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Drug delivery strategies for local immunomodulation hold tremendous promise compared to current clinical gold-standard systemic immunosuppression as they could improve the benefit to risk ratio of life-saving or life-enhancing transplants. Such strategies have facilitated prolonged graft survival in animal models at lower drug doses while minimizing off-target effects. Despite the promising outcomes in preclinical animal studies, progression of these strategies to clinical trials has faced challenges. A comprehensive understanding of the translational barriers is a critical first step towards clinical validation of effective immunomodulatory drug delivery protocols proven for safety and tolerability in pre-clinical animal models. This review overviews the current state-of-the-art in local immunomodulatory strategies for transplantation and outlines the key challenges hindering their clinical translation.
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Throughout pregnancy, the mother's nutritional and mental health significantly influences the kid's long-term growth and wellness. This review's objective is to provide a comprehensive assessment of the literature on the link between pregnancy nutrition and a sound mind and a foetus' growth, considering factors in the physical, cognitive, emotional, and social domains. A balanced, nutrient-rich diet is crucial for the baby to grow and develop properly during pregnancy. An appropriate diet of significant macronutrients and micronutrients supports good foetal organ development, cognitive function, and immune system resiliency. For instance, studies have linked iron and omega-3 fatty acids to a reduced risk of developmental delays and improved cognitive performance. Contrarily, malnutrition in mothers, such as undernutrition or excessive weight gain, has been connected with negative results, including low birth weight, poor neurodevelopment, and increased susceptibility to chronic diseases in later life. The mother's mental health, including emotional equilibrium and psychological stability, significantly impacts the child's development. Stress, anxiety, and depression experienced by mothers during pregnancy harm the developing foetus and increase the risk of cognitive, behavioural, and emotional difficulties in the offspring. The growing foetus is exposed to high levels of stress hormones due to chronic maternal stress, which might alter the fetus's brain's shape and function. Factors influencing child development outcomes include maternal-infant attachment, breastfeeding start and duration, and general caring practices. A comprehensive approach is critical since new research indicates a synergistic relationship between maternal nutrition and mental health. Inadequate nutritional intake might result from maternal mental health problems that interfere with appetite control and eating habits. On the other hand, inadequate maternal nutrition may raise maternal stress and result in mental health problems. Therefore, integrative therapies focusing on both areas are essential to maximise child development results. In conclusion, maternal nutrition and mental health during pregnancy significantly impact a child's development in various domains. Understanding the complex relationships between maternal nutrition and mental health is necessary to develop effective therapies and promote the most remarkable results for children. Further research is needed to understand better the underlying mechanisms to develop evidence-based recommendations for optimal mother care throughout pregnancy. The need of this review is to know how maternal health, physical or mental affects the child's development and how we can further prevent it by taking precautions during pregnancy.
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Cell death, survival, or growth decisions in T-cell subsets depend on interplay between cytokine-dependent and metabolic processes. The metabolic requirements of T-regulatory cells (Tregs) for their survival and how these are satisfied remain unclear. Herein, we identified a necessary requirement of methionine uptake and usage for Tregs survival upon IL-2 deprivation. Activated Tregs have high methionine uptake and usage to S-adenosyl methionine, and this uptake is essential for Tregs survival in conditions of IL-2 deprivation. We identify a solute carrier protein SLC43A2 transporter, regulated in a Notch1-dependent manner that is necessary for this methionine uptake and Tregs viability. Collectively, we uncover a specifically regulated mechanism of methionine import in Tregs that is required for cells to adapt to cytokine withdrawal. We highlight the need for methionine availability and metabolism in contextually regulating cell death in this immunosuppressive population of T cells.
