5′-cyclic phosphodiesterase 4D and 17-β-hydroxysteroid dehydrogenase type 10, which provides a new explanation for its efficiency in the treatment of Alzheimer’s disease. We firmly believe that our computational results will complement and direct future experimental studies on curcumin’s anticancer activity as well as on its therapeutic effects against Alzheimer’s disease.
... In human HCT-116 colon cancer cells, curcumin has been reported to inhibit PKC activation by control the release of Ca2+ from the endoplasmic reticulum (Dyer et al. 2002;Wang et al. 2006). In another study, curcumin was shown to inhibit carcinogen-induced JNK activation (Chen and Tan 1998). Curcumin inhibits the proliferation of LNCaP prostate cancer cells via inhibiting AP-1 transcription factors (Polytarchou et al. 2005). ...
Drug resistance remains a major challenge in the treatment of patients with ovarian cancer. Therefore, the development of new anticancer drugs is a clinical priority to develop more effective therapies. New approaches to improve clinical outcomes and limit the toxicity of anticancer drugs focus on chemoprevention. The aim of this study was to determine the effects of dendrosomal nanocurcumin (DNC) and oxaliplatin (Oxa) and their combination on cell death and apoptosis induction in human ovarian carcinoma cell lines analyzed by MTT assay and flow cytometry, respectively. The synergism effect of Oxa and DNC was analyzed using the equation derived from Chou and Talalay. In addition, real-time PCR was used to measure the effect of this combination on the expression levels of long non-coding RNAs with different expression in ovarian cancer and normal ovaries. Our data showed that the effect of DNC on cell death is more than curcumin alone in the same concentration. The greatest cell death effect was observed in combination of Oxa with DNC, while Oxa was added first, followed by DNC at 4 h interval (0/4 h). The findings indicated that DNC induced apoptosis significantly in both cell lines as compared to control groups; however, combination of both agents had no significant effect in apoptosis induction. In addition, combination of both agents significantly affects the relative expression of long non-coding RNAs investigated in the study as compared with mono therapy.
... Curcumin is a major component of C. longa and its anti-inflammatory effect via suppression of NF-κB or AP-1 signaling pathways has been reported [23,24]. It is presumed that curcumin contributes to the anti-inflammatory effects of WEC. ...
We wished to search for the compounds contributing to the anti-inflammatory effects of the water extract of Curcuma longa (WEC). WEC was fractioned and the fractions were evaluated with regard to their inhibitory effect on the production of nitric oxide (NO) from the macrophage cell line stimulated by lipopolysaccharide. Compounds in the active fractions were isolated and identified. One isolated compound was identified as new: (6S)-2-methyl-5-hydroxy-6-(3-hydroxy-4-methylphenyl)-2-heptene-4-one (1). Four isolated compounds were identified as known: (6S)-2-methyl-6-(4-hydroxyphenyl)-2-heptene-4-one (4), bisabolone-4-one (5), curcumenone (6), and turmeronol A (8). Three isolated compounds were not identified their stereostructures but their planar structures: 2-methyl-6-(4-hydroxymethyl-phenyl)-2-heptene-4-one (2), 2-methyl-6-(2,3-epoxy-4-methyl-4-cyclohexene)-2-heptene (3), and 4-methylene-5-hydroxybisabola-2,10-diene-9-one (7). Compounds 1, 4, 7 and 8 inhibited production of prostaglandin E2 and NO. Others inhibited NO production only. These results (at least in part) show the active compounds contributing to the anti-inflammatory effects of WEC, and may be useful for elucidating its various beneficial physiologic effects.
... Curcuminoids are well-known for their various biological activities and especially anti-cancer effects (Chang and Chen, 2015). Curcumin has been reported to suppress NF-κB, AP-1, and the MAPK signaling pathways among many biological effects (Chen and Tan, 1998;Han et al., 2002). Previous research indicated that enhancement of the cytotoxicity to CDDP by administration of curcumin was mediated by down-regulation of the expression levels of TP and ERCC1 and by inactivation of ERK1/2 (Rezaee et al., 2017;Tsai et al., 2011). ...
... CUR targets c-jun N terminal Kinase (JNK) pathway preventing JNK1/2 and c-jun phosphorylation and caspase 3 activation [76]. CUR does not directly inhibit kinase activity of JNK [77] but probably interferes with the proximal upstream and not the distal upstream of mitogen activated kinase kinase kinase level. The inhibition of the upstream activators might not affect JNK cascade [78]. ...
Considering the anti‐inflammatory properties of curcumin, the present study was designed to investigate the effect of nano‐curcumin on respiratory indices and interleukin‐6 (IL‐6) levels in severe chronic obstructive pulmonary disease (COPD) patients as a common pulmonary disease causing restricted airflow and breathing problems. In the current double‐blind placebo‐controlled randomized clinical trial study, 60 patients with stages 3 and 4 COPD were randomly assigned into 80 mg nano‐curcumin ( n = 30) and placebo groups ( n = 30) for 3 months. The effect of nano‐curcumin on pulmonary function was evaluated by the first second of forced expiration (FEV1) to the full, forced vital capacity (FVC) ratio. IL‐6 serum level, blood pressure, and anthropometric indices were also measured. Nano‐curcumin supplementation led to a significant decrease in IL‐6 level ( p < 0.001) and an increase in FEV1 ( p < 0.001), FVC ( p = 0.003), and FEV1/FVC ( p < 0.001) compared to placebo at the endpoint. Nano‐curcumin had a significantly increasing effect on weight and body mass index compared to the placebo group ( P ANCOVA adjusted for baseline values = 0.042). There was a meaningful improvement in systolic blood pressure in the nano‐curcumin group compared to the placebo group ( P ANCOVA adjusted for baseline values = 0.026). There was no significant difference between the two groups in terms of waist circumference, waist‐to‐hip ratio, and diastolic blood pressure ( P ANCOVA adjusted for baseline values >0.05). Nano‐curcumin supplement seems to have favorable effects on inflammation status and respiratory indices of patients with severe COPD.
The curry powder spices turmeric (Curcuma longa L.), which contains curcumin (diferuloylmethane), an orange-yellow chemical. Polyphenols are the most commonly used sources of curcumin. It combats oxidative stress and inflammation in diseases, such as hyperlipidemia, metabolic syndrome, arthritis, and depression. Most of these benefits are due to their anti-inflammatory and antioxidant properties. Curcumin consumption leads to decreased bioavailability, resulting in limited absorption, quick metabolism, and quick excretion, which hinders health improvement. Numerous factors can increase its bioavailability. Piperine enhances bioavailability when combined with curcumin in a complex. When combined with other enhancing agents, curcumin has a wide spectrum of health benefits. This review evaluates the therapeutic potential of curcumin with a specific emphasis on its approach based on molecular signaling pathways. This study investigated its influence on the progression of cancer, inflammation, and many health-related mechanisms, such as cell proliferation, apoptosis, and metastasis. Curcumin has a significant potential for the prevention and treatment of various diseases. Curcumin modulates several biochemical pathways and targets involved in cancer growth. Despite its limited tissue accumulation and bioavailability when administered orally, curcumin has proven useful. This review provides an in-depth analysis of curcumin's therapeutic applications, its molecular signaling pathway-based approach, and its potential for precision medicine in cancer and human health.
