Phorbol

CAS# 17673-25-5

Phorbol

Catalog No. BCN3726----Order now to get a substantial discount!

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Chemical structure

Phorbol

3D structure

Chemical Properties of Phorbol

Cas No. 17673-25-5 SDF Download SDF
PubChem ID 442070 Appearance Powder
Formula C20H28O6 M.Wt 364.4
Type of Compound Diterpenoids Storage Desiccate at -20°C
Synonyms 4β-Phorbol
Solubility DMSO : 66.67 mg/mL (182.94 mM; Need ultrasonic)
H2O : ≥ 20 mg/mL (54.88 mM)
*"≥" means soluble, but saturation unknown.
SMILES CC1C(C2(C(C2(C)C)C3C1(C4C=C(C(=O)C4(CC(=C3)CO)O)C)O)O)O
Standard InChIKey QGVLYPPODPLXMB-UBTYZVCOSA-N
Standard InChI InChI=1S/C20H28O6/c1-9-5-13-18(24,15(9)22)7-11(8-21)6-12-14-17(3,4)20(14,26)16(23)10(2)19(12,13)25/h5-6,10,12-14,16,21,23-26H,7-8H2,1-4H3/t10-,12+,13-,14-,16-,18-,19-,20-/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Source of Phorbol

The roots of Euphorbia pekinensis Rupr.

Biological Activity of Phorbol

DescriptionPhorbol is a natural product from Euphorbia pekinensis Rupr.

Protocol of Phorbol

Structure Identification
Chinese Journal of Spectroscopy Laboratory, 2011 , 28 (2) :801-805.

Determination of Phorbol in the Seeds of Croton Tiglium Linn by RP-HPLC[Reference: WebLink]


METHODS AND RESULTS:
The determination of Phorbol in the seeds of Croton tiglium linn by HPLC was investigated. Shimadzu LC-2010 HPLC,Diamonsil C18 column(250mm×4.6mm,5μm) were uesd,and the mobile phase was consisted of acetonitrile-water(gradient elution) with the flow rate of 1mL/min.The detection wavelength was 234nm,and the column temperature was 25℃.There was a good linear relationship of Phorbol in the range of 6.096—101.600μg/mL(r=0.9999),while the average standard recovery was 96.40% with RSD of 1.03%.
CONCLUSIONS:
The method is established for determination of Phorbol in the seeds of Croton tiglium linn by RP-HPLC,and provides a means for future study.

Phorbol Dilution Calculator

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Preparing Stock Solutions of Phorbol

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.7442 mL 13.7212 mL 27.4424 mL 54.8847 mL 68.6059 mL
5 mM 0.5488 mL 2.7442 mL 5.4885 mL 10.9769 mL 13.7212 mL
10 mM 0.2744 mL 1.3721 mL 2.7442 mL 5.4885 mL 6.8606 mL
50 mM 0.0549 mL 0.2744 mL 0.5488 mL 1.0977 mL 1.3721 mL
100 mM 0.0274 mL 0.1372 mL 0.2744 mL 0.5488 mL 0.6861 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Phorbol

Phorbol is a highly toxic diterpene, whose esters have important biological properties.

References:
[1]. Matsuzawa Y, et al. Activation of cytosolic phospholipase A2alpha by epidermal growth factor (EGF) and phorbol ester in HeLa cells: different effects of inhibitors for EGF receptor, protein kinase C, Src, and C-Raf. J Pharmacol Sci. 2009 Oct;111(2):182-92

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References on Phorbol

Neutrophil Effector Functions Are Not Impaired in Duffy Antigen Receptor for Chemokines (DARC)-Null Black South Africans.[Pubmed:30972057]

Front Immunol. 2019 Mar 26;10:551.

