Small Molecule Inhibitors of CRM1 Ferreira, Bibiana I.; Cautain, Bastien; Grenho, Inês ...
Frontiers in pharmacology,
05/2020, Letnik:
11
Journal Article
Recenzirano
Odprti dostop
The transport through the nuclear pore complex is used by cancer cells to evade tumor-suppressive mechanisms. Several tumor-suppressors have been shown to be excluded from the cell nucleus in cancer ...cells by the nuclear export receptor CRM1 and abnormal expression of CRM1 is oncogenic. Inhibition of CRM1 has long been postulated as potential approach for the treatment of cancer and to overcome therapy resistance. Furthermore, the nuclear export of viral components mediated by the CRM1 is crucial in various stages of the viral lifecycle and assembly of many viruses from diverse families, including coronavirus. However, the first nuclear export inhibitors failed or never entered into clinical trials. More recently CRM1 reemerged as a cancer target and a successful proof of concept was achieved with the clinical approval of Selinexor. The chemical complexity of natural products is a promising perspective for the discovery of new nuclear export inhibitors with a favorable toxicity profile. Several screening campaigns have been performed and several natural product-based nuclear export inhibitors have been identified. With this review we give an overview over the role of CRM1-mediated nuclear export in cancer and the effort made to identify and develop nuclear export inhibitors in particular from natural sources.
Forkhead box O (FOXO) proteins are transcription factors involved in cancer and aging and their pharmacological manipulation could be beneficial for the treatment of cancer and healthy aging. FOXO ...proteins are mainly regulated by post-translational modifications including phosphorylation, acetylation and ubiquitination. As these modifications are reversible, activation and inactivation of FOXO factors is attainable through pharmacological treatment. One major regulatory input of FOXO signaling is mediated by protein kinases. Here, we use specific inhibitors against different kinases including PI3K, mTOR, MEK and ALK, and other receptor tyrosine kinases (RTKs) to determine their effect on FOXO3 activity. While we show that inhibition of PI3K efficiently drives FOXO3 into the cell nucleus, the dual PI3K/mTOR inhibitors dactolisib and PI-103 induce nuclear FOXO translocation more potently than the PI3Kδ inhibitor idelalisib. Furthermore, specific inhibition of mTOR kinase activity affecting both mTORC1 and mTORC2 potently induced nuclear translocation of FOXO3, while rapamycin, which specifically inhibits the mTORC1, failed to affect FOXO3. Interestingly, inhibition of the MAPK pathway had no effect on the localization of FOXO3 and upstream RTK inhibition only weakly induced nuclear FOXO3. We also measured the effect of the test compounds on the phosphorylation status of AKT, FOXO3 and ERK, on FOXO-dependent transcriptional activity and on the subcellular localization of other FOXO isoforms. We conclude that mTORC2 is the most important second layer kinase negatively regulating FOXO activity.
Therapy resistance is responsible for most relapses in patients with cancer and is the major challenge to improving the clinical outcome. The pseudokinase Tribbles homologue 2 (TRIB2) has been ...characterized as an important driver of resistance to several anti-cancer drugs, including the dual ATP-competitive PI3K and mTOR inhibitor dactolisib (BEZ235). TRIB2 promotes AKT activity, leading to the inactivation of FOXO transcription factors, which are known to mediate the cell response to antitumor drugs. To characterize the downstream events of TRIB2 activity, we analyzed the gene expression profiles of isogenic cell lines with different TRIB2 statuses by RNA sequencing. Using a connectivity map-based computational approach, we identified drug-induced gene-expression profiles that invert the TRIB2-associated expression profile. In particular, the natural alkaloids harmine and piperlongumine not only produced inverse gene expression profiles but also synergistically increased BEZ235-induced cell toxicity. Importantly, both agents promote FOXO nuclear translocation without interfering with the nuclear export machinery and induce the transcription of FOXO target genes. Our results highlight the great potential of this approach for drug repurposing and suggest that harmine and piperlongumine or similar compounds might be useful in the clinic to overcome TRIB2-mediated therapy resistance in cancer patients.
