Artocarpus tonkinensis Protects Mice Against Collagen-Induced Arthritis and Decreases Th17 Cell Function.

Artocarpus tonkinensis (Moraceae) is a tree that grows in north Vietnam whose leaf decoction is used as a traditional remedy by the Hmong ethnic group to treat arthritis and backache. Our study evaluated the decoction's efficacy and mechanism of action in DBA/1J mice with collagen-induced arthritis (CIA). Mice treated with the decoction (At) either from the first collagen immunization or after CIA development experienced significantly less joint edema and inflammatory infiltration, whereas CIA-induced cartilage damage could only be prevented by early At treatment. Autoimmune gene expression profiles showed that Th17 cell-associated chemokine CCL20 and cytokines IL-6, IL-17, and IL-22 were strongly downregulated by At. Reduced expression of IL-2, IL-17, IL-22, and FasL in lymph node cells from At-treated mice was further confirmed by real-time PCR. The decoction also inhibited polarization of Th17 cells from CD4+ splenic T cells according to levels of IL-17 and RORC, a Th17 cell-specific transcription factor. Chromatographic analysis identified At's major component as maesopsin-ß-D-glucoside, which could inhibit in vitro differentiation of Th17 cells. The decoction significantly alleviated the signs and symptoms of CIA and inhibited the development and function of Th17 cells, highlighting its potent anti-inflammatory activity.

The Hexane Fraction of Bursera microphylla A. Gray Induces p21-Mediated Anti-Proliferative and Pro-Apoptotic Effects in Human Cancer-Derived Cell Lines.

Bursera microphylla (BM), one of the common elephant trees, is widely distributed in the Sonoran Desert in Mexico. The Seri ethnic group in the Sonoran Desert uses BM as an anti-inflammatory and painkiller drug for the treatment of sore throat, herpes labialis, abscessed tooth, and wound healing. Dried stems and leaves of BM are used in a tea to relieve painful urination and to stimulate bronchial secretion. Furthermore, BM is used for fighting venereal diseases. To investigate the effects of the hexane fraction of resin methanol extract (BM-H) on cell growth, the acute myeloid cell line (OCI-AML3) was treated with 250, 25, or 2.5 µg/mL of BM-H. The first 2 concentrations were able to significantly decrease OCI-AML3 cell number. This reduced cell number was associated with decreased S-phase, blockade of the G2/M phase of the cell cycle, and increased cell death. Similar results were obtained on all tested tumor cell lines of different origins. We found that blockade of the cell cycle was due to upregulation of p21 protein in a p53-independent way. Increase of p21 was possibly due to upstream upregulation of p-ERK (which stabilizes p21 protein) and downregulation of p-38 (which promotes its degradation). Regarding cell death, activation of caspase-3, but not of caspase-8 or -9, was detectable after BM-H treatment. In conclusion, these data suggest that the BM's hexane fraction inhibited proliferation of cell lines mainly by a p21-dependent, p53-independent mechanism and promoted apoptosis through activation of caspase-3, but not caspase-8 or -9.

The Hexane Fraction of Bursera microphylla A Gray Induces p21-Mediated Antiproliferative and Proapoptotic Effects in Human Cancer-Derived Cell Lines.

Bursera microphylla (BM), one of the common elephant trees, is widely distributed in the Sonoran desert in Mexico. The Seri ethnic group in the Sonoran desert uses BM as an anti-inflammatory and painkiller drug for the treatment of sore throat, herpes labialis, abscessed tooth, and wound healing. Dried stems and leaves of BM are used in a tea to relieve painful urination and to stimulate bronchial secretion. Furthermore, BM is used for fighting venereal diseases. To investigate the effects of the hexane fraction of resin methanol extract (BM-H) on cell growth, the acute myeloid cell line (OCI-AML3) was treated with 250, 25, or 2.5 µg/mL of BM-H. The first 2 concentrations were able to significantly decrease OCI-AML3 cell number. This reduced cell number was associated with decreased S-phase, blockade of G2/M phase of the cell cycle, and increased cell death. Similar results were obtained on all tested tumor cell lines of different origins. We found that blockade of the cell cycle was a result of upregulation of p21 protein in a p53-independent way. Increase of p21 was possibly a result of upstream upregulation of p-ERK (which stabilizes p21 protein) and downregulation of p-38 (which promotes its degradation). Regarding cell death, activation of caspase-3, but not of caspase-8 or -9, was detectable after BM-H treatment. In conclusion, these data suggest that BM-H inhibited proliferation of cell lines mainly by a p21-dependent, p53-independent mechanism and promoted apoptosis through activation of caspase-3 but not caspase-8 or -9.