This chapter entitled “ROS/Redox Regulation with Dietary Phytochemicals and Role in Anticancer Activity” initially introduces the classification of various plant products (phytochemicals) with experimental anticancer activities. Redox regulation and anticancer activities of various natural dietary compounds have been discussed extensively at experimental, preclinical, and clinical situations. Further, a few select important phytochemicals with dietary anticancer properties were presented to demonstrate their molecular and redox signaling activities in various studies. In the end, the role of specific natural chemopreventive antioxidants has been discussed.
Curcumin (CUR) has been discovered to have many biological activities, including anti-inflammatory, anti-cancer, anti-oxygenation, anti-human immunodeficiency virus, anti-microbial and exhibits a good effect on the prevention and treatment of many diseases. However, the limited properties of CUR, including the poor solubility, bioavailability and instability caused by enzymes, light, metal irons, and oxygen, have compelled researchers to turn their attention to drug carrier application to overcome these drawbacks. Encapsulation may provide potential protective effects to the embedding materials and/or have a synergistic effect with them. Therefore, nanocarriers, especially polysaccharides-based nanocarriers, have been developed in many studies to enhance the anti-inflammatory capacity of CUR. Consequently, it's critical to review current advancements in the encapsulation of CUR using polysaccharides-based nanocarriers, as well as further study the potential mechanisms of action where polysaccharides-based CUR nanoparticles (the complex nanoparticles/Nano CUR-delivery systems) exhibit their anti-inflammatory effects. This work suggests that polysaccharides-based nanocarriers will be a thriving field in the treatment of inflammation and inflammation-related diseases.
Cancer is a multi-step process involving alterations in epigenetic and genetic processes. Oral squamous cell carcinoma is a frequent oral malignancy that originates from the transformation of normal cells into malignant cells as a consequence of failures in a series of normal molecular and cellular processes. The mechanism of human carcinogenesis is often seen as a double-edged sword, with the body's system being thought to counteract the detrimental consequences of neoplastic cell proliferation while simultaneously promoting tumor development. Various transcription factors play a significant part in cancer regulation, with the activator protein-1 family of transcription factors (TFs) being the most prominent regulatory protein family. The Jun, Fos, ATF, and MAF protein families are all present in the AP-1 dimeric complex. While certain AP-1 proteins, including JunB and c-Fos, are known to be majorly oncogenic in function, experimental studies have shown that other AP-1 proteins, such as JunB and c-Fos, also play a critical role in tumor suppression. The aim of this review is to offer breakthrough information on the role of molecular mechanisms mediated by AP-1 TFs in tumor development and its environment.
Purpose: The poor efficacy of traditional antitumor drugs in the treatment of cancer is mainly due to poor water solubility, systemic cytotoxicity, poor tumor targeting and other factors. In recent years, the nano-drug system has been widely studied in tumor therapy and drug targeting, but the design process requires repeated experiments, which are time consuming and laborious. In this context, we developed a novel synergistic co-delivery nanomicelle of gambogic acid and curcumin through molecular dynamics (MD) and dissipative particle dynamics (DPD) simulation.
Methods: The synergistic effect was verified by the comprehensive index, apoptosis, reactive oxygen species (ROS) detection, and apoptosis-related protein experiments. MD and DPD simulations were utilized to design micelles. According to the results, methoxypolyethylene glycol (mPEG)-gambogic acid (GA)-curcumin (CU) micelles were synthesized and prepared for the co-delivery of GA and curcumin, and then, the micelles were characterized and released in vitro. Finally, a cytotoxicity study of micelles was carried out to prove its anti-tumor effect.
Results: It was verified that the combined administration of GA and curcumin showed a synergistic effect in tumor cells (HepG2) and an antagonistic or weak synergistic effect in normal cells (BV2, HEK293). According to the design of computer simulation, mPEG-GA-CU micelles were synthesized and characterized. Cytotoxicity experiments proved that mPEG-GA-CU micelles are more toxic to HepG2 cells than BV2, HEK293 cells.
Conclusions: Studies have shown that the mPEG-GA-CU nanomicelles designed by computer simulation have the ability to co-deliver drugs, play a synergistic anti-tumor effect, and have great potential in further anti-cancer practical applications.
Inflammation is a vital process that maintains tissue homeostasis. However, it is widely known that uncontrolled inflammation can contribute to the development of various diseases. This study aimed to discover anti-inflammatory metabolites from Penicillium bialowiezense. Seven spiroditerpenoids, including two new compounds, breviones P and Q (1 and 2), were isolated and characterized by various spectroscopic and spectrometric methods. All isolated compounds were initially tested for their inhibitory effects against lipopolysaccharide-induced nitric oxide (NO) production in RAW 264.7 macrophages. Of these, brevione A (3) exhibited this activity with a half-maximal inhibitory concentration value of 9.5 μM. Further mechanistic studies demonstrated that 3 could suppress the expression of pro-inflammatory cytokines and mediators, such as NO, prostaglandin E2, interleukin (IL)-1β, tumor necrosis factor-α, IL-6, and IL-12 by inhibiting the activation of nuclear factor-kappa B and c-Jun N-terminal kinase.
This review deals with the various aspects involved in the medicinal action of curcumin, from the photosensitivity and its relevance to storage and shelf-life, to the different routes of administration, which influence the bioavailability. The focus of the review is on the antitumor properties of curcumin and the currently available solutions for their amelioration. The work starts by presenting a brief historical perspective on the origins and uses of curcumin, from early days until the present time. The following sections describe the physico-chemical properties of curcumin and their impact on the biological activity and pharmacokinetics, raising awareness to the need for formulations able to improve the bioavailability. The last section is focused on research efforts being made to circumvent curcumin’s instability and low availability due to the extensive hepatic first pass metabolism, describing innovative scientific advances and new patented formulations and emerging products on the market.