Neutrophils are well-recognized for their pathogen killing mechanisms and disorders of neutrophil count and function are associated with recurrent infections. The Duffy Antigen Receptor for Chemokines (DARC)-null genotype is predominant in sub-Saharan African ancestry populations and is the major genetic determinant of benign ethnic neutropenia which has been associated with increased risk of Human Immunodeficiency Virus (HIV)-1 acquisition and mother-to-child transmission. However, the impact of DARC-null-linked neutropenia on HIV disease progression remains controversial. While the DARC-null genotype is associated with low numbers of circulating neutrophils, the effects of the polymorphism on neutrophil functions is unknown. We investigated the impact of the DARC-null trait and lower absolute neutrophil counts (ANCs) on key neutrophil effector functions [proteolytic activity within the phagosome following Fc receptor-mediated phagocytosis, reactive oxygen species (ROS) production, and neutrophil extracellular trap (NET) formation] in 20 HIV negative and 22 HIV-1 chronically infected black South Africans. Phagosome maturation was measured by flow cytometry following Fc-mediated uptake of IgG opsonized beads; ROS production was measured by chemi-luminescence after activation of neutrophils with Phorbol 12-myristate 13-acetate (PMA). Activated neutrophils were also visualized by fluorescent microscopy for NET quantification. Study subjects were genotyped for the DARC trait using TaqMan allelic discrimination assays and ANCs were measured by full blood count. As expected, the DARC-null polymorphism was highly prevalent in our participant cohort (69%) and was strongly associated with lower ANCs in uninfected (p = 0.0007) and HIV-1 infected (p = 0.03) subjects. We observed enhanced proteolytic activity within the phagosome in the absence of DARC at 10 min (p = 0.05 and p = 0.009) and 60 min (p = 0.05 and p = 0.07) in uninfected and HIV-1 infected subjects, respectively. ROS was unaffected by DARC trait irrespective of HIV status. Furthermore, formation of NETs was reduced in neutrophils from DARC-null subjects (p = 0.04) following prolonged in vitro stimulation, but only in HIV-1 infected subjects. The data indicate differential neutrophil function in the absence of DARC that may be moderately modulated by HIV-1 infection but overall, the data suggest that DARC-null trait is not deleterious to neutrophil effector functions in African populations.

Skin and Systemic Inflammation in Schnitzler's Syndrome Are Associated With Neutrophil Extracellular Trap Formation.[Pubmed:30967871]

Front Immunol. 2019 Mar 22;10:546.

Schnitzler's syndrome is a rare autoinflammatory disorder characterized by interleukin-1ss-mediated and neutrophil-dominated inflammation. Neutrophil extracellular traps (NETs) are web-like structures of decondensed chromatin, histones, and antimicrobial peptides released by neutrophils. NETs were initially described in the context of pathogen defense but are also involved in autoimmune-mediated skin diseases. Here, we assessed the role of neutrophil extracellular trap formation (NETosis) in Schnitzler's syndrome. Immunofluorescence co-staining of myeloperoxidase and subnucleosomal complex was performed on lesional skin samples from patients with Schnitzler's syndrome, other neutrophilic dermatoses (cryopyrin-associated periodic syndrome, Sweet syndrome, and pyoderma gangrenosum), urticarial vasculitis and chronic spontaneous urticaria as well as healthy control skin. Blood neutrophils from patients with Schnitzler's syndrome and controls were isolated, and NETosis was induced by Phorbol 12-myristate 13-acetate (PMA). Also, NETosis of control neutrophils induced by symptomatic Schnitzler's syndrome sera, cytokines and sub-threshold PMA doses was studied. Immunofluorescence co-staining revealed widespread and substantial NET formation in lesional skin of Schnitzler's syndrome patients but absence of NETs in chronic spontaneous urticaria and control skin. Neutrophils undergoing NETosis were observed in the skin of other neutrophilic diseases too. Correspondingly, blood neutrophils from Schnitzler's syndrome patients showed significantly elevated NETosis rates compared to control neutrophils following stimulation with PMA. Increased NETosis correlated well with high levels of C-reactive protein (CRP). SchS patients with the lowest NETosis rates had persistent joint and bone pain despite IL-1 blockade. Stimulation of control neutrophils and sub-threshold PMA with sera of symptomatic Schnitzler's syndrome patients disclosed enhanced NETosis as compared to control sera. Our results suggest that the induction of NET formation by neutrophils contributes to skin and systemic inflammation and may support the resolution of local inflammation in Schnitzler's syndrome.

Sumoylation of a small isoform of NFATc1 is promoted by PIAS proteins and inhibits transactivation activity.[Pubmed:30952432]

Biochem Biophys Res Commun. 2019 Apr 2. pii: S0006-291X(19)30571-6.