Induction of Glucocorticoid-induced Leucine Zipper (GILZ) Contributes to Anti-inflammatory Effects of the Natural Product Curcumin in Macrophages.

GILZ (glucocorticoid-induced leucine zipper) is inducible by glucocorticoids and plays a key role in their mode of action. GILZ attenuates inflammation mainly by inhibition of NF-κB and mitogen-activated protein kinase activation but does not seem to be involved in the severe side effects observed after glucocorticoid treatment. Therefore, GILZ might be a promising target for new therapeutic approaches. The present work focuses on the natural product curcumin, which has previously been reported to inhibit NF-κB. GILZ was inducible by curcumin in macrophage cell lines, primary human monocyte-derived macrophages, and murine bone marrow-derived macrophages. The up-regulation of GILZ was neither associated with glucocorticoid receptor activation nor with transcriptional induction or mRNA or protein stabilization but was a result of enhanced translation. Because the GILZ 3'-UTR contains AU-rich elements (AREs), we analyzed the role of the mRNA-binding protein HuR, which has been shown to promote the translation of ARE-containing mRNAs. Our results suggest that curcumin treatment induces HuR expression. An RNA immunoprecipitation assay confirmed that HuR can bind GILZ mRNA. In accordance, HuR overexpression led to increased GILZ protein levels but had no effect on GILZ mRNA expression. Our data employing siRNA in LPS-activated RAW264.7 macrophages show that curcumin facilitates its anti-inflammatory action by induction of GILZ in macrophages. Experiments with LPS-activated bone marrow-derived macrophages from wild-type and GILZ knock-out mice demonstrated that curcumin inhibits the activity of inflammatory regulators, such as NF-κB or ERK, and subsequent TNF-α production via GILZ. In summary, our data indicate that HuR-dependent GILZ induction contributes to the anti-inflammatory properties of curcumin.

Integration of Traditional and Western Medicine in Vietnamese Populations: A Review of Health Perceptions and Therapies.

In Vietnam, two types of traditional medicine (TM) are practiced: thuoc nam, medicine of the South, and thuoc bac, medicine of the North, both of which are largely based on herbal drugs used by different Vietnamese ethnic groups. This review presents recently published information from various databases regarding TM, especially herbal drugs, and its integration with Western medical practices outside and inside Vietnam. We first discuss the integration of traditional and modem health concepts by Vietnamese immigrants living outside Vietnam. Next, we describe native and emigrated health education and practices of pharmacy students, health professionals, and citizens living in Vietnam. Finally, we report the recent biological validation of medicinal plants and non-herbal therapies emerging from Vietnamese TM and their current and potential medical uses as identified by Western approaches. The main example described here involves utilization of the tree Artocarpus tonkinensis by the ethnic minority of Black Hmong in northern Vietnam, who use a decoction of its leaves to treat arthritis and backache without apparent adverse effects. Our comprehensive review emphasizes that, although Vietnam has a very rich collection of TM practices (particularly the use of herbal drugs), these therapies should be biologically and clinically validated with modem Western methods for optimal integration of Western and traditional medicine in global populations.

The viability of Lactobacillus fermentum CECT5716 is not essential to exert intestinal anti-inflammatory properties.

Probiotics have been used as alternative therapies in intestinal inflammatory disorders. Many studies have shown that different bacterial probiotic strains possess immuno-modulatory and anti-inflammatory properties. However, there is an increasing interest in the use of non-viable bacteria to reduce the risk of microbial translocation and infection. The aim of this study was to evaluate whether the viability of L. fermentum CECT5716 is essential to exert its intestinal anti-inflammatory effect. We compared the preventative effects of viable and non-viable probiotic in the TNBS model of rat colitis. In vitro studies were also performed in Caco-2 and RAW 264.7 cells to evaluate the probiotic effects on IL-8, IL-1ß and nitrite production, and p44/42 and p38 MAP kinase protein expressions. In vitro results revealed a decrease in the stimulated production of pro-inflammatory mediators regardless of the viability of the probiotic. Likewise, both forms of the probiotic administered to colitic rats produced a significant reduction of IL-1ß and TNF-α levels and colonic iNOS expression. In conclusion, both live and dead L. fermentum CECT5716 have been demonstrated to attenuate the inflammatory process and diminish the production of some of the inflammatory mediators. In fact, the viability of this probiotic did not affect its immuno-modulatory and anti-inflammatory properties.