Oxidative stress is a toxic cellular condition, strictly related to inflammation and known to be a common feature of many neurodegenerative diseases. The imbalanced redox state modifies several molecular processes including protein SUMOylation, JNK and Tau protein activation, important actors in Alzheimer's disease. In this study, we showed a strong interaction among SUMO-1-JNK-Tau proteins and their molecular targets in an in vitro model (SHSY5Y cell line) of oxidative stress in which a significant reduction of cell viability and an augmented cell death was induced by increased doses of H2O2. The evoked oxidative stress led to a deficiency in the degradation system showing altered levels of Caspase-3, LC3BI/II and Ubiquitin. Curcumin, a natural compound with anti-oxidant and anti-inflammatory effects, demonstrated to tackle oxidative stress re-equilibrating SUMO-1, JNK and Tau functions. Importantly, 5 μM of curcumin induced an efficient recovery of cell viability, a reduction of cell death and a normalization of altered protein degradation marker levels. Interestingly, we found that H2O2 treatment induced a strong co-localization of SUMO-1-p-JNK-Tau proteins in nuclear bodies (NBs) and that curcumin was able to reduce these nuclear aggregates. These results highlight the SUMO-1-JNK-Tau axis key role in oxidative stress and the protective effect of curcumin against this pathological event, focusing on the importance of SUMO/deSUMOylation balance to regulate essential cellular processes.
Background
Cancer is a havoc and killer disease. Several ways including allopathic chemotherapy have been used in the cancer treatment. Allopathic chemotherapy has several limitations and side effects. Unani medicine is also one of the therapies to cure cancer.
Objective
In this type of treatment, herbal drugs are used for the treatment and prevention of cancer. The main attractive thing about herbal drug is no side effect as compared to allopathic chemotherapy.
Methods
Actually, herbal drugs are the extracts of medicinal plants. The plant extracts are obtained by crushing and heating the main part of the plants; showing anticancer activity. The main plants used in the treatment of cancer are oroxylum indicum, dillenia indica, terminalia arjuna etc.
Results
Mainly the cancers treated are of digestive system, breast, cervical, brain, blood, bone, lungs, thyroid, uterine, bladder, throat etc.
Conclusion
The present review article discusses the importance of Unani system of medicine for the treatment of cancer. Besides, the future perspectives of Unani medicine in cancer treatment are also highlighted.
La glutathion S-Transférase Pl-1 (GSTP1-1), impliquée dans la conjugaison de composés électrophiles au glutathion, la cancérogénèse et le développement de résistances aux anticancéreux, reste peu étudiée dans le cas des leucémies humaines en ce qui concerne l'expression du gène ainsi que des voies de transduction du signal impliquées. Dans une étude précédente, notre équipe a montré l'importance du site AP-1 en tant que régulateur du promoteur minimal de la GSTP1-1. Pour ce travail, nous montrons dans un premier temps que des inducteurs typiques d'AP-1 comme l'ester de phorbol TPA ou les métaux lourds n'induisent pas l'expression de l'ARNm de la GSTP1-1 dans la lignée leucémique K562. Par contre, nous confirmons l'importance de c-Jun, c-Fos et de la voie de signalisation menant à l'induction de AP-1 dans la régulation de l'expression de la GSTP1-1. La plupart des gènes régulés par AP-1 étant aussi régulés par NF-kB, nous avons décidé de vérifier le rôle de ce facteur dans la régulation de la GSTP1-1dont l'ARNm est inductible au TNFa. Grâce à un outil informatique, nous avons pu découvrir la présence d'un site NF-KB qui fixe les sous-unités p50 et p65 de NF-KB en réponse à un traitement au TNF[alpha]. Des expériences de co-transfections nous ont permis de compléter nos études en prouvant que la voie de signalisation NF-kB est bien impliquée dans la régulation de la GSTP1-1. Finalement, nous avons démontré l'efficacité d'agents chimiopréventifs, grâce à l'utilisation de la curcumine dont nous démontrons ici la capacité d'inhiber l'expression de la GSTP1-1 en bloquant la fixation d' AP-1 et de NF-kB tout en induisant l'apoptose dans les cellules leucémiques K562. Nous avons élargi nos résultats vers à l'utilisation d'autres agents chimiopréventifs dont la capsaicine et l'émodine. En résumé, nos résultats montrent que la GSTP1-1 est régulée par les facteurs de transcription AP-1 et NF-kB et inhibée par des agents chimiopréventifs qui présentent un intérêt potentiel pour de nouvelles thérapies anti-cancéreuses.
Curcumin is a component of turmeric and is isolated from the rhizomes of the plant Curcuma longa. Curcumin was reported to have therapeutic effects on prostate cancer. Yet the molecular mechanism of curcumin remains unclear. In this study, mouse prostate cancer xenograft model was established and subjected to curcumin treatment. GST-c-Jun pull down kinase assays were performed to study the phospho-c-Jun level. Cell Counting Kit-8 assay kit was utilized to detect the cell viability. Immunoblotting and qRT-PCR were performed for target gene expression analysis. Curcumin inhibited growth of prostate cancer in vivo as well as promoted apoptosis of LNCaP cells in vitro. Curcumin inhibited JNK pathway and repressed H3K4me3 in LNCaP cells. Combined use of curcumin and JQ-1 inhibited the prostate cancer efficiently. In conclusion, curcumin inhibits JNK pathway and plays a role in epigenetic regulation of prostate cancer cells by repressing H3K4me3.
The c-Jun N-terminal kinases (JNKs) are located downstream of Ras-mitogen activated protein kinase signaling cascades. More than 20 years of study has shown that JNKs control cell fate and many cellular functions. JNKs and their interacting proteins form a complicated network with diverse biological functions and physiological effects. Members of the JNK interactome include Jun, amyloid precursor protein, and insulin receptor substrate. Recent studies have shown that the JNK interactome is involved in tumorigenesis, neuron development, and insulin resistance. In this review, we summarize the features of the JNK interactome and classify its members into three groups: upstream regulators, downstream effectors, and scaffold partners. We also highlight the unique cellular signaling mechanisms of JNKs and provide more insights into the roles of the JNK interactome in human diseases.
Tumour necrosis factor-alpha (TNF-alpha) is secreted by macrophages in response to inflammation, infection and cancer. Sublethal doses of recombinant TNF-alpha to rats causes cachexia, anaemia and inflammation. TNF-alpha plays a major part in tissue inflammation and remodelling by stimulating production of collagenase. Cellular responses to TNF-alpha are initiated by binding to high-affinity cell surface receptors. TNF-alpha then profoundly affects gene regulation, stimulating the fos, myc, interleukin-1 and interleukin-6 genes and inhibiting the type I collagen gene. Here we demonstrate that TNF-alpha also stimulates collagenase gene transcription; this stimulation is mediated by an element of the gene that is responsive to the transcription factor AP-1, the major component of which (jun/AP-1) is encoded by the jun gene; and that TNF-alpha stimulates prolonged activation of jun gene expression. This prolonged induction of jun contrasts with its transient activation by the phorbol ester TPA and provides a physiological example of the ability of jun/AP-1 to stimulate its own transcription. This may be a key mechanism for mediating at least some of the biological effects of TNF-alpha.