The NFAT family of transcription factors plays an important role in immune system development and function. NFATc1 and NFATc2 are highly expressed in peripheral T cells, and several isoforms are produced via the use of different promoters and polyadenylation sites. The specific isoforms with relatively long C-termini, NFATc1/C and NFATc2/A, have been shown to be modified by SUMO within their specific C-terminal regions, which regulates NFAT protein localization and transactivation activity. Here, we demonstrate that an isoform NFATc1/A, which has a short C-terminus and does not contain the sumoylation sites found in the long isoforms, is also modified by SUMO. NFATc1/A sumoylation increased with low level expression of SUMO E3 ligases, specifically PIAS1, PIAS3, and PIASy, in co-transfected cells. PIAS3 interacted with NFATc1/A and an active site mutant failed to promote NFATc1/A sumoylation, indicating a role for PIAS3 as a SUMO E3 ligase. A lysine residue at 351 within the central regulatory domain was identified as the major SUMO attachment site in both co-transfection and in vitro assays. Sumoylation of NFATc1/A did not affect nuclear translocation upon ionomycin and Phorbol 12-myristate 13-acetate treatment. However, although sumoylation of NFATc1/A slightly increased protein stability, it inhibited transactivation activity for reporter genes driven by promoters containing NFAT sites. Our results indicate that the transactivation activity of NFATc1/A is negatively regulated by PIAS protein-mediated sumoylation, and that SUMO is a general regulator of NFAT family members with either long or short C-termini.

Electrochemiluminescence cytosensing platform based on Ru(bpy)3(2+)@silica-Au nanocomposite as luminophore and AuPd nanoparticles as coreaction accelerator for in situ evaluation of intracellular H2O2.[Pubmed:30952288]

Talanta. 2019 Jul 1;199:485-490.

An electrochemiluminescence (ECL) cytosensor was fabricated onto a microfluidic paper-based analytical device (mu-PAD) in order to detect hydrogen peroxide (H2O2) which was released from tumor cells. The ECL probe Ru(bpy)3(2+)@silica-Au nanocomposite (Ru@SiO2-Au) was fabricated and served as ECL reagent. The ECL of Ru@SiO2-Au nanocomposite was quenched by the ferrocene (Fc). AuPd nanoparticles (AuPd NPs), which were modified on the paper working electrode (PWE), were served as the catalyst of H2O2 to produce hydroxyl radicals (*OH) for cleaving Fc-labelled DNA to achieve "signal-on", and AuPd NPs also severed as coreaction accelerator. H2O2 was released from cells under the stimulation of Phorbol myristate acetate. Fc-labelled DNA strand was cleaved via *OH. Fc molecule departed from the PWE surface, The ECL could be recovered. An ECL cytosensor on a 3D origami device was constructed. The ECL response of the Ru@SiO2-Au-Fc system was related to the number of cells. The ECL intensity was quantitatively related with the logarithm of MCF-7 cells number and H2O2 concentration, the detection limit was 30 cellsmL(-1). As a consequence, this work provided a really low-cost and disposable mu-PAD for sensitive detection of intracellular H2O2. What's more, this work had potential application value for studying cellular biology and pathophysiology.

The Liver X Receptor Is Upregulated in Monocyte-Derived Macrophages and Modulates Inflammatory Cytokines Based on LXRalpha Polymorphism.[Pubmed:30944547]

Mediators Inflamm. 2019 Feb 28;2019:6217548.

Liver X receptors (LXRs) have emerged as important regulators of inflammatory gene expression. Previously, we had reported that an LXRalpha gene promoter polymorphism (-1830 T > C) is associated with systemic lupus erythematosus (SLE). Therefore, we assessed cytokine expression in relation to LXRalpha polymorphism in monocyte-derived macrophages from patients with SLE. Macrophages were obtained after 72 hours of culture of human monocytes supplemented with Phorbol 12-myristate 13-acetate. Cells were transfected with LXRalpha promoter constructs. Additionally, peripheral blood mononuclear cell- (PBMC-) derived macrophages from the patients were evaluated for proinflammatory cytokines in relation to the genotypes of LXRalpha -1830 T > C. The expression of LXRalpha was increased in macrophages; levels of proinflammatory cytokines were decreased with LXRalpha expression. Production of proinflammatory cytokines varied depending on LXRalpha -1830 T > C genotype. In particular, expression of LXRalpha was decreased and that of proinflammatory cytokines was increased for LXRalpha -1830 TC genotype compared to that for TT genotype. The data were consistent in PBMC-derived macrophages from patients with SLE. Increased proinflammatory cytokines is related to TLR7 and TLR9 expression. These data suggest that the expression levels of LXRalpha, according to LXRalpha -1830 T > C genotype, may contribute to the inflammatory response by induction of inflammatory cytokines in SLE.