FOXO family isoforms Santos, Bruno F; Grenho, Inês; Martel, Paulo J ...
Cell death & disease,
10/2023, Letnik:
14, Številka:
10
Journal Article
Recenzirano
Odprti dostop
FOXO family of proteins are transcription factors involved in many physiological and pathological processes including cellular homeostasis, stem cell maintenance, cancer, metabolic, and ...cardiovascular diseases. Genetic evidence has been accumulating to suggest a prominent role of FOXOs in lifespan regulation in animal systems from hydra, C elegans, Drosophila, and mice. Together with the observation that FOXO3 is the second most replicated gene associated with extreme human longevity suggests that pharmacological targeting of FOXO proteins can be a promising approach to treat cancer and other age-related diseases and extend life and health span. However, due to the broad range of cellular functions of the FOXO family members FOXO1, 3, 4, and 6, isoform-specific targeting of FOXOs might lead to greater benefits and cause fewer side effects. Therefore, a deeper understanding of the common and specific features of these proteins as well as their redundant and specific functions in our cells represents the basis of specific targeting strategies. In this review, we provide an overview of the evolution, structure, function, and disease-relevance of each of the FOXO family members.
We estimated comparative primary and booster vaccine effectiveness (VE) of SARS-CoV-2 Omicron BA.5 and BA.2 lineages against infection and disease progression. During April-June 2022, we implemented ...a case-case and cohort study and classified lineages using whole-genome sequencing or spike gene target failure. For the case-case study, we estimated the adjusted odds ratios (aORs) of vaccination using a logistic regression. For the cohort study, we estimated VE against disease progression using a penalized logistic regression. We observed no reduced VE for primary (aOR 1.07 95% CI 0.93-1.23) or booster (aOR 0.96 95% CI 0.84-1.09) vaccination against BA.5 infection. Among BA.5 case-patients, booster VE against progression to hospitalization was lower than that among BA.2 case-patients (VE 77% 95% CI 49%-90% vs. VE 93% 95% CI 86%-97%). Although booster vaccination is less effective against BA.5 than against BA.2, it offers substantial protection against progression from BA.5 infection to severe disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several chemical compounds including natural products have been suggested as being effective against age-related diseases or as beneficial for a healthy life. On the other hand, forkhead box O (FOXO) ...proteins are emerging as key cellular components associated with extreme human longevity. FOXO proteins are mainly regulated by posttranslational modifications and as these modifications are reversible, activation and inactivation of FOXO are attainable through pharmacological treatment. Here, we questioned whether a panel of compounds with known health-beneficial properties has the capacity to induce the activity of FOXO factors. We show that resveratrol, a phytoalexin present in grapes and other food products, the amide alkaloid piperlongumine found in the fruit of the long pepper, and the plant-derived β-carboline compound harmine induced nuclear translocation of FOXO3. We also show that piperlongumine and harmine but not resveratrol activate FOXO-dependent transcription. We determined the half maximal effective concentration (EC50) values for resveratrol, piperlongumine, and harmine for FOXO translocation, and analyzed their inhibitory impact on chromosomal maintenance 1 (CRM1)-mediated nuclear export and the production of reactive oxygen species (ROS). We also used chemical biology approach and Western blot analysis to explore the underlying molecular mechanisms. We show that harmine, piperlongumine, and resveratrol activate FOXO3 independently of phosphoinositide 3-kinase (PI3K)/AKT signaling and the CRM1-mediated nuclear export. The effect of harmine on FOXO3 activity is at least partially mediated through the inhibition of dual-specificity tyrosine (Y) phosphorylationregulated kinase 1A (DYRK1A) and can be reverted by the inhibition of sirtuins (SIRTs).
•Information regarding average width and length of goats’ dairy claws is provided.•Increased width of the front claws was associated with increased likelihood of having deformation.•There was a ...significant correlation between lameness score and the number of deformed claws.
