Factores clínicos y ambientales asociados a la tiroiditis de Hashimoto / Clinical and environmental factors associated with Hashimoto's thyroiditis

Introducción: La tiroiditis de Hashimoto es una enfermedad tiroidea autoinmune poligénica y multifactorial resultante de una interacción compleja de factores genéticos y ambientales. Objetivo: Determinar la posible asociación de los factores clínicos y ambientales con los niveles de anticuerpos antitiroideos y las pruebas de función tiroidea en la tiroiditis de Hashimoto. Métodos: Estudio observacional, descriptivo y transversal con 120 personas con diagnóstico de tiroiditis de Hashimoto. Variables estudiadas: edad, sexo, color de la piel, estado nutricional, paridad, hábito de fumar, consumo de alcohol, preparados estrogénicos, antecedentes familiares de enfermedad autoinmune tiroidea y personales de otras enfermedades autoinmunes. Se realizaron determinaciones de anticuerpos AbTPO, TSH, T3 y T4. Resultados: Predominio del sexo femenino (92,5 por ciento), de pacientes de piel blanca (50,8 por ciento) y con sobrepeso corporal (40 por ciento). El 73 por ciento no consumían preparados estrogénicos. El 20 por ciento tenían antecedentes familiares de enfermedad tiroidea y personales de diabetes mellitus tipo 1 (7,5 por ciento). La media del anticuerpo en pacientes con antecedentes de infecciones virales fue superior a los que no tuvieron este antecedente (732,6 vs. 624,6). El resto de las variables no mostraron diferencias entre las medias del anticuerpo. Ninguno de los factores estudiados mostró asociación con el estado de la función tiroidea. (p>0,05). Conclusiones: No existió asociación entre los factores clínicos y ambientales en relación a los niveles de Ac TPO y el estado de la función tiroidea, con predominio del hipotiroidismo manifiesto al diagnóstico de la TH(AU)

Introduction: Hashimoto's thyroiditis is a polygenic and multifactorial autoimmune thyroid disease, resulting from a complex interaction of genetic and environmental factors. Objective: To determine the possible association of clinical and environmental factors with antithyroid antibody levels and thyroid function tests in HT. Methods: An observational, descriptive, cross-sectional study was carried out with 120 subjects diagnosed with Hashimoto's thyroiditis. We studied variables such as age, sex, skin color, nutritional status, parity, smoking, alcohol consumption, estrogen preparations, family history of autoimmune thyroid disease and personal history of other autoimmune diseases. Additionally, AbTPO, TSH, T3 and T4 antibody determinations were made. Results: Predominance of the female sex (92.5 percent), white skin (50.8 percent) and body overweight (40 percent). 73 percent did not consume estrogenic preparations. Twenty percent had family history of thyroid disease and personal history of type 1 diabetes mellitus (7.5 percent). The mean antibody in patients with history of viral infections was higher than those without this history (732.6 vs. 624.6). The rest of the variables did not show differences between the means of the antibody. None of the factors studied showed association with the state of thyroid function. (p > 0.05). Conclusions: There was no association between clinical and environmental factors in relation to Ac TPO levels and the state of thyroid function, with a predominance of overt hypothyroidism at diagnosis of HT(AU)

The eudesmanolide tanapsin from Tanacetum oshanahanii and its acetate induce cell death in human tumor cells through a mechanism dependent on reactive oxygen species.

In this study the cytotoxicities of two species of Tanacetum were evaluated against human tumor cells. Tanacetum oshanahanii extract was more cytotoxic than Tanacetum ptarmiciflorum. Analyses of both extracts of Tanacetum by ultrahigh performance liquid chromatography-tandem mass spectrometry revealed that T. oshanahanii extract contains the eudesmanolide tanapsin, while T. ptarmiciflorum lacks this sesquiterpene lactone. Tanapsin was cytotoxic against leukemia and melanoma cells, including cells that overexpress Bcl-2 and Bcl-xL, with IC50 values of approximately 10 µM, but not against quiescent or proliferating human peripheral blood mononuclear cells. Treatment of cells with tanapsin induced apoptosis. This was prevented by the non-specific caspase inhibitor z-VAD-fmk, and reduced by the selective caspase-3/7 inhibitor z-DEVD-fmk. Tanapsin acetate was also cytotoxic against leukemia and melanoma cells and a potent apoptotic inducer. Tanapsin-induced cell death was found to be associated with (i) the loss of inner mitochondrial membrane potential (ΔΨm) and release of mitochondrial cytochrome c, (ii) the activation of multiple caspases and the mitogen-activated protein kinase pathway, and (iii) an increase in reactive oxygen species generation. Generation of reactive oxygen species in response to tanapsin seems to play a crucial role in the cell death process since the antioxidant N-acetyl-l-cysteine blocked both ROS generation and cell death.