NOX4 is a major regulator of cord blood-derived endothelial colony-forming cells which promotes postischaemic revascularisation.[Pubmed:30937452]

Cardiovasc Res. 2019 Apr 1. pii: 5425328.

AIMS: Cord blood-derived endothelial colony-forming cells (CB-ECFCs) are a defined progenitor population with established roles in vascular homeostasis and angiogenesis, which possess low immunogenicity and high potential for allogeneic therapy, and are highly sensitive to regulation by reactive oxygen species (ROS). The aim of this study was to define the precise role of the major ROS-producing enzyme, NOX4 NADPH oxidase, in CB-ECFC vasoreparative function. METHODS AND RESULTS: In vitro CB-ECFC migration (scratch-wound assay) and tubulogenesis (tube length, branch number) was enhanced by Phorbol 12-myristate 13-acetate (PMA)-induced superoxide in a NOX-dependent manner. CB-ECFCs highly-expressed NOX4 which was further induced by PMA, whilst NOX4 siRNA and plasmid overexpression reduced and potentiated in vitro function, respectively. Increased ROS generation in NOX4-overexpressing CB-ECFCs (DCF fluorescence, flow cytometry) was specifically reduced by superoxide dismutase, highlighting induction of ROS-specific signalling. Laser Doppler imaging of mouse ischaemic hindlimbs at 7 days indicated that NOX4-knockdown CB-ECFCs inhibited blood flow recovery which was enhanced by NOX4-overexpressing CB-ECFCs. Tissue analysis at 14 days revealed consistent alterations in vascular density (lectin expression) and eNOS protein despite clearance of injected CB-ECFCs, suggesting NOX4-mediated modulation of host tissue. Indeed, proteome array analysis indicated that NOX4-knockdown CB-ECFCs largely suppressed tissue angiogenesis, whilst NOX4-overexpressing CB-ECFCs upregulated a number of pro-angiogenic factors specifically-linked with eNOS signalling, in parallel with equivalent modulation of NOX-dependent ROS generation, suggesting that CB-ECFC NOX4 signalling may promote host vascular repair. CONCLUSIONS: Taken together, these findings indicate a key role for NOX4 in CB-ECFCs, thereby highlighting its potential as a target for enhancing their reparative function through therapeutic priming to support creation of a pro-reparative microenvironment and effective postischaemic revascularisation.

Heterologous regulation of CXCR4 lysosomal trafficking.[Pubmed:30936203]

J Biol Chem. 2019 Apr 1. pii: RA118.005991.

G-protein coupled receptor (GPCR) signaling is regulated by members of the protein kinase C (PKC) and GPCR kinase (GRK) families, although the relative contribution of each to GPCR function varies among specific GPCRs. The CXC motif receptor 4 (CXCR4) is a member of the GPCR superfamily that binds the CXC motif chemokine ligand 12 (CXCL12) initiating signaling that is subsequently terminated in part by internalization and lysosomal degradation of CXCR4. The purpose of this study is to define the relative contribution of protein kinase C (PKC) and GRK to CXCR4 signaling attenuation by studying their effects on CXCR4 lysosomal trafficking and degradation. Our results demonstrate that direct activation of PKC via the Phorbol ester PMA mimics CXCL12-mediated desensitization, internalization, ubiquitination and lysosomal trafficking of CXCR4. In agreement, heterologous activation of PKC by stimulating the chemokine receptor CXCR5 with its ligand CXCL13, also mimics CXCL12-mediated desensitization, internalization, ubiquitination and lysosomal degradation of CXCR4. Similar to CXCL12, PMA promotes PKC-dependent phosphorylation of serine residues within CXCR4 C-tail that are required for binding and ubiquitination by the E3 ubiquitin ligase AIP4 (atrophin interacting protein 4). However, inhibition of PKC activity does not alter CXCL12-mediated ubiquitination and degradation of CXCR4, suggesting that other kinases are also required. Accordingly, siRNA mediated depletion of GRK6 results in decreased degradation and ubiquitination of CXCR4. Overall these results suggest that PKC and GRK6 contribute to unique aspects of CXCR4 phosphorylation and lysosomal degradation that ensue proper signal propagation and termination.