Lameness due to claw overgrowth remains one of the main welfare challenges in dairy goat farms. Although claw trimming is a crucial part of the solution, most times there is a delay in its implementation, with no perceived consequences. The goal of this cross-sectional study was to assess the correlation between the size and deformation of dairy goats claws with lameness score. The width and length of the claws of 38 adult dairy goats were taken and classified as deformed (DEF) or non-deformed (NO_DEF). Lameness was also scored in the majority of the animals assessed for claw deformation. Deformation of at least one claw was present in 34 animals (89% of the total sample). From the 34 goats with deformed claws, 33 presented at least one deformed rear claw and 18 presented at least one deformed front claw. From the 152 claws assessed 58% were deformed (n = 88), of which 19% (n = 29) were front claws and 39% were rear claws (n = 59). Increased width of the front claws was associated with increased likelihood of having deformation with odds of 1.24, and the increased length explained 16% of the variation in lameness scores. A positive relation between lameness score and the number of deformed claws was also shown. Overall, these results suggest that the size of dairy goats’ claws influences the prevalence of deformation and lameness severity and that the number of deformed claws affects goats’ gait. They also help to build the argument in favor of regular trimming in dairy goat farms.
One of the major causes of lameness in intensive dairy goat farms is claws' overgrowth and deformation. These problems are thought to be painful but more studies are needed to assess the degree and ...extension of pain. The demand for more objective ways to assess pain is growing. Infrared thermography may be one of them. In our study ninety four dairy goats from the same pen were classified for claw deformation and overgrowth. Each claw was photographed with a thermography camera on day 0 (before trimming) and on the day 15 (15 days after trimming). The incidence of deformed claws was 45%. A significant difference between the temperature of the deformed (24.18º C) and the not deformed claws (20.77º C) on day 0 (p= 0.01) was shown. On day 15 there was no difference in claw temperature between both groups (p= 0.605). We concluded that overgrowth and deformation does cause deep inflammation that is detected by thermography, and that trimming reduces the severity of this condition.
Nos últimos anos temos assistido a uma modernização da produção animal em resposta a uma maior exigência por parte do consumidor. Em consequência desta modernização, as explorações leiteiras deixaram ...de ser pequenas explorações familiares sem qualquer tipo de gestão económica, e têm sido reconvertidas em explorações de maior dimensão em que cada cêntimo deve ser contabilizado. O setor do leite foi um dos setores da produção animal em que mais se sentiu esta mudança, exigindo uma gestão cada vez mais cuidada.Esta necessidade de uma maior qualidade na gestão é também consequência de toda a conjuntura à volta do setor do leite. Se por um lado o seu consumo per capita está a aumentar, os preços do leite no produtor estão a baixar, ao mesmo tempo que os preços das matériasprimas estão a aumentar. Tudo isto leva a que a gestão da exploração tenha de ser apertada não deixando grande margem para erros. Uma grande parte da gestão de uma exploração leiteira relaciona-se com as instalações. Estas requerem um grande investimento inicial, elevados custos de manutenção e acabam por influenciar diversas áreas como a produção, a reprodução e o próprio bem-estar animal. Esta última é de uma importância extrema uma vez que se correlaciona e afeta todas as outras áreas. Posto isto há que, não só ponderar bem a construção de um novo estábulo, como fazer o acompanhamento após a mudança dos animais, tentando assim minimizar qualquer problema que possa advir do novo sistema instalado. É neste contexto que surge a presente dissertação: “Alterações derivadas de uma mudança de instalações de parques de palha para cubículos de areia a nível comportamental, a nível da saúde e a nível produtivo, num grupo de vacas leiteiras de alta produção”.O objetivo deste trabalho foi acompanhar uma mudança de um tipo de estabulação livre com camas de palha para uma estabulação livre com cubículos de areia. Para que esta avaliação fosse feita foram efetuadas várias classificações (higiene, claudicações, lesões na região do tarso) e foram recolhidos vários dados (comportamentais, produtivos, incidência de mastites).
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