Eupatorin-induced cell death in human leukemia cells is dependent on caspases and activates the mitogen-activated protein kinase pathway.

Eupatorin is a naturally occurring flavone that inhibits cell proliferation in human tumor cells. Here we demonstrate that eupatorin arrests cells at the G2-M phase of the cell cycle and induces apoptotic cell death involving activation of multiple caspases, mitochondrial release of cytochrome c and poly(ADP-ribose) polymerase cleavage in human leukemia cells. This flavonoid induced the phosphorylation of members of the mitogen-activated protein kinases and cell death was attenuated by inhibition of c-jun N-terminal kinases/stress activated protein kinases. Eupatorin-induced cell death is mediated by both the extrinsic and the intrinsic apoptotic pathways and through a mechanism dependent on reactive oxygen species generation.

Synthesis and effects on cell viability of flavonols and 3-methyl ether derivatives on human leukemia cells.

Flavonoids are polyphenolic compounds which display an array of biological activities and are considered potential antitumor agents. Here we evaluated the antiproliferative activity of selected synthetic flavonoids against human leukemia cell lines. We found that 4'-bromoflavonol (flavonol 3) was the most potent. This compound inhibited proliferation in a concentration-dependent manner, induced apoptosis and blocked cell cycle progression at the S phase. Cell death was found to be associated with the cleavage and activation of multiple caspases, the activation of the mitogen-activated protein kinase pathway and the up-regulation of two death receptors (death receptor 4 and death receptor 5) for tumor necrosis factor-related apoptosis-inducing ligand. Moreover, combined treatments using 4'-bromoflavonol and TRAIL led to an increased cytotoxicity compared to single treatments. These results provide a basis for further exploring the potential applications of this combination for the treatment of cancer.

Induction of G2/M phase arrest and apoptosis by the flavonoid tamarixetin on human leukemia cells.

Flavonoids are naturally occurring polyphenolic compounds which display a vast array of biological activities. In this study, we investigated the effects of tamarixetin on viability of human tumor cell lines and found that it was cytotoxic against leukemia cells and in particular P-glycoprotein-overexpressing K562/ADR cells. This compound inhibited proliferation in a concentration- and time-dependent manner, induced apoptosis and blocked cell cycle progression at G2 -M phase. This was associated with the accumulation of cyclin B1, Bub1 and p21(Cip1/Waf-1), changes in the phosphorylation status of cyclin B1, Cdk1, Cdc25C and MPM-2, and inhibition of tubulin polymerization. Moreover, cell death was found to be associated with cytochrome c release and cleavage of caspases and of poly(ADP-ribose) polymerase, and completely abrogated by the free-radical scavenger N-acetyl-L-cysteine. The sensitivity of leukemic cells to tamarixetin suggests that it should be considered for further preclinical and in vivo testing.

A chemotaxonomic study of endemic species of genus Tanacetum from the Canary Islands.

Aerial parts of Tanacetum oshanahanii collected at "Jardín Canario Viera y Clavijo", Tanacetum ptarmiciflorum collected at Los Moriscos (Tejeda), and Tanacetum ferulaceum var. latipinnum collected at Anden Verde (Agaete) in Gran Canaria, Canary Islands, afforded three sesquiterpenes related to nerolidol and six sesquiterpene lactones whose structures were established on the basis of their spectroscopic data and chemical transformations. In this work we show that this type of sesquiterpene lactones could be used as chemotaxonomic markers. A series of sesquiterpene lactones described in this paper were assessed for cytotoxicity against HL-60 and U937 cancer cell lines. The derivatives 106a and 98a displayed cytotoxic properties showing IC50 values between 5 and 11 µM. Furthermore, we demonstrated that these selected sesquiterpene lactones induce apoptotic cell death in human leukemia cells through a mechanism that involves activation of multiple caspases and moreover cell death was found to be associated with the release of cytochrome c.

Secondary metabolites from two species of Tolpis and their biological activities.

Phytochemical research of two Tolpis species, T. proustii and T. lagopoda, led to the isolation of three new compounds: 30-chloro-3β-acetoxy-22α-hydroxyl-20(21)-taraxastene (1), 3β,22α-diacetoxy-30-ethoxy-20(21)-taraxastene (2) and 3β,28-dihydroxy-11α-hydroperoxy-12-ursene (3). The structures of the new compounds were elucidated by means of extensive IR, NMR, and MS data and by comparison of data reported in the literature. The in vitro antioxidant activities of the extracts were assessed by the DPPH and ABTS scavenging methods. The cytotoxicity of several known compounds and its derivatives was also assessed against human myeloid leukemia K-562 and K-562/ADR cell lines.

