Natural products afford a window of opportunity to study important biology. If the natural product is used or abused by human beings, finding its biological target(s) is all the more significant. Hot pepper is eaten on a daily basis by an estimated one-quarter of the world’s population and

Vanilloid (Capsaicin) Receptors and Mechanisms

Differentiated macrophages are the resident tissue phagocytes and sentinel cells of the innate immune response. The phenotype of mature tissue macrophages represents the composite of environmental and differentiation-dependent imprinting. Phorbol-12-myristate-13-acetate (PMA) and 1,25-dihydroxyvitamin D3 (VD3) are stimuli commonly used to induce macrophage differentiation in monocytic cell lines but the extent of differentiation in comparison to primary tissue macrophages is unclear. We have compared the phenotype of the promonocytic THP-1 cell line after various protocols of differentiation utilising VD3 and PMA in comparison to primary human monocytes or monocyte-derived macrophages (MDM). Both stimuli induced changes in cell morphology indicative of differentiation but neither showed differentiation comparable to MDM. In contrast, PMA treatment followed by 5 days resting in culture without PMA (PMAr) increased cytoplasmic to nuclear ratio, increased mitochondrial and lysosomal numbers and altered differentiation-dependent cell surface markers in a pattern similar to MDM. Moreover, PMAr cells showed relative resistance to apoptotic stimuli and maintained levels of the differentiation-dependent anti-apoptotic protein Mcl-1 similar to MDM. PMAr cells retained a high phagocytic capacity for latex beads, and expressed a cytokine profile that resembled MDM in response to TLR ligands, in particular with marked TLR2 responses. Moreover, both MDM and PMAr retained marked plasticity to stimulus-directed polarization. These findings suggest a modified PMA differentiation protocol can enhance macrophage differentiation of THP-1 cells and identify increased numbers of mitochondria and lysosomes, resistance to apoptosis and the potency of TLR2 responses as important discriminators of the level of macrophage differentiation for transformed cells.

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The Identification of Markers of Macrophage Differentiation in PMA-Stimulated THP-1 Cells and Monocyte-Derived Macrophages

Natural products to drugs: natural product derived compounds in clinical trials

An evaluation of multipurpose oil seed crop for industrial uses (Jatropha curcas L.): A review

Exploitation of the tropical oil seed plant Jatropha curcas L.

Irritant phorbol derivatives from four Jatropha species

From leaves of E. OPPOSITIFOLIA the irritant EXCOECARIA factor O (1) was isolated. Its structure 1 was shown to be identical with that of a factor obtained by transesterification of the cryptic EXCOECARIA factor group O (')(z) from the latex of the plant. From the non-irritant ethyl acetate fractions of the latices of E. AGALLOCHA, E. OPPOSITIFOLIA and E. BICOLOR, three TLC-homogenous non-irritant mixtures A (')(z), O (')(z) and B (')(z) were isolated and shown to represent non-separable cryptic EXCOECARIA factor groups containing 9,13,14-orthoesters of 5beta-hydroxyresiniferonol esterified in 20-position. The mixtures may be activated by mild treatment with sodium methoxide to generate mixtures of highly irritant factor groups A (z), O (z) and B (z) together with mixtures of aliphatic acid methylesters. The former may be separated partially by reversed phase TLC and yielded EXCOECARIA factors O (1), O (2), A (3), B (3) and B (4) together with residual non-separable factor groups. The structures 1-5 of the individual daphnane type irritant EXCOECARIA factors were elucidated by spectroscopic means. Their irritant activities were determined quantitatively on the mouse ear. The mixtures of methyl esters of aliphatic acids were analyzed by GC. Thus the complete structures of the cryptic factor groups from latex were deduced.