Curcumin, a dietary pigment responsible for the yellow color of curry, is a potent inhibitor of tumor promotion by phorbol esters. Functional activation of transcriptional factor c-Jun/AP-1 is believed to play an important role in signal transduction of phorbol 12-myristate 13-acetate-induced tumor promotion. Suppression of the c-Jun/AP-1 activation by curcumin is observed in mouse fibroblast cells. In vitro experiments indicate that inhibition of c-Jun/AP-1 binding to its cognate motif by curcumin may be responsible for the inhibition of c-Jun/AP-1-mediated gene expression. These findings show that the effect of curcumin on phorbol 12-myristate 13-acetate-induced inflammation/tumor promotion could be studied at the molecular level.
Human epidemiological and laboratory animal model studies have suggested that nonsteroidal antiinflammatory drugs reduce the risk of development of colon cancer and that the inhibition of colon carcinogenesis is mediated through the alteration in cyclooxygenase metabolism of arachidonic acid. Curcumin, which is a naturally occurring compound, is present in turmeric, possesses both antiinflammatory and antioxidant properties, and has been tested for its chemopreventive properties in skin and forestomach carcinogenesis. The present study was designed to investigate the chemopreventive action of dietary curcumin on azoxymethane-induced colon carcinogenesis and also the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phospholipase C gamma 1, lipoxygenase, and cyclooxygenase activities in male F344 rats. At 5 weeks of age, groups of animals were fed the control (modified AIN-76A) diet or a diet containing 2000 ppm of curcumin. At 7 weeks of age, all animals, except those in the vehicle (normal saline)-treated groups, were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight. All groups were continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A2, phospholipase C gamma 1, ex vivo prostaglandin (PG) E2, cyclooxygenase, and lipoxygenase activities. The results indicate that dietary administration of curcumin significantly inhibited incidence of colon adenocarcinomas (P < 0.004) and the multiplicity of invasive (P < 0.015), noninvasive (P < 0.01), and total (invasive plus noninvasive) adenocarcinomas (P < 0.001). Dietary curcumin also significantly suppressed the colon tumor volume by > 57% compared to the control diet. Animals fed the curcumin diet showed decreased activities of colonic mucosal and tumor phospholipase A2 (50%) and phospholipase C gamma 1 (40%) and levels of PGE2 (> 38%). The formation of prostaglandins such as PGE2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, and thromboxane B2 through the cyclooxygenase system and production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the lipoxygenase pathway from arachidonic acid were reduced in colonic mucosa and tumors of animals fed the curcumin diet as compared to control diet. Although the precise mechanism by which curcumin inhibits colon tumorigenesis remains to be elucidated, it is likely that the chemopreventive action, at least in part, may be related to the modulation of arachidonic acid metabolism.
The mitogen-activated protein (MAP) kinases Erk-1 and Erk-2 are proline-directed kinases that are themselves activated through concomitant phosphorylation of tyrosine and threonine residues. The kinase p54 (M(r) 54,000), which was first isolated from cycloheximide-treated rats, is proline-directed like Erks-1/2, and requires both Tyr and Ser/Thr phosphorylation for activity. p54 is, however, distinct from Erks-1/2 in its substrate specificity, being unable to phosphorylate pp90rsk but more active in phosphorylating the c-Jun transactivation domain. Molecular cloning of p54 reveals a unique subfamily of extracellularly regulated kinases. Although they are 40-45% identical in sequence to Erks-1/2, unlike Erks-1/2 the p54s are only poorly activated in most cells by mitogens or phorbol esters. However, p54s are the principal c-Jun N-terminal kinases activated by cellular stress and tumour necrosis factor (TNF)-alpha, hence they are designated stress-activated protein kinases, or SAPKs. SAPKs are also activated by sphingomyelinase, which elicits a subset of cellular responses to TNF-alpha (ref. 9). SAPKs therefore define a new TNF-alpha and stress-activated signalling pathway, possibly initiated by sphingomyelin-based second messengers, which regulates the activity of c-Jun.
The mechanism by which circulating monocytes are attracted to sites of bone remodeling is unknown. We now report that tumor necrosis factor-alpha (TNF-alpha), a potent osteotrophic cytokine, was stimulatory for expression of the monocyte chemoattractant JE gene in osteoblastic MC3T3-E1 cells. TNF-alpha stimulated this JE gene expression transcriptionally. The presence of JE gene product in conditioned medium of the cytokine-treated cells was evidenced by an immunoprecipitation assay with antiserum specific for JE/MCP-1. The stimulated JE gene expression was markedly inhibited by H-7, a potent inhibitor of protein kinase C. Phorbol 12-myristate 13-acetate induced the JE gene expression, and the cytokine-induced JE gene expression was down-regulated by the phorbol ester pretreatment. TNF-alpha induced expression of both early protooncogenes, c-fos and c-jun, in the cells. Antisense oligonucleotides to these oncogenes significantly inhibited the cytokine-induced monocyte chemotactic activity. Furthermore, curcumin, a specific inhibitor of c-jun/AP-1, markedly inhibited JE gene expression and monocyte chemotactic activity induced by the cytokine. These results suggest that TNF-alpha may contribute to the regulation of remodeling and inflammation of bone tissues through the JE gene product.
The mitogen-activated protein kinase (MAPK) pathway is a conserved eukaryotic signaling module that converts receptor signals
into various outputs. MAPK is activated through phosphorylation by MAPK kinase (MAPKK), which is first activated by MAPKK
kinase (MAPKKK). A genetic selection based on a MAPK pathway in yeast was used to identify a mouse protein kinase (TAK1) distinct
from other members of the MAPKKK family. TAK1 was shown to participate in regulation of transcription by transforming growth
factor-β (TGF-β). Furthermore, kinase activity of TAK1 was stimulated in response to TGF-β and bone morphogenetic protein.
These results suggest that TAK1 functions as a mediator in the signaling pathway of TGF-β superfamily members.
Signal-dependent activation of the transcription factor NF-κB is dominantly regulated by degradation of IκB-α protein. However,
the signaling pathways that lead to the degradation are not clear. Here we report that mitogen-activated protein kinase/extracellular
signal-regulated kinase kinase (MEK) kinase, an activator of stress-activated protein kinases/jun kinase-1 (SAPKs/JNK1), is
involved in such signaling pathways. The transient overexpression of MEK kinase in NIH3T3 fibroblasts activates κB-CAT reporter
expression in a synergistic manner with TNFα stimulation. In contrast, overexpression of kinase-negative MEK kinase suppresses
TNFα-induced reporter expression. The overexpression of MEK kinase suppresses the inhibitory activity of co-transfected IκB-α
on the κB-CAT or human immunodeficiency virus-long terminal repeat-luciferase reporter expression and causes the simultaneous
disappearance of the overexpressed IκB-α. The disappearance of exogenous IκB-α by the overexpression of MEK kinase is prevented
by calpain inhibitor-I, an inhibitor of IκB-α degradation. These results suggest that MEK kinase is a signal mediator involved
in TNFα-induced NF-κB activation and that the activation of NF-κB by MEK kinase is regulated through the degradation of IκB-α.
