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1.
Biomed Pharmacother ; 142: 112043, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34411919

RESUMO

Despite its adverse effects, chemotherapy is generally used for the treatment of colorectal cancer (CRC). Development of supplement preparations targeting cancer stem cells (CSCs) that cause distant metastasis and drug resistance is required. Although curcumin is known to have anti-tumor, hepatoprotective, and hypoglycemic-like actions, its low water solubility, oral absorption, and bioavailability impede its therapeutic uses. Patient-derived organoid cultures can recapitulate heterogeneity, epithelial structures, and molecular imprints of their parental tissues. In the present study, anti-carcinogenic properties of amorphous curcumin (AC), a compound with improved solubility and bioavailability, were evaluated against human CRC organoids. Treatment with AC inhibited the cell viability of CRC organoids in a concentration-dependent manner. AC arrested the cell cycle of CRC organoids and induced apoptosis. AC inhibited phosphorylation of ERK. Expression of downstream signals of ERK, namely c-MYC and cyclin-D1, were inhibited. Expressions of CSC markers, CD44, LGR5, and CD133, were declined in the AC-treated CRC organoids. The combinational treatment of CRC organoids with AC and anti-cancer drugs, oxaliplatin, 5-FU, or irinotecan showed a synergistic activity. In vivo, AC decreased the tumor growth of CRC organoids in mice with the induction of necrotic lesions. In conclusion, AC diminished the cell viability of CRC organoids through the inhibition of proliferation-related signals and CSC marker expression in addition to arresting the cell cycle. Collectively, these data suggest the value of AC as a promising supplement that could be used in combination with anti-cancer drugs to prevent the recurrence and metastasis of CRC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Curcumina/farmacologia , Organoides/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Curcumina/uso terapêutico , Sinergismo Farmacológico , Fluoruracila/farmacologia , Humanos , Irinotecano/farmacologia , Masculino , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Organoides/patologia , Oxaliplatina/farmacologia
2.
Biol Reprod ; 89(3): 57, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23884646

RESUMO

Because of recent advancements in reproductive technology, oocytes have attained an increasingly enriched value as a unique cell population in the production of offspring. The growing oocytes in the ovary are an immediate potential source that serve this need; however, complete oocyte growth before use is crucial. Our research objective was to create in vitro-grown (IVG) oocytes that would have the ability to perform specialized activities, including nuclear reprogramming, as an alternative to in vivo-grown oocytes. Bovine oocyte-granulosa cell complexes with a mean oocyte diameter of approximately 100 µm were cultured on Millicell membrane inserts, with culture medium supplemented with 4% polyvinylpyrrolidone (molecular weight, 360,000), 20 ng/ml androstenedione, 2 mM hypoxanthine, and 5 ng/ml bone morphogenetic protein 7. Oocyte viability after the 14-day culture period was 95%, and there was a 71% increase in oocyte volume. Upon induction of oocyte maturation, 61% of the IVG oocytes extruded a polar body. Eighty-four percent of the reconstructed IVG oocytes that used cumulus cells as donor cells underwent cleavage, and half of them became blastocysts. DNA methylation analyses of the satellite I and II regions of the blastocysts revealed a similar highly methylated status in the cloned embryos derived from in vivo-grown and IVG oocytes. Finally, one of the nine embryos reconstructed from the IVG oocytes developed into a living calf following embryo transfer. Fertility of the offspring was confirmed. In conclusion, the potential of a proportion of the IVG oocytes was comparable to that of in vivo-grown oocytes.


Assuntos
Bovinos , Clonagem de Organismos/métodos , Técnicas de Maturação in Vitro de Oócitos/veterinária , Técnicas de Transferência Nuclear/veterinária , Oócitos/citologia , Animais , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Clonagem de Organismos/veterinária , Técnicas de Cultura Embrionária/veterinária , Transferência Embrionária/veterinária , Feminino , Fertilidade , Oócitos/fisiologia , Gravidez
3.
Reprod Fertil Dev ; 25(4): 589-99, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22954232

RESUMO

High lipid content in embryos is associated with low freezing tolerance. This study assessed the effects of exogenous L-carnitine, an enhancer of lipid metabolism, on the in vitro development and freezing survival of bovine embryos. Also, effects on metabolic activity, reactive oxygen species (ROS) and apoptosis were investigated. Supplementation of embryo culture medium with 1.518 mM or 3.030 mM L-carnitine significantly increased the rates of zygote development to the blastocyst stage and blastocyst cell numbers whereas 6.072 mM of this compound did not improve embryo development. Survival rates after slow freezing of blastocysts were significantly higher when embryos were cultured in the presence of 1.518 mM or 3.030 mM L-carnitine compared with the control. A lower density of lipid droplets was detected in L-carnitine-treated blastocysts compared with the control. L-carnitine significantly reduced ROS levels in 2-cell embryos but did not reduce ROS levels at later stages. The apoptotic cell rate was not different between control and L-carnitine-treated blastocysts. L-carnitine significantly increased ATP levels in 2-cell embryos but not at the 8-cell or blastocyst stages. L-carnitine increased the expression of metabolism-related ATP6 and COX1 genes in blastocysts. In conclusion, L-carnitine supplementation enhanced lipid metabolism in embryos resulting in improved development and cryotolerance of bovine blastocysts produced in vitro.