Pharmaceutical immunoglobulins reduce neutrophil extracellular trap formation and ameliorate the development of MPO-ANCA-associated vasculitis.[Pubmed:30932727]

Mod Rheumatol. 2019 Apr 1:1-7.

OBJECTIVES: Intravenous immunoglobulin (IVIG) therapy is effective against some autoimmune diseases. We examined the effects of pharmaceutical immunoglobulins on the development of MPO-ANCA-associated vasculitis (MPO-AAV). METHODS: Peripheral blood neutrophils were pretreated with 5 mg/ml sulfo-immunoglobulins (IVIG-S) and then exposed to 100 nM Phorbol myristate acetate (PMA). Thereafter, neutrophil extracellular traps (NETs) were detected by flow cytometry. Next, Wistar-Kyoto rats were given oral administration of 10 mg/kg/day propylthiouracil for 28 days and intraperitoneal (i.p.) injection of 1 mug PMA on days 0 and 7. These rats were divided into two groups: Group 1 with i.p. injection of 400 mg/kg IVIG-S on days 8-12 and Group 2 with vehicle similarly. ANCA titers were chronologically determined by indirect immunofluorescence. On day 28, all rats were killed to examine NET formation in the peritoneum and the development of AAV. RESULTS: IVIG-S significantly inhibited NET formation induced by PMA in vitro. NET amounts in the peritoneum in Group 1 were significantly smaller than in Group 2, and ANCA titers in Group 1 were significantly lower than in Group 2. The degree of pulmonary hemorrhage in Group 1 was also smaller than in Group 2. CONCLUSION: IVIG-S reduce NET formation and ameliorate the development of MPO-AAV.

Sodium Orthovanadate Changes Fatty Acid Composition and Increased Expression of Stearoyl-Coenzyme A Desaturase in THP-1 Macrophages.[Pubmed:30927246]

Biol Trace Elem Res. 2019 Mar 29. pii: 10.1007/s12011-019-01699-2.

Vanadium compounds are promising antidiabetic agents. In addition to regulating glucose metabolism, they also alter lipid metabolism. Due to the clear association between diabetes and atherosclerosis, the purpose of the present study was to assess the effect of sodium orthovanadate on the amount of individual fatty acids and the expression of stearoyl-coenzyme A desaturase (SCD or Delta(9)-desaturase), Delta(5)-desaturase, and Delta(6)-desaturase in macrophages. THP-1 macrophages differentiated with Phorbol 12-myristate 13-acetate (PMA) were incubated in vitro for 48 h with 1 muM or 10 muM sodium orthovanadate (Na3VO4). The estimation of fatty acid composition was performed by gas chromatography. Expressions of the genes SCD, fatty acid desaturase 1 (FADS1), and fatty acid desaturase 2 (FADS2) were tested by qRT-PCR. Sodium orthovanadate in THP-1 macrophages increased the amount of saturated fatty acids (SFA) such as palmitic acid and stearic acid, as well as monounsaturated fatty acids (MUFA)-oleic acid and palmitoleic acid. Sodium orthovanadate caused an upregulation of SCD expression. Sodium orthovanadate at the given concentrations did not affect the amount of polyunsaturated fatty acids (PUFA) such as linoleic acid, arachidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). In conclusion, sodium orthovanadate changed SFA and MUFA composition in THP-1 macrophages and increased expression of SCD. Sodium orthovanadate did not affect the amount of any PUFA. This was associated with a lack of influence on the expression of FADS1 and FADS2.

Alcohol dehydrogenase of Candida albicans triggers differentiation of THP-1 cells into macrophages.[Pubmed:30923636]

J Adv Res. 2019 Feb 28;18:137-145.