Dietary PUFA modulate the expression of proliferation and differentiation markers in Morris 3924A hepatoma cells.

The effect of dietary polyunsaturated fatty acids on the expression of differentiation and proliferation markers in Morris 3924A hepatoma cells was investigated. ACT/I rats were conditioned 10 days with diets enriched with linoleic acid or alpha-linolenic acid before subcutaneous hepatoma cell transplantation. After 19 days from the inoculum, the mRNA levels of liver-enriched transcription factors and of their target genes were quantified. Both linoleic acid- and linolenic acid-enriched diets induced a decrease of beta-actin, AFP, PCNA, c-myc and of hepatocyte nuclear factors HNF-1alpha and HNF-4alpha mRNA levels in tumor tissue whereas HNF-3beta expression was induced by both dietary treatments. Only the alpha-linolenic acid-enriched diet was effective in reducing c-jun and increasing albumin mRNA levels. Since albumin is a C/EBPalpha target gene, C/EBPalpha gene transcription was evaluated at both protein and mRNA levels. It was found that alpha-linolenic acid-enriched diet did not enhance the C/EBPalpha mRNA content in hepatoma tissue while inducing C/EBPalpha protein expression with an isoform pattern similar to the hepatic phenotype. This evidence implies that alpha-linolenic acid or one of its metabolic products induce albumin synthesis in hepatoma cells by modulating C/EBPalpha gene expression at post-transcriptional level.

Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis.

In rheumatoid arthritis (RA), a widespread autoimmune/inflammatory joint disease, early activation of effector CD4+ T lymphocytes, and cytokine production is followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, and disease. GITR (glucocorticoid-induced TNFR family-related gene), a costimulatory molecule for T lymphocytes, increases CD4+CD25- effector T cell activation while inhibiting suppressor activity of CD4+CD25+ T regulatory (Treg) cells. We analyzed the role of GITR in type II collagen (CII) -induced arthritis (CIA) using GITR-/- and GITR+/+ mice. Results indicate significantly less CIA induction in GITR-/- mice than in GITR+/+ mice, with marked differences in erythema, edema, neutrophil infiltration, joint injury, and bone erosion. Production of IFNgamma, IL-6, TNFalpha, MIP-1alpha, and MIP-2, inducible NOS (iNOS), COX-2, and nitrotyrosine poly-ADP-ribose (PAR) were also less in CII-treated GITR-/- mice. Although CD4+CD25+ Treg cells from GITR+/+ and GITR-/- CII-challenged mice exerted similar suppressor activity in vitro, GITR triggering abrogated GITR+/+ Treg suppressor activity and costimulated CD4+CD25- GITR+/+ effector cells. Furthermore, Treg cells from GITR-/- protected more than Treg cells from GITR+/+ mice against CIA when cotransferred with Treg-depleted splenocytes from arthritic GITR+/+ animals into severe combined immunodeficient (SCID) mice. In conclusion, GITR plays a critical role in the immunological response against CII and in the development of CIA.

Synthesis and evaluation of anti-apoptotic activity of L-carnitine cyclic analogues and amino acid derivatives.

Two series of derivatives were synthesised. In one series (R)-4-hydroxy-2-pyrrolidinone was used as a mimic of cyclic L-carnitine analogue and in the second series 3-amino-2-piperidinone was used as a cyclic ornithine analogue. N-Benzyloxycarbonyl derivatives of some amino acids were also prepared. The newly synthesised compounds were tested for their ability to inhibit Fas-activated apoptosis of human Jurkatt T-cell line. The results confirm the previously described anti-apoptotic activity of carnitine and indicate new carnitine and amino acid analogues (1, 3, 6, 7, 20) that inhibit Fas-induced apoptosis.