Investigations of medicinal plants of euphorbiaceae and thymelaeaceae occurring and used in Thailand; II. Cryptic irritants of the diterpene ester type from three Excoecaria species

Specific binding of [3H]phorbol-12,13-dipropionate ([3H]PDPr) to a particulate fraction of mouse skin is demonstrated (KD = 35 nM; Rt = 1.2 pmol/mg protein). A series of compounds of the diterpene ester, indole akaloid and polyacetate types with different degrees of activity as skin tumor promoters and/or irritants have been tested for their capacity to inhibit specific [3H]PDPr binding. Three main categories are found: (i) compounds which exhibit a positive correlation between their potency as irritants and promoters in vivo and their inhibition of specific binding in vitro: 12-O-tetradecanoylphorbol-13-acetate, 3-O-tetradecanoylingenol, pimelea factor P2, 'teleocidin', dihydroteleocidin B, and lyngbyatoxin are active in vivo and in vitro, whereas phorbol and ingenol are inactive and 4-O-methyl-12-O-tetradecanoyl-phorbol-13-acetate is weakly active; (ii) compounds which are strong irritants and inhibitors of binding but are weak or practically non-promoters: mezerein, 12-O-retinoylphorbol-13-acetate and milliamine C; (iii) strong irritants which are weak or marginally active inhibitors of binding: debromoaplysiatoxin and resiniferatoxin. Some consequences of these findings with respect to interpretations of the biochemical mechanism(s) of tumor promotion are discussed.

Inhibition of specific binding of [3H]phorbol-12,13-dipropionate to an epidermal fraction by certain irritants and irritant promoters of mouse skin.

Investigations of E. antiquorum, E. helioscopia, E. palustris, E. peplus and E. quadrialata for irritant and tumor promoting constituents afforded several new ingenane type diterpene esters derived from the parent alcohols ingenol and 20-deoxyingenol and from the hitherto unknown 20- deoxy-16-hydroxyingenol and 20-deoxy-13.16-dihydroxyingenol. The irritant activities of the natural compounds are reported together with some aspects on structure activity relationships

On the Active Principles of the Euphorbiaceae, IXa Ingenane Type Diterpene Esters from Five Euphorbia Species

12-)-Tetradecanoylphorbol-13-acetate (TPA), the prototype polyfunctional diterpene ester tumor promoter of two-step carcinogenesis in mouse skin, induced differentiation of human promyelocytic leukemia cells (HL-60) in culture. Differentiation of HL-60 cells was characterized by increased phagocytosis, increased lysozyme activity (EC 3.2.1.17) in the growth medium, and changes in morphology to those characteristics of more mature cells resembling macrophages. Many of the cells treated with TPA became aggregated, attaching firmly to culture flasks. The average intracellular myeloperoxidase activity (EC 1.11.1.7) per cell decreased during induction of differentiation by TPA. It was also found that TPA enhanced, rather than inhibited, differentiation of HL-60 cells induced by DMSO. In addition to TPA, several polyfunctional diterpene esters of the tigliane, ingenane, and daphnane type have been tested for their ability to induce morphological and functional changes of HL-60 cells. The activities of the compounds to induce these changes correlated well with their activities as tumor promoters in two-step carcinogenesis in mouse skin. In particular, half the concentrations required for induction of adhesion of the cells to flasks were roughly correlated to the potency of these compounds as tumor promoters. Among the compounds tested, phorbol-12,13-didecanoate (PDD), ingenol-3-hexadecanoate, Pimelea factor P1 and Pimelea factor P2 were as active as TPA, while 4-O-methyl-TPA and 4 alpha-PDD were much less active. Phorbol and ingenol were totally inactive up to a concentrations 10,000-fold higher than that of TPA.

W. Adolf

Papers

Irritant phorbol derivatives from four Jatropha species

Investigations of medicinal plants of euphorbiaceae and thymelaeaceae occurring and used in Thailand; II. Cryptic irritants of the diterpene ester type from three Excoecaria species

Inhibition of specific binding of [3H]phorbol-12,13-dipropionate to an epidermal fraction by certain irritants and irritant promoters of mouse skin.

On the Active Principles of the Euphorbiaceae, IXa Ingenane Type Diterpene Esters from Five Euphorbia Species

Induction of differentiation in human promyelocytic leukemia cells by tumor promoters.