Certain small GTP-binding proteins control the enzymatic activity of a family of closely related serine-threonine kinases known as mitogen-activated protein kinases (MAPKs). In turn, these MAPKs, such as p44(mapk) and p42(mapk), referred to herein as MAPKs, and stress-activated protein kinases, also termed c-Jun N-terminal kinases (JNKs), phosphorylate and regulate the activity of key molecules that ultimately control the expression of genes essential for many cellular processes. Whereas Ras controls the activation of MAPK, we and others have recently observed that two members of the Rho family of small GTP-binding proteins, Rac1 and Cdc42, regulate the activity of JNKs. The identity of molecules communicating Rac1 and Cdc42 to JNK is still poorly understood. It has been suggested that Pak1 is the most upstream kinase connecting these GTPases to JNK; however, we have observed that coexpression of Pak1 with activated forms of Cdc42 or Rac1 diminishes rather than enhances JNK activation. This prompted us to explore the possibility that kinases other than Pak might participate in signaling from GTP-binding proteins to JNK. In this regard, a computer-assisted search for proteins containing areas of homology to that in Pak1 that is involved in binding to Rac1 and Cdc42 led to the identification of mixed lineage kinase 3 (MLK3), also known as protein-tyrosine kinase 1, as a potential candidate for this function. In this study, we found that MLK3 overexpression is sufficient to activate JNK potently without affecting the phosphorylating activity of MAPK or p38. Furthermore, we present evidence that MLK3 binds the GTP-binding proteins Cdc42 and Rac1 in vivo and that MLK3 mediates activation of MEKK-SEK-JNK kinase cascade by Rac1 and Cdc42. Taken together, these findings strongly suggest that members of the novel MLK family of highly related kinases link small GTP-binding proteins to the JNK signaling pathway.
The mitogen-activated protein (MAP) kinase family includes extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38/RK/CSBP (p38) as structurally and functionally distinct
enzyme classes. Here we describe two new dual specificity phosphatases of the CL100/MKP-1 family that are selective for inactivating
ERK or JNK/SAPK and p38 MAP kinases when expressed in COS-7 cells. M3/6 is the first phosphatase of this family to display
highly specific inactivation of JNK/SAPK and p38 MAP kinases. Although stress-induced activation of p54 SAPKβ, p46 SAPKγ (JNK1)
or p38 MAP kinases is abolished upon co-transfection with increasing amounts of M3/6 plasmid, epidermal growth factor-stimulated
ERK1 is remarkably insensitive even to the highest levels of M3/6 expression obtained. In contrast to M3/6, the dual specificity
phosphatase MKP-3 is selective for inactivation of ERK family MAP kinases. Low level expression of MKP-3 blocks totally epidermal
growth factor-stimulated ERK1, whereas stress-induced activation of p54 SAPKβ and p38 MAP kinases is inhibited only partially
under identical conditions. Selective regulation by M3/6 and MKP-3 was also observed upon chronic MAP kinase activation by
constitutive p21ras GTPases. Hence, although M3/6 expression effectively blocked p54 SAPKβ activation by p21rac (G12V), ERK1 activated by p21ras (G12V) was insensitive to this phosphatase. ERK1 activation by oncogenic p21ras was, however, blocked totally by co-expression of MKP-3. This is the first report demonstrating reciprocally selective inhibition
of different MAP kinases by two distinct dual specificity phosphatases.
Mitogen-activated protein kinases (MAPKs) are components of sequential kinase cascades that are activated in response to a variety of extracellular signals. Members of the MAPK family include the extracellular response kinases (ERKs or p42/44(MAPK)), the c-Jun amino-terminal kinases (JNKs), and the p38/Hog 1 protein kinases. MAPKs are phosphorylated and activated by MAPK kinases (MKKs or MEKs), which in turn are phosphorylated and activated by MKK/MEK kinases (Raf and MKKK/MEKKs). We have isolated two cDNAs encoding splice variants of a novel MEK kinase, MEKK4. The MEKK4 mRNA is widely expressed in mouse tissues and encodes for a protein of approximately 180 kDa. The MEKK4 carboxyl-terminal catalytic domain is approximately 55% homologous to the catalytic domains of MEKKs 1, 2, and 3. The amino-terminal region of MEKK4 has little sequence homology to the previously cloned MEKK proteins. MEKK4 specifically activates the JNK pathway but not ERKs or p38, distinguishing it from MEKKs 1, 2 and 3, which are capable of activating the ERK pathway. MEKK4 is localized in a perinuclear, vesicular compartment similar to the Golgi. MEKK4 binds to Cdc42 and Rac; kinase-inactive mutants of MEKK4 block Cdc42/Rac stimulation of the JNK pathway. MEKK4 has a putative pleckstrin homology domain and a proline-rich motif, suggesting specific regulatory functions different from those of the previously characterized MEKKs.
The c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is activated by phosphorylation on Thr and Tyr. Here we report the molecular cloning of a new member of the mammalian MAP kinase kinase group (MKK7) that functions as an activator of JNK. In vitro protein kinase assays demonstrate that MKK7 phosphorylates and activates JNK, but not the p38 or extracellular signal-regulated kinase groups of MAP kinase. Expression of MKK7 in cultured cells causes activation of the JNK signal transduction pathway. MKK7 is therefore established to be a novel component of the JNK signal transduction pathway.
Transforming growth factor beta (TGF-beta)-activated kinase (TAK1) is known for its involvement in TGF-beta signaling and its ability to activate the p38-mitogen-activated protein kinase (MAPK) pathway. This report shows that TAK1 is also a strong activator of c-Jun N-terminal kinase (JNK). Both the wild-type and a constitutively active mutant of TAK1 stimulated JNK in transient transfection assays. Mitogen-activated protein kinase kinase 4 (MKK4)/stress-activated protein kinase/extracellular signal-regulated kinase (SEK1), a dual-specificity kinase that phosphorylates and activates JNK, synergized with TAK1 in activating JNK. Conversely, a dominant-negative (MKK4/SEK1 mutant inhibited TAK1-induced JNK activation. A kinasedefective mutant of TAK1 effectively suppressed hematopoietic progenitor kinase-1 (HPK1)-induced JNK activity but had little effect on germinal center kinase activation of JNK. There are two additional MAPK kinase kinases, MEKK1 and mixed lineage kinase 3 (MLK3), that are also downstream of HPK1 and upstream of MKK4/SEK mutant. However, because the dominant-negative mutants of MEKK1 and MLK3 did not inhibit TAK1-induced JNK activity, we conclude that activation of JNK1 by TAK1 is independent of MEKK1 and MLK3. In addition to TAK1, TGF-beta also stimulated JNK activity. Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway. Our results also suggest the potential roles of TAK1 not only in the TGF-beta pathway but also in the other HPK1/JNK1-mediated pathways.
