A relação entre duas síndromes pró-inflamatórias da atualidade: sepse e obesidade

Several studies shows that patients with obesity have more chance to develop sepsis, moreover they possess a higher risk of mortality. Sepsis, which is a systemic infection, that culminates in modulation of cell activation and secretion of pro-inflammatory cytokines. In addition, obesity, now acknowledged as a metabolic syndrome, described as pro-inflammatory as well. This review aims to clarify and point out the relations between two disturbing syndromes of modern times.Estudos mostram que pacientes obesos têm maior chance de serem acometidos pela sepse, além de possuírem maiores riscos de mortalidade. A sepse, sendo uma infecção sistêmica que culmina na modulação da ativação de células e secreção de citocinas pró-inflamatórias e a obesidade, reconhecida como síndrome metabólica caracterizada, também, como pró-inflamatória. Esta revisão tem o objetivo de esclarecer e apontar relações entre duas síndromes dos tempos modernos

The role of Translesion Synthesis Cisplatin and TMZ resistance in glioma cells.

O glioblastoma é um câncer que, em geral, apresenta mau prognóstico, onde a recidiva é quase sempre certa. As polimerases de síntese translesão (TLS) são enzimas capazes de replicar o DNA contendo lesões não removidas por outros mecanismos de reparo. As células tumorais podem utilizar esse mecanismo para sobreviver a lesões causadas pelos quimioterápicos (QMT), sendo, portanto, um possível mecanismo de resistência aos tratamentos. Além disso, esse processo de TLS é sujeito a erro e pode levar à mutagênese, podendo aumentar o potencial de resistência das células tumorais. O tratamento com QMT, como cisplatina ou temozolomida (TMZ), por exemplo, induzem lesões no DNA a fim de induzir morte das células tumorais. Pouco é conhecido sobre o papel das polimerases TLS na resposta ao TMZ. Portanto, identificamos uma lista de genes associados à resistência ao TMZ, utilizando uma biblioteca de genes ativados ou nocauteados pelo sistema CRISPRCas9. Nesta lista, destaca-se a participação de algumas polimerases TLS, como, Pol e Pol . Assim, nosso objetivo é compreender melhor o papel das polimerases TLS, em especial Pol , Pol e Pol , na resistência à cisplatina e a TMZ, QMT utilizado em protocolos terapêuticos de glioma. Inicialmente, tratamos células POLH mutadas (XP-V) e células complementadas para este gene (XP-V comp) com TMZ. Observamos que células XP-V são mais sensíveis ao TMZ, indicando que Pol deve ser importante para superar o dano no DNA. Desenvolvemos células de U251-MG nocautes para os genes das polimerases POLK e POLI pelo sistema CRISPR/Cas9. Essas células mutadas também tiveram sua viabilidade diminuída após tratamento com TMZ, aumento do estresse genotóxico e parada de ciclo celular, principalmente em fase G2, mas não em fase S - após 48 h de tratamento em todas as três células mutadas, não observado em células controle, selvagens para esses genes. Para aprofundarmos a investigação na replicação do DNA, realizamos ensaios de fibra de DNA, e, surpreendentemente, não observamos diferença entre as células mutadas para POLK e as células selvagens tratadas com TMZ. Concluímos que as polimerases TLS protegem as células tumorais do dano causado por TMZ, e, portanto, desempenham função importante em superar a resistência a este quimioterápico. Pretendemos ainda compreender como a replicação é afetada nas células tratadas com TMZ. A ausência de parada em fase S, onde geralmente essas enzimas atuam, e a falta de efeito no progresso da forquilha de replicação indicam que o papel desempenhado por essas polimerases na resistência ao TMZ pode ser além da TLS. Estamos, portanto, buscando outras possíveis funções responsáveis pelos efeitos observados. Assim, queremos entender melhor o mecanismo de resistência promovido pelas polimerases de TLS e buscar novos alvos que colaborem com a quebra de resistência à TMZ utilizada na clínica para tratamento de glioma, para assim contribuir para melhorar o prognóstico dos pacientes com essa neoplasia.Glioblastoma is a cancer that presents poor prognosis, with a high ratio of recurrence. Translesion synthesis (TLS) DNA polymerases are enzymes capable of replicating unrepaired DNA damage. Tumor cells can use this process to survive lesions caused by genotoxic chemotherapeutic drugs (CMT), contributing to the mechanisms of therapy resistance. In addition, TLS is error prone and can lead to mutagenesis, increasing the resistance potential of tumor cells. Treatment with CMT, such as cisplatin or temozolomide (TMZ), induces DNA damage to promote tumor cell death. Little is known about the role of TLS polymerases in the responses to TMZ. Preliminary results obtained by Dr. Clarissa R. R. Rocha, in our group, identified a list of genes associated with the resistance to TMZ, using a library of genes activated or knocked out by the CRISPR-Cas9 system. In this list, the participation of some TLS polymerases, such as, Pol and Pol , are remarkable. Thus, our aim is to better understand the role of TLS polymerases, especially Pol , Pol and Pol , in the resistance to cisplatin and TMZ, CMT used in therapeutic glioma protocols. At first, we treated mutated POLH cells (XP-V) and complemented cells for this gene (XP-V comp) with TMZ. We observed that XP-V cells are more sensitive to TMZ, indicating that Pol must be important to overcome DNA damage promoted by TMZ. We developed U251-MG knockout cells for the POLK and POLI polymerase genes by CRISPR/Cas9. These mutated cells also had their viability impaired after treatment with TMZ, increased in genotoxic stress and cell cycle arrest, mainly in G2 phase, but not in S phase - after 48 h of treatment, in all three mutated cells, not observed in cells wild-type for these genes. To further investigate DNA replication, we performed DNA fiber assay, and, surprisingly, there was no difference between cells mutated to POLK and wild-type cells treated with TMZ. We conclude that TLS polymerases protect tumor cells from damage caused by TMZ, and, therefore, play an important role to overcome resistance to this chemotherapy. Now, we intend to understand how replication is affected in cells treated with TMZ. There is no S-phase arrest, where these enzymes generally act, and no difference in the progression fork replication indicating that the role played by these polymerases in the resistance to TMZ may be beyond TLS. Thus, we are looking for other possible functions responsible for the observed effects. In summary, we want to better understand the resistance mechanism promoted by TLS polymerases and seek new targets that collaborate with the overcome of resistance to TMZ, used in the clinic for the glioma treatment, and contribute to improve the prognosis of patients with this neoplasia