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Metionina , Linfócitos T Reguladores , Linfócitos T Reguladores/metabolismo , Metionina/metabolismo , Interleucina-2/metabolismo , Racemetionina/metabolismo , Proteínas Carreadoras de Solutos/metabolismoRESUMO
Polo-like kinase 1 (Plk1) is a mitotic serine/threonine kinase implicated in spindle formation and cytokinesis in mammalian cells. Here, purified Plk1 was found to bind to reconstituted microtubules in vitro. Further, Plk1 was found to co-localize with interphase microtubules in MCF-7 cells and to co-immunoprecipitate with polymerized tubulin. The binding of Plk1 to interphase microtubules appeared to increase with an increase in the level of tubulin acetylation in MCF-7 cells. Interestingly, Plk1 inhibitor III, an inhibitor of Plk1 kinase activity, treatment increased the association of Plk1 with the interphase microtubules in MCF-7 cells. Therefore, the effect of inhibition of Plk1 kinase activity on the dynamic instability of microtubules was determined by time-lapse imaging in MCF-7 cells. Plk1 inhibitor III dampened the dynamic instability of microtubules. For example, Plk1 inhibitor III (3 µM) reduced the rate and extent of the growing phase by 28 and 48%, respectively, and inhibited the dynamicity of microtubules by 53% as compared to the microtubules in control MCF-7 cells. Plk1 inhibitor III treatment also increased the level of acetylated microtubules, indicating that it stabilizes microtubules. The findings indicated that Plk1 interacts with microtubules and Plk1 may have a role in the regulation of microtubule dynamics.
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Proteínas de Ciclo Celular/metabolismo , Microtúbulos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Feminino , Humanos , Células MCF-7 , Microtúbulos/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Quinase 1 Polo-LikeRESUMO
We investigated the role of a spindle assembly checkpoint protein, BubR1, in determining the mechanism of cell killing of an anti-microtubule agent CXI-benzo-84. CXI-benzo-84 dampened microtubule dynamics in live MCF-7 cells. The compound arrested MCF-7 cells in mitosis and induced apoptosis in these cells. Though CXI-benzo-84 efficiently depolymerized microtubules in the BubR1-depleted MCF-7 cells, it did not arrest the BubR1-depleted cells at mitosis. Interestingly, apoptosis occurred in the BubR1-depleted MCF-7 cells in the absence of a mitotic block suggesting that the mitotic block is not a prerequisite for the induction of apoptosis by anti-microtubule agents. In the presence of CXI-Benzo-84, the level of apoptosis was initially found to be lesser in the BubR1-depleted MCF-7 cells than the control cells; however, the BubR1-depleted cells displayed a similar level of apoptosis as the control cells at 72â¯h of drug treatment. The depletion of BubR1 enhanced DNA damage in MCF-7 cells upon microtubule depolymerization. In addition, CXI-benzo-84 in combination with cisplatin induced more cell death in BubR1-depleted cells than the BubR1-expressing MCF-7 cells. The results indicated a possibility that the BubR1-compromised cancer patients can be treated with combination therapy.
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Apoptose/fisiologia , Microtúbulos/metabolismo , Polimerização , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Anilidas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Células HeLa , Humanos , Células MCF-7 , Microtúbulos/patologia , Polimerização/efeitos dos fármacosRESUMO
Twenty-three combretastatin A-4 (CA-4) analogues were synthesized by judiciously incorporating a functional N-heterocyclic motif present in Celecoxib (a marketed drug) while retaining essential pharmacophoric features of CA-4. Combretastatin-(trifluoromethyl)pyrazole hybrid analogues, i.e., 5-trimethoxyphenyl-3-(trifluoromethyl)pyrazoles with a variety of relevantly substituted aryls and heteroaryls at 1-position were considered as potential tubulin polymerization inhibitors. The cytotoxicity of the compounds was evaluated using MCF-7 cells. Analog 23 (C-23) was found to be the most active among the tested compounds. It showed pronounced cytotoxicity against HeLa, B16F10, and multidrug-resistant mammary tumor cells EMT6/AR1. Interestingly, C-23 displayed significantly lower toxicity toward noncancerous cells, MCF10A and L929, than their cancerous counterparts, MCF-7 and B16F10, respectively. C-23 depolymerized interphase microtubules, disrupted mitotic spindle formation, and arrested MCF-7 cells at mitosis, leading to cell death. C-23 inhibited the assembly of tubulin in vitro. C-23 bound to tubulin at the colchicine binding site and altered the secondary structures of tubulin. The data revealed the importance of (trimethoxyphenyl)(trifluoromethyl)pyrazole as a cis-restricted double bond-alternative bridging motif, and carboxymethyl-substituted phenyl as ring B for activities and interaction with tubulin. The results indicated that the combretastatin-(trifluoromethyl)pyrazole hybrid class of analogues has the potential for further development as anticancer agents.