Mitogen-activated protein kinase (MAPK) kinases (MKKs) are dual-specificity protein kinases that phosphorylate and activate MAPK. We have isolated a cDNA encoding a novel protein kinase that has significant homology to MKKs. The novel kinase MKK7 has a nucleotide sequence that encodes an open reading frame of 347 amino acids with 11 kinase subdomains. MKK7 is ubiquitously expressed in all adult and embryonic organs but displays high expression in epithelial tissues at later stages of fetal development. When transiently expressed in 293 cells, MKK7 specifically activated stress-activated protein kinases (SAPKs)/c-Jun N-terminal protein kinases (JNKs) but not extracellular-regulated kinase or p38 kinase. A kinase-negative mutant of MKK7 inhibits interleukin-1beta, lipopolysaccharide, and MEKK1-induced SAPK/JNK activation. Thus, MKK7 is a new member of the MAPK kinase family that functions upstream of SAPK/JNK in the SAPK/JNK signaling pathway.
The p21-activated protein kinases (PAKs) are members of a growing family of regulatory enzymes that may play roles in diverse phenomena such as cellular morphogenesis, the stress response and the pathogenesis of AIDS. PAKs were initially discovered as binding partners for small (21 kDa) GTPases that regulate actin polymerization, and recent evidence has shown that some members of the PAK family may be effectors for related GTPases that are involved in intracellular vesicle trafficking. Because the downstream signalling pathways for all such GTPases are poorly understood, intense studies are under way to discern the role of PAK and its cousins. In this review, the authors highlight some of the established properties of the extended PAK family and discuss current controversies regarding their possible roles as GTPase effectors.
Both NF-κB and c-Jun are activated by cytokines such as TNF-α and by stresses such as UV irradiation. A key step in the activation of NF-κB is the phosphorylation of its inhibitor, IκBα, by a ubiquitination-inducible multiprotein kinase complex (IκBα kinase). A central kinase in the c-Jun activation pathway is mito- gen-activated protein kinase/ERK kinase kinase-1 (MEKK1). Here, we show that MEKK1 induces the site-specific phosphorylation of IκBα in vivo and, most strikingly, can directly activate the IκBα kinase complex in vitro. Thus, MEKK1 is a critical component of both the c-Jun and NF-κB stress response pathways. Since the IκBα kinase complex can be independently activated by ubiquitination or MEKK1-dependent phosphorylation, it may be an integrator of multiple signal transduction pathways leading to the activation of NF-κB.
Signal-induced activation of the transcription factor NF-κB requires specific phosphorylation of the inhibitor IκBα and its subsequent proteolytic degradation. Phosphorylation of serine residues 32 and 36 targets IκBα to the ubiquitin (Ub)–proteasome pathway. Here we report the identification of a large, multisubunit kinase (molecular mass ∼700 kDa) that phosphorylates IκBα at S32 and S36. Remarkably, the activity of this kinase requires the Ub-activating enzyme (E1), a specific Ub carrier protein (E2) of the Ubc4/Ubc5 family, and Ub. We also show that a ubiquitination event in the kinase complex is a prerequisite for specific phosphorylation of IκBα. Thus, ubiquitination serves a novel regulatory function that does not involve proteolysis.
We present evidence that the glucocorticoid receptor (GR) and transcription factor Jun/AP-1 can reciprocally repress one another's transcriptional activation by a novel mechanism that is independent of DNA binding. Overexpression of c-Jun prevents the glucocorticoid-induced activation of genes carrying a functional glucocorticoid response element (GRE). Conversely, GR is able to repress AP-1-mediated transcriptional activation. Mutant analysis reveals that the ligand binding and DNA binding domains of GR and the region including the leucine zipper of c-Jun are required for repression. Gel retardation analysis demonstrates that bacterially expressed c-Jun disrupts GR-GRE complexes. These data indicate that members of two distinct classes of transcription factors can oppose one another's activity through a mechanism likely involving protein-protein interactions.
Glucocorticoid hormones counteract inflammation and phorbol ester tumor promotion and drastically decrease the expression of several extracellular proteases, including collagenase I. Glucocorticoid hormone inhibits basal and induced transcription of collagenase by interfering with AP-1, the major enhancer factor of the collagenase promoter. The mechanism of interference is novel in that it does not require protein synthesis, it depends on the hormone receptor but not its binding to DNA, it occurs at hormone doses one order of magnitude below those required for gene activation, and it involves down-modulation of the trans-activating function of preexisting unbound and DNA-bound AP-1. Coprecipitation experiments suggest direct AP-1-hormone receptor interaction, which also possibly explains the reverse experiment: overexpression of Fos or Jun inhibits the expression of hormone-dependent genes.
Interleukin-1 (IL-1) is a major regulator of inflammation and immunity. IL-1 induces T lymphocyte growth by acting as a second signal (together with antigen) in enhancing the production of interleukin-2 (IL-2). An IL-1-responsive element in the promoter region of the human IL-2 gene was similar to the binding site for the transcription factor AP-1. IL-1 enhanced expression of c-jun messenger RNA, whereas the antigenic signal enhanced messenger RNA expression of c-fos. Thus, the two components of the AP-1 factor are independently regulated and the AP-1 factor may serve as a nuclear mediator for the many actions of IL-1 on cells.
The promoter regions of several phorbol diester-(TPA-) inducible genes (collagenase, stromelysin, hMT IIA, and SV40) share a conserved 9 bp motif. Synthetic copies of these closely related sequences conferred TPA inducibility upon heterologous promoters. Footprinting analysis indicated that these TPA-responsive elements (TREs) are recognized by a common cellular protein: the previously described transcription factor AP-1. A point mutation that eliminated the basal and induced activity of the TRE also interfered with its ability to bind AP-1. Treatment of cultured cells with TPA led to a rapid 3- to 4-fold increase in TRE binding activity, by a posttranslational mechanism. These results strongly suggest that AP-1 is at the receiving end of a complex pathway responsible for transmitting the effects of phorbol ester tumor promoters from the plasma membrane to the transcriptional machinery.