Candida albicans proteins located on the cell wall and in the cytoplasm have gained great attention because they are not only involved in cellular metabolism and the maintenance of integrity but also interact with host immune systems. Previous research has reported that enolase from C. albicans exhibits high immunogenicity and effectively protects mice against disseminated candidiasis. In this study, alcohol dehydrogenase (ADH) of C. albicans was cloned and purified for the first time, and this study focused on evaluating its effects on the differentiation of the human monocytic cell line THP-1. The morphological features of THP-1 cells exposed to ADH were similar to those of Phorbol-12-myristate acetate-differentiated (PMA-differentiated) macrophages. Functionally, ADH enhanced the adhesion, phagocytosis, and killing capacities of THP-1 cells. A flow cytometric assay demonstrated that ADH-induced THP-1 cells significantly increased CD86 and CD11b expression. The production of IL-1beta, IL-6, and TNF-alpha by cells increased in the presence of ADH. As expected, after pretreatment with a MEK inhibitor (U0126), ADH-induced THP-1 cells exhibited unaltered morphological features, eliminated ERK1/2 phosphorylation, prevented CD86/CD11b upregulation and inhibited pro-inflammatory cytokine increase. Collectively, these results suggest that ADH enables THP-1 cells to differentiate into macrophages via the ERK pathway, and it may play an important role in the immune response against fungal invasion.

Distinctive requirement of PKCepsilon in the control of Rho GTPases in epithelial and mesenchymally transformed lung cancer cells.[Pubmed:30923343]

Oncogene. 2019 Mar 28. pii: 10.1038/s41388-019-0796-4.

Diacylglycerol (DAG)/Phorbol ester-regulated protein kinase C (PKC) isozymes have been widely linked to tumor promotion and the development of a metastatic phenotype. PKCepsilon, an oncogenic member of the PKC family, is abnormally overexpressed in lung cancer and other cancer types. This kinase plays significant roles in proliferation, survival, and migration; however, its role in epithelial-to-mesenchymal transition (EMT) has been scarcely studied. Silencing experiments in non-small lung cancer (NSCLC) cells revealed that PKCepsilon or other DAG-regulated PKCs (PKCalpha and PKCdelta) were dispensable for the acquisition of a mesenchymal phenotype induced by transforming growth factor beta (TGF-beta). Unexpectedly, we found a nearly complete down-regulation of PKCepsilon expression in TGF-beta-mesenchymally transformed NSCLC cells. PMA and AJH-836 (a DAG-mimetic that preferentially activates PKCepsilon) promote ruffle formation in NSCLC cells via Rac1, however they fail to induce these morphological changes in TGF-beta-mesenchymally transformed cells despite their elevated Rac1 activity. Several Rac guanine nucleotide exchange-factors (Rac-GEFs) were also up-regulated in TGF-beta-treated NSCLC cells, including Trio and Tiam2, which were required for cell motility. Lastly, we found that silencing or inhibiting PKCepsilon enhances RhoA activity and stress fiber formation, a phenotype also observed in TGF-beta-transformed cells. Our studies established a distinctive involvement of PKCepsilon in epithelial and mesenchymal NSCLC cells, and identified a complex interplay between PKCepsilon and small GTPases that contributes to regulation of NSCLC cell morphology and motile activity.

Sequence characterization and expression pattern analysis of six kinds of IL-17 family genes in the Asian swamp eel (Monopterus albus).[Pubmed:30922887]

Fish Shellfish Immunol. 2019 Mar 26;89:257-270.

Interleukin-17 (IL-17) is an important cytokine that plays a critical role in the inflammatory response and host defense against extracellular pathogens. In the present study, six novel IL-17 family genes (MaIL-17) were identified by analyzing Asian swamp eel (Monopterus albus) genome. Sequence analysis revealed that the MaIL-17 family genes shared similar features, comprising a signal peptide, an IL-17 superfamily region, and four conserved cysteines. Phylogenetic analysis showed that the MaIL-17 genes were clustered together with their corresponding IL-17 genes from other species. The similarity and identity of all IL-17 family genes indicated that the MaIL-17 genes are conserved among teleosts, while Ma-IL-17D is more conserved than the other Ma-IL-17s. Except for MaIL-17A/F3 and MaIL-17D, all MaIL-17s shared the same genomic structure as the genes from other fish, namely three exons and two introns. The MaIL-17s showed conserved synteny among fish, and we found that the MaIL-17D locus has a more conserved syntenic relationship with the loci from other fish and humans. These results demonstrated that MaIL-17D and human IL-17D might have evolved from a common ancestral gene and subsequently diverged. The analysis of swamp eel reference genes revealed that EEF1A1 (encoding eukaryotic translation elongation factor 1 alpha 1) was an ideal reference gene for accurate real-time qRT-PCR normalization in the swamp eel. The MaIL-17 genes are widely distributed throughout tissues, suggesting that MaIL-17s carry out their biological functions in immune and non-immune tissues compartments. The transcript of Ma-IL17s exhibited different fold changes in head kidney cells in response to Aeromonas veronii Phorbol 12-myristate 13-acetate (PMA) and polyinosinic:polycytidylic acid (poly I:C) challenge, showing that MaIL-17A/F1 has stronger antiviral activities compared with other MaIL-17 family genes, and that MaIL-17A/F3 and MaIL-17A/F2 possess stronger effects against extracellular pathogens compared with the others; however, MaIL-17C2 and MaIL-17D may play vital roles during pathogen infection. The differential immune responses of these genes to Aeromonas veronii, PMA and poly I:C implied distinct mechanisms of host defense against extracellular pathogens.