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Understanding the mechanism of resistance to tubulin-targeted anticancer drugs is important for improved chemotherapy. In this work, a colchicine-resistant MCF-7 cell line (MCF-7Col30) was generated by the gradual increment of colchicine treatment and the MCF-7Col30 showed â¼8-fold resistance towards colchicine. MCF-7Col30 cells showed â¼2.5-fold resistance against microtubule depolymerizing agents, vinblastine, and nocodazole. In contrast, it displayed more sensitivity towards paclitaxel, a microtubule-polymerizing agent. MCF-7 and MCF-7Col30 cells showed similar sensitivity towards cisplatin. Further, the level of P-glycoprotein did not increase in MCF-7Col30 cells. MCF-7Col30 cells resisted the microtubule depolymerizing effects of colchicine. The time-lapse imaging of individual microtubules in live cells showed that the dynamics of microtubules in MCF-7Col30 cells was suppressed as compared to the parent MCF-7 cells. The levels of tubulin acetylation and glutamylation increased in MCF-7Col30 cells than the parent MCF-7 cells suggesting that microtubules are stabilized in MCF-7Col30 cells. Interestingly, the level of ßIII tubulin was increased by 2.3 folds whereas that of ßII and ßIV tubulin was decreased by 55 and 150%, respectively in MCF-7Col30 cells. The results suggested that the changes in the level of ß-tubulin isoforms and the post-translational modifications of microtubules altered the stability and dynamics of microtubules and contributed to the development of colchicine-resistance in MCF-7 cells.
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Colchicina/farmacologia , Microtúbulos/metabolismo , Acetilação , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Ácido Glutâmico/metabolismo , Humanos , Células MCF-7 , Mutação , Paclitaxel/farmacologia , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismoRESUMO
Five enantiomeric pairs of palladium complexes of 1,2,4-triazole-derived chiral N-heterocyclic carbene ligands were investigated to probe the influence of chirality on the compound's anticancer activity. Although no chirality-related influence was observed for any of the enantiomeric pair, strong anticancer activity was seen for a particular pair, (1S,2S,5R)-1c and (1R,2R,5S)-1c, which was significantly more active than the benchmark drug cisplatin for human breast cancer cells, MCF-7 (ca. 24-27-fold), and human cervical cancer cells, HeLa (ca. three- to fourfold). Broadening its scope of application, (1R,2R,5S)-1c also exhibited antiproliferative activity against lung cancer (A549), skin cancer (B16F10), and multidrug-resistant mammary tumor (EMT6/AR1) cell lines. Interestingly, (1R,2R,5S)-1c displayed 8- and 16-fold stronger antiproliferative activity toward B16F10 and MCF-7 relative to their respective noncancerous counterparts, L929 (fibroblast skin cells) and MCF10A (epithelial breast cells), thereby upholding the potential of these complexes for further development as anticancer agents. (1R,2R,5S)-1c inhibited tumor-cell proliferation by blocking the cells at the G2 phase. (1R,2R,5S)-1c caused DNA damage in MCF-7 cells, leading to mitochondrial reactive oxygen species production and subsequently cell death. We also present evidence indicating that (1R,2R,5S)-1c induced p53-dependent programmed cell death in MCF-7 cells.