Ayanin diacetate-induced cell death is amplified by TRAIL in human leukemia cells.

Here we demonstrate that the semi-synthetic flavonoid ayanin diacetate induces cell death selectively in leukemia cells without affecting the proliferation of normal lymphocytes. Incubation of human leukemia cells with ayanin diacetate induced G(2)-M phase cell cycle arrest and apoptosis which was prevented by the non-specific caspase inhibitor z-VAD-fmk and reduced by the overexpression of Bcl-x(L). Ayanin diacetate-induced cell death was found to be associated with: (i) loss of inner mitochondrial membrane potential, (ii) the release of cytochrome c, (iii) the activation of multiple caspases, (iv) cleavage of poly(ADP-ribose) polymerase and (v) the up-regulation of death receptors for TRAIL, DR4 and DR5. Moreover, the combined treatment with ayanin diacetate and TRAIL amplified cell death, compared to single treatments. These results provide a basis for further exploring the potential applications of this combination for the treatment of cancer.

Effect of C-ring modifications on the cytotoxicity of spirostan saponins and related glycosides.

Twelve C-ring modified spirostanyl glycosides were synthesized and evaluated for their cytotoxicity against the human myeloid leukemia cell line (HL-60). With the aim of assessing the influence of the hydrophobic character, the conformational flexibility and the stereochemistry of the C-ring functionalities on the cytotoxic activity, a variety of spirostanic aglycones incorporating methylene, methoxyl, α,ß-unsaturated ketone and lactone groups were subjected to a linear glycosylation strategy leading to glycosides derived from the 3,6-dipivaloylated ß-D-glucoside and the ß-chacotrioside moieties. The 3,6-dipivaloylated spirostanyl ß-D-glucosides showed moderate to good cytotoxic activity against HL-60, but no significant cytotoxicity against benign blood cells. However, the cytotoxicity of spirostanyl ß-chacotriosides was highly dependent on the nature of the C-ring functional groups of the steroidal aglycones. Actually, the chacotrioside-based saponins either with no functionality or bearing a hydrophobic methylene group at C-12 were the most cytotoxic ones against both HL-60 and benign blood cells. On the other hand, the incorporation of very polar functionalities and the opening of the ring C with the consequent loss of rigidity led to a significant drop in the cytotoxicity against HL-60. These results confirm that spirostanyl ß-chacotriosides including very lipophilic aglycones are the most cytotoxic ones among their congeners.

Synthetic menthyl α/ß-(1→6)-diglucopyranosides-induced cell death in human leukemia cells is dependent on caspases.

A series of alkyl α/ß-(1→6)-diglucopyranosides 1-12 were synthesized and assessed for cytotoxicity against HL-60, U937, Molt-3 and MCF-7 cancer cell lines. The menthyl derivatives displayed strong cytotoxic properties showing IC(50) values between 6 and 16 µM. Furthermore, we demonstrated that the selected synthetic (+)-menthyl ß-(1→6)-diglucopyranoside 5 induces apoptotic cell death in human leukemia cells through a mechanism that involves activation of multiple caspases. Cell death was completely prevented by the non-specific caspase inhibitor z-VAD-fmk and found to be associated with the release of cytochrome c, an increase in the expression of Bax levels and a decrease in the generation of reactive oxygen species.

New insights into the structure-cytotoxicity relationship of spirostan saponins and related glycosides.

A variety of spirostan saponins and related glycosides were synthesized and evaluated for their cytotoxicity against the human myeloid leukemia cell line (HL-60). A linear glycosylation strategy allowed for accessing a variety of functionalization patterns at both the spirostanic and the saccharide moieties, which provides new information regarding the structure-cytotoxicity relationship of this family of steroidal glycosides. Intriguing results were achieved with respect to hecogenyl and 5α-hydroxy-laxogenyl ß-chacotriosides, turning out to be the former very cytotoxic and the latter no cytotoxic at all. Importantly, the partially pivaloylated ß-d-glucosides of 5α-hydroxy-laxogenin were the most potent cytotoxic compounds among all tested glycosides. This comprises the first report on acylated spirostanyl glucosides displaying significant cytotoxicity, and therefore, it opens up new opportunities toward the development of saponin analogues as anticancer agents.