PKC regulates the production of fibroblast growth factor 23 (FGF23).[Pubmed:30921339]

PLoS One. 2019 Mar 28;14(3):e0211309.

Serine/threonine protein kinase C (PKC) is activated by diacylglycerol that is released from membrane lipids by phospholipase C in response to activation of G protein-coupled receptors or receptor tyrosine kinases. PKC isoforms are particularly relevant for proliferation and differentiation of cells including osteoblasts. Osteoblasts/osteocytes produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D handling. PKC activates NFkappaB, a transcription factor complex controlling FGF23 expression. Here, we analyzed the impact of PKC on FGF23 synthesis. Fgf23 expression was analyzed by qRT-PCR in UMR106 osteoblast-like cells and in IDG-SW3 osteocytes, and FGF23 protein was measured by ELISA. Phorbol ester 12-O-tetradecanoylPhorbol-13-acetate (PMA), a PKC activator, up-regulated FGF23 production. In contrast, PKC inhibitors calphostin C, Go6976, sotrastaurin and ruboxistaurin suppressed FGF23 formation. NFkappaB inhibitor withaferin A abolished the stimulatory effect of PMA on Fgf23. PKC is a powerful regulator of FGF23 synthesis, an effect which is at least partly mediated by NFkappaB.

Epimagnolin A inhibits IL-6 production by inhibiting p38/NF-kappaB and AP-1 signaling pathways in PMA-stimulated THP-1 cells.[Pubmed:30919561]

Environ Toxicol. 2019 Mar 27.

Epimagnolin A is a lignan obtained from the flower buds of Magnolia fargesii, which is traditionally used in Asian medicine for treating headache and nasal congestion. A herbal compound fargesin obtained from M. fargesii, has exerted anti-inflammatory effects in human monocytic THP-1 cells in the previous study. The anti-inflammatory effects of epimagnolin A, however, have been not elucidated yet. In this study, it was demonstrated that epimagnolin A reduced Phorbol-12-myristate-13-acetate (PMA)-induced IL-6 promoter activity and IL-6 production in human monocytic THP-1 cells. Furthermore, it was investigated the modulating effects of epimagnolin A on mitogen-activated protein kinase, nuclear factor-kappa B (NF-kappaB), and activator protein 1 (AP-1) activities. Phosphorylation of p38 and nuclear translocation of p50 and c-Jun were down-regulated by epimagnolin A in the PMA-stimulated THP-1 cell. The results revealed that epimagnolin A attenuated the binding affinity of NF-kappaB and AP-1 transcription factors to IL-6 promoter and IL-6 production through p38/NF-kB and AP-1 signaling pathways in the PMA-stimulated THP-1 cells. These results suggest that epimagnolin A can be a useful drug for the treatment of inflammatory diseases.

A new macrocyclic diterpenoid from Anisomeles indica.[Pubmed:30908093]

Nat Prod Res. 2019 Mar 25:1-9.

A new macrocyclic diterpenoid, 4beta,5beta-dihydroxyovatodiolide (1), together with twenty-two known compounds (2-23) were isolated from the MeOH extract of the dried aerial parts of Anisomeles indica (L.) O. Kuntze (Labiatae). The structure of 1 was established on the basis of spectral evidence. Phenylethanoids, acteoside (5) and isoacteoside (6) showed significant inhibitory to IL-2 secretion of with respect to Phorbol myristate acetate and anti-CD28 monoclonal antibody co-stimulated activation of human peripheral blood T cells.

Description

Phorbol is a highly toxic diterpene, whose esters have important biological properties.

Keywords:

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