Assuntos
Aclimatação/efeitos dos fármacos , Carnitina/farmacologia , Meios de Cultura/química , Embrião de Mamíferos/fisiologia , Desenvolvimento Embrionário/efeitos dos fármacos , Congelamento , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Bovinos , Técnicas de Cultura Embrionária/métodos , Embrião de Mamíferos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
4.
Reprod Fertil Dev ; 23(7): 912-20, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21871210

RESUMO

The aim of the present study was to assess the effects of L-carnitine, an enhancer of lipid metabolism and mitochondrial activity, during in vitro maturation (IVM) on nuclear maturation and in vitro fertilisation of porcine follicular oocytes and subsequent embryo development. Mitochondrial functions, intracellular lipid content and reactive oxygen species (ROS) levels in oocytes were also investigated. L-carnitine supplementation in 0.6-5mgmL(-1) concentration during IVM significantly improved (P<0.05) the rates of metaphase-II (MII) stage oocytes compared with the control; however, fertilisation rates and monospermy were not improved. Although supplementation of IVM medium with L-carnitine significantly increased oocyte cleavage (P<0.05), further development to the blastocyst stage was not improved. The density of active mitochondria was significantly higher and the density of lipid droplets was significantly lower (P<0.05) in L-carnitine-treated oocytes compared with the control. Furthermore, the ROS levels in L-carnitine-treated oocytes were significantly lower than those in the control. In conclusion, enhancing mitochondrial functions by L-carnitine improved oocyte maturation and cleavage underlining the importance of lipid metabolism for nuclear and cytoplasmic maturation of porcine oocytes.


Assuntos
Carnitina/metabolismo , Núcleo Celular/metabolismo , Técnicas de Maturação in Vitro de Oócitos/veterinária , Metabolismo dos Lipídeos , Oócitos/metabolismo , Sus scrofa/metabolismo , Animais , Blastocisto/citologia , Contagem de Células/veterinária , Divisão Celular , Fenômenos Químicos , Cruzamentos Genéticos , Células do Cúmulo/fisiologia , Ectogênese , Feminino , Fertilização , Metáfase , Mitocôndrias/química , Mitocôndrias/metabolismo , Oócitos/citologia , Oócitos/enzimologia , Oogênese , Espécies Reativas de Oxigênio/metabolismo , Sus scrofa/embriologia
5.
Mol Reprod Dev ; 78(4): 250-62, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21381146

RESUMO

Melatonin is a multifunctional molecule that mediates several circadian and seasonal reproductive processes. The exact role of melatonin in modulating reproduction, however, is not fully understood-especially its effects on the ovarian follicles and oocytes. This study was conducted to investigate the expressions of the ASMT and melatonin-receptor MTNR1A and MTNR1B genes in bovine oocytes and their cumulus cells, as well as the effects of melatonin on oocyte nuclear and cytoplasmic maturation in vitro. Cumulus-oocyte complexes (COCs) from abattoir ovaries were cultured in TCM-199 supplemented with melatonin at concentrations of 0, 10, 50, and 100 ng/ml. The expression of ASMT, MTNR1A, and MTNR1B genes was evaluated by RT-PCR. Moreover, the effects of melatonin on cumulus cell expansion, nuclear maturation, mitochondrial characteristics and COCs steroidogenesis were investigated. Furthermore, the level of reactive oxygen species (ROS) was evaluated in denuded oocytes. Our study revealed that ASMT and MTNR1A genes were expressed in COCs, while the MTNR1B gene was expressed only in oocytes. Additionally, melatonin supplementation at 10 and 50 ng/ml to in vitro maturation medium significantly enhanced oocyte nuclear maturation, cumulus cell expansion and altered the mitochondrial distribution patterns, but had no effects on oocyte mitochondrial activity and COCs steroidogenesis. Melatonin-treated oocytes had a significantly lower level of ROS than controls. The presence of melatonin receptors in COCs and its promoting effects on oocyte nuclear and cytoplasmic events, indicate the potentially important roles of this hormone in regulating bovine oocyte maturation. Moreover, the presence of ASMT transcript in COCs suggests the possible involvement of these cells in melatonin biosynthesis.


Assuntos
Acetilserotonina O-Metiltransferasa/metabolismo , Células do Cúmulo/enzimologia , Melatonina , Oócitos/enzimologia , Oogênese/fisiologia , Receptor MT1 de Melatonina/biossíntese , Receptor MT2 de Melatonina/biossíntese , Animais , Bovinos , Núcleo Celular/metabolismo , Células do Cúmulo/citologia , Citoplasma/metabolismo , Feminino , Melatonina/biossíntese , Mitocôndrias/metabolismo , Oócitos/citologia , Oócitos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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