The effects of topically applied curcumin, chlorogenic acid, caffeic acid, and ferulic acid on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal ornithine decarboxylase activity, epidermal DNA synthesis, and the promotion of skin tumors were evaluated in female CD-1 mice. Topical application of 0.5, 1, 3, or 10 mumol of curcumin inhibited by 31, 46, 84, or 98%, respectively, the induction of epidermal ornithine decarboxylase activity by 5 nmol of TPA. In an additional study, the topical application of 10 mumol of curcumin, chlorogenic acid, caffeic acid, or ferulic acid inhibited by 91, 25, 42, or 46%, respectively, the induction of ornithine decarboxylase activity by 5 nmol of TPA. The topical application of 10 mumol of curcumin together with 2 or 5 nmol of TPA inhibited the TPA-dependent stimulation of the incorporation of [3H]-thymidine into epidermal DNA by 49 or 29%, respectively, whereas lower doses of curcumin had little or no effect. Chlorogenic acid, caffeic acid, and ferulic acid were less effective than curcumin as inhibitors of the TPA-dependent stimulation of DNA synthesis. Topical application of 1, 3, or 10 mumol of curcumin together with 5 nmol of TPA twice weekly for 20 weeks to mice previously initiated with 7,12-dimethylbenz[a]anthracene inhibited the number of TPA-induced tumors per mouse by 39, 77, or 98%, respectively. Similar treatment of mice with 10 mumol of chlorogenic acid, caffeic acid, or ferulic acid together with 5 nmol of TPA inhibited the number of TPA-induced tumors per mouse by 60, 28, or 35%, respectively, and higher doses of the phenolic acids caused a more pronounced inhibition of tumor promotion. The possibility that curcumin could inhibit the action of arachidonic acid was evaluated by studying the effect of curcumin on arachidonic acid-induced edema of mouse ears. The topical application of 3 or 10 mumol of curcumin 30 min before the application of 1 mumol of arachidonic acid inhibited arachidonic acid-induced edema by 33 or 80%, respectively.
Eukaryotic cells respond to different extracellular stimuli by recruiting homologous signalling pathways that use members of the MEKK, MEK and ERK families of protein kinases. The MEKK-->MEK-->ERK core pathways of Saccharomyces cerevisiae may themselves be regulated by members of the STE20 family of protein kinases. Here we report specific activation of the mammalian stress-activated protein kinase (SAPK) pathway by germinal centre kinase (GCK), a human STE20 homologue. SAPKs, members of the ERK family, are activated in situ by inflammatory stimuli, including tumour-necrosis factor (TNF) and interleukin-1, and phosphorylate and probably stimulate the transactivation function of c-Jun. Although GCK is found in many tissues, its expression in lymphoid follicles is restricted to the cells of the germinal centre, where it may participate in B-cell differentiation. Activation of the SAPK pathway by GCK illustrates further the striking conservation of eukaryotic signalling mechanisms and defines the first physiological function of a mammalian Ste20.
Immediate early genes induced by triggering of the TCR frequently encode proteins that act in signal transduction cascades. Recent advances concerning several immediate-early proteins have been made, including signal-induced regulation of NF-kappa B by I kappa-B, the role of Nur77 in T-cell selection and apoptosis, and the function of PAC-1 in regulating the Ras/ERK pathway.
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The ternary complex factor (TCF) subfamily of ETS-domain transcription factors bind with serum response factor (SRF) to the serum response element (SRE) and mediate increased gene expression. The TCF protein Elk-1 is phosphorylated by the JNK and ERK groups of mitogen-activated protein (MAP) kinases causing increased DNA binding, ternary complex formation, and transcriptional activation. Activated SRE-dependent gene expression is induced by JNK in cells treated with interleukin-1 and by ERK after treatment with phorbol ester. The Elk-1 transcription factor therefore integrates MAP kinase signaling pathways in vivo to coordinate biological responses to different extracellular stimuli.
Matural curcuminoids, curcumin, I, II and III isolated from turmeric (Curcuma longa) were compared for their cytotoxic, tumour reducing and antioxidant activities. Curcumin III was found to be more active than the other two as a cytotoxic agent and in the inhibition of Ehrlich ascites tumour in mice (ILS 74.1%). These compounds were also checked for their antioxidant activity which possibly indicates their potential use as anti-promoters. The amount of curcuminoids (I, II and III) needed for 50% inhibition of lipid peroxidation was 20, 14 and 11 g/m. Concentrations needed for 50% inhibition of superoxides were 6.25, 4.25 and 1.9 micrograms/ml and those for hydroxyl radical were 2.3, 1.8 and 1.8 micrograms/ml, respectively. The ability of these compounds to suppress the superoxide production by macrophages activated with phorbol-12-myristate-13-acetate (PMA) indicated that all the three curcuminoids inhibited superoxide production and curcumin III produced maximum effect. These results indicate that curcumin III is the most active of the curcuminoids present in turmeric. Synthetic curcumin I and III had similar activity to natural curcumins.
One Ras-dependent protein kinase cascade leading from growth factor receptors to the ERK (extracellular signal-regulated kinases) subgroup of mitogen-activated protein kinases (MAPKs) is dependent on the protein kinase Raf-1, which activates the MEK (MAPK or ERK kinase) dual specificity kinases. A second protein kinase cascade leading to activation of the Jun kinases (JNKs) is dependent on MEKK (MEK kinase). A dual-specificity kinase that activates JNK, named JNKK, was identified that functions between MEKK and JNK. JNKK activated the JNKs but did not activate the ERKs and was unresponsive to Raf-1 in transfected HeLa cells. JNKK also activated another MAPK, p38 (Mpk2; the mammalian homolog of HOG1 from yeast), whose activity is regulated similarly to that of the JNKs.
Treatment of cells with pro-inflammatory cytokines or ultraviolet radiation causes activation of the c-Jun NH2-terminal protein
kinase (JNK). Activating transcription factor-2 (ATF2) was found to be a target of the JNK signal transduction pathway. ATF2
was phosphorylated by JNK on two closely spaced threonine residues within the NH2-terminal activation domain. The replacement
of these phosphorylation sites with alanine inhibited the transcriptional activity of ATF2. These mutations also inhibited
ATF2-stimulated gene expression mediated by the retinoblastoma (Rb) tumor suppressor and the adenovirus early region 1A (E1A)
oncoprotein. Furthermore, expression of dominant-negative JNK inhibited ATF2 transcriptional activity. Together, these data
demonstrate a role for the JNK signal transduction pathway in transcriptional responses mediated by ATF2.
Mammalian mitogen-activated protein (MAP) kinases include extracellular signal-regulated protein kinase (ERK), c-Jun amino-terminal
kinase (JNK), and p38 subgroups. These MAP kinase isoforms are activated by dual phosphorylation on threonine and tyrosine.
Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. These MKK isoforms
did not activate the ERK subgroup of MAP kinases, but MKK4 did activate JNK. These data demonstrate that the activators of
p38 (MKK3 and MKK4), JNK (MKK4), and ERK (MEK1 and MEK2) define independent MAP kinase signal transduction pathways.