Update on Renal Replacement Therapy: Implantable Artificial Devices and Bioengineered Organs

Recent advances in the fields of artificial organs and regenerative medicine are now joining forces in the areas of organ transplantation and bioengineering to solve continued challenges for patients with end-stage renal disease. The waiting lists for those needing a transplant continue to exceed demand. Dialysis, while effective, brings different challenges, including quality of life and susceptibility to infection. Unfortunately, the majority of research outputs are far from delivering satisfactory solutions. Current efforts are focused on providing a self-standing device able to recapitulate kidney function. In this review, we focus on two remarkable innovations that may offer significant clinical impact in the field of renal replacement therapy: the implantable artificial renal assist device (RAD) and the transplantable bioengineered kidney. The artificial RAD strategy utilizes micromachining techniques to fabricate a biohybrid system able to mimic renal morphology and function. The current trend in kidney bioengineering exploits the structure of the native organ to produce a kidney that is ready to be transplanted. Although these two systems stem from different technological approaches, they are both designed to be implantable, long lasting, and free standing to allow patients with kidney failure to be autonomous. However, for both of them, there are relevant issues that must be addressed before translation into clinical use and these are discussed in this review

Temozolomide Resistance in Glioblastoma by NRF2: Protecting the Evil

The transcription factor NRF2 is constitutively active in glioblastoma, a highly aggressive brain tumor subtype with poor prognosis. Temozolomide (TMZ) is the primary chemotherapeutic agent for this type of tumor treatment, but resistance to this drug is often observed. This review highlights the research that is demonstrating how NRF2 hyperactivation creates an environment that favors the survival of malignant cells and protects against oxidative stress and TMZ. Mechanistically, NRF2 increases drug detoxification, autophagy, DNA repair, and decreases drug accumulation and apoptotic signaling. Our review also presents potential strategies for targeting NRF2 as an adjuvant therapy to overcome TMZ chemoresistance in glioblastoma. Specific molecular pathways, including MAPKs, GSK3β, βTRCP, PI3K, AKT, and GBP, that modulate NRF2 expression leading to TMZ resistance are discussed, along with the importance of identifying NRF2 modulators to reverse TMZ resistance and develop new therapeutic targets. Despite the significant progress in understanding the role of NRF2 in GBM, there are still unanswered questions regarding its regulation and downstream effects. Future research should focus on elucidating the precise mechanisms by which NRF2 mediates resistance to TMZ, and identifying potential novel targets for therapeutic intervention