Curcumin (diferuloylmethane), a yellow pigment that is obtained from the rhizomes of Curcuma longa Linn., is a major component of turmeric and is commonly used as a spice and food-coloring agent. The inhibitory effects of feeding commercial grade curcumin (77% curcumin, 17% demethoxycurcumin, and 3% bisdemethoxycurcumin) in AIN 76A diet on carcinogen-induced tumorigenesis in the forestomach, duodenum, and colon of mice were evaluated. Administration p.o. of commercial grade curcumin in the diet inhibited benzo(a)pyrene-induced forestomach tumorigenesis in A/J mice, N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumorigenesis in C57BL/6 mice, and azoxymethane (AOM)-induced colon tumorigenesis in CF-1 mice. Dietary commercial grade curcumin was given to mice at: (a) 2 weeks before, during, and for 1 week after carcinogen administration (during the initiation period); (b) 1 week after carcinogen treatment until the end of the experiment (during the postinitiation period); or (c) during both the initiation and postinitiation periods. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of benzo(a)pyrene-induced forestomach tumors per mouse by 51-53% when administered during the initiation period and 47-67% when administered during the postinitiation period. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumors per mouse by 47-77% when administered during the postinitiation period. Administration of 0.5-4.0% commercial grade curcumin in the diet both during the initiation and postinitation periods decreased the number of AOM-induced colon tumors per mouse by 51-62%. Administration of 2% commercial grade curcumin in the diet inhibited the number of AOM-induced colon tumors per mouse by 66% when fed during the initiation period and 25% when fed during the postinitiation period. The ability of commercial grade curcumin to inhibit AOM-induced colon tumorigenesis is comparable to that of pure curcumin (purity greater than 98%). Administration of pure or commercial grade curcumin in the diet to AOM-treated mice resulted in development of colon tumors which were generally smaller in number and size as compared to the control group of AOM-treated mice. These results indicate that not only did curcumin inhibit the number of tumors per mouse and the percentage of mice with tumors but it also reduced tumor size. Histopathological examination of the tumors showed that dietary curcumin inhibited the number of papillomas and squamous cell carcinomas of the forestomach as well as the number of adenomas and adenocarcinomas of the duodenum and colon.
The ultraviolet (UV) response of mammalian cells is characterized by a rapid and selective increase in gene expression mediated by AP-1 and NF-kappa B. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. Here, we describe the molecular cloning and characterization of JNK1, a distant relative of the MAP kinase group that is activated by dual phosphorylation at Thr and Tyr during the UV response. Significantly, Ha-Ras partially activates JNK1 and potentiates the activation caused by UV. JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. Thus, JNK1 is a component of a novel signal transduction pathway that is activated by oncoproteins and UV irradiation. These properties indicate that JNK1 activation may play an important role in tumor promotion.
Transcription of lymphokine genes in activated T cells is inhibited by the immunosuppressive agents cyclosporin A and FK506, which act by blocking the phosphatase activity of calcineurin. NFAT, a DNA-binding protein required for interleukin-2 gene transcription, is a potential target for calcineurin, cyclosporin A and FK506. NFAT contains a subunit (NFATp) which is present in unstimulated T cells and which forms a complex with Fos and Jun proteins in the nucleus of activated T cells. Here we report that NFATp is a DNA-binding phosphoprotein of relative molecular mass approximately 120,000 and is a substrate for calcineurin in vitro. Purified NFATp forms DNA-protein complexes with recombinant Jun homodimers or Jun-Fos heterodimers; the DNA-binding domains of Fos and Jun are essential for the formation of the NFATp-Fos-Jun-DNA complex. The interaction between the lymphoid-specific factor NFATp and the ubiquitous transcription factors Fos and Jun provides a novel mechanism for combinatorial regulation of interleukin-2 gene transcription, which integrates the calcium-dependent and the protein-kinase C-dependent pathways of T-cell activation.
The c-Jun amino-terminal kinases (JNKs)/stress-activated protein kinases (SAPKs) play a crucial role in stress responses in mammalian cells. The mechanism underlying this pathway in the hematopoietic system is unclear, but it is a key in understanding the molecular basis of blood cell differentiation. We have cloned a novel protein kinase, termed hematopoietic progenitor kinase 1 (HPK1), that is expressed predominantly in hematopoietic cells, including early progenitor cells. HPK1 is related distantly to the p21(Cdc42/Rac1)-activated kinase (PAK) and yeast STE20 implicated in the mitogen-activated protein kinase (MAPK) cascade. Expression of HPK1 activates JNK1 specifically, and it elevates strongly AP-1-mediated transcriptional activity in vivo. HPK1 binds and phosphorylates MEKK1 directly, whereas JNK1 activation by HPK1 is inhibited by a dominant-negative MEKK1 or MKK4/SEK mutant. Interestingly, unlike PAK65, HPK1 does not contain the small GTPase Rac1/Cdc42-binding domain and does not bind to either Rac1 or Cdc42, suggesting that HPK1. activation is Rac1/Cdc42-independent. These results indicate that HPK1 is a novel functional activator of the JNK/SAPK signaling pathway.
Mitogen-activated protein (MAP) kinases are proline-directed serine/threonine kinases that are activated by dual phosphorylation on threonine and tyrosine residues in response to a wide array of extracellular stimuli. Three distinct groups of MAP kinases have been identified in mammalian cells [extracellular-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38]. These MAP kinases are mediators of signal transduction from the cell surface to the nucleus. One nuclear target of these MAP kinase signaling pathways is the transcription factor AP-1. MAP kinases regulate AP-1 transcriptional activity by multiple mechanisms. Here we review recent progress towards understanding AP-1 regulation by the ERK, JNK, and p38 MAP kinase signal transduction pathways.
Regulation of the mitogen-activated protein kinase (MAPK) family members - which include the extracellular response kinases (ERKs), p38/HOG1, and the c-Jun amino-terminal kinases (JNKs) - plays a central role in mediating the effects of diverse stimuli encompassing cytokines, hormones, growth factors and stresses such as osmotic imbalance, heat shock, inhibition of protein synthesis and irradiation. A rapidly increasing number of kinases that activate the JNK pathways has been described recently, including the MAPK/ERK kinase kinases, p21-activated kinases, germinal center kinase, mixed lineage kinases, tumor progression locus 2, and TGF-beta-activated kinase. Thus, regulation of the JNK pathway provides an interesting example of how many different stimuli can converge into regulating pathways critical for the determination of cell fate.
Nearly all cell surface receptors utilize one or more of the mitogen-activated protein kinase cascades in their repertoire of signal transduction mechanisms. Recent advances in the study of such cascades include the cloning of genes encoding novel members of the cascades, further definition of the roles of the cascades in responses to extracellular signals, and examination of cross-talk between different cascades.
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