Investigation of the effects of fetal microchimeric cells isolated from maternal blood on brain injury in mice

Fetal kökenli hücrelerin az miktarda maternal dolaşımda ve maternal dokularda bulunması fetal mikrokimerizm olarak tanımlanmaktadır. Fetal mikrokimerik hücrelerin (FMH) hamilelik sırasında plasentayı geçerek maternal dolaşıma katıldığı ve maternal dokulara göç ettiği bilinmektedir. Ayrıca, hamilelik sonrasında fetal mikrokimerik hücreler, maternal kan ve dokularda tespit edilebilmiştir. Maternal dokuda hasar oluştuğu durumlarda ise hasara yönelerek burada fonksiyonel hücrelere dönüştüğü ve hasarlı bölgenin onarılmasına katkıda bulundukları düşünülmektedir. İskemik beyin felci dünyada ölüm nedenleri arasında ön sıralarda gelmekte, fonksiyonel ve psikolojik aktivitelerde bozulmaya yol açmaktadır. Uygulanabilir tek tedavisi doku plazminojen aktivatörü (tPA) olmasına rağmen, tedavi uygulamasındaki zaman kısıtlaması nedeniyle çoğu hasta bu tedavi için elverişli değildir. Bu durum FMH'leri iskemi beyin felci tedavisinde yeni bir yaklaşım olabileceğini akla getirmiştir. FMH'lerin iskemik beyin felci üzerine etkilerini anlayabilmek için, insanda beyin felci hastalarının %80'ine yakınının etkilendiği iskemik beyin felci olan orta serebral arter oklüzyonu modeli kullanılmıştır. Tedavi olarak uygulanan FMH'lerin maternal ortam dışında kan-beyin bariyerini geçebildikleri, kısa dönemde (72 saat) iskemik hasarda nöronal sağkalımı artırıp ödemi azaltarak tedavi potansiyeline sahip oldukları görülmüştür. Ayrıca, FMH'lerin, immün sisteminden saklanarak uzun dönemde (30 gün) hayatta kalabildikleri görülmüştür. FMH'lerin hasar sonrası uzun dönemde iskemik beyin bölgesine göç ettiği biyolüminesans tomografi tekniği kullanılarak gösterilmiştir. Ayrıca yapılan immünfloresan boyamalarla bu hücrelerin hasarlı beyin alanında nörona farklılaştığı tespit edilmiştir. FMH'lerin fetal ve maternal doku dışında başka bir canlının immün sistemini aşarak uzun dönem hayatta kalması, kan beyin bariyerini geçmesi ve hasara yönelmesi hücre tedavisi temelli translasyonel çalışmalarda kullanılması için umut vadetmektedir.The presence of fetal-derived cells in small amounts in the maternal circulation and maternal tissues is defined as fetal microchimerism. Transition of fetal microchimeric cells (FMC) into the maternal circulation by crossing the placenta during pregnancy, migration of them to maternal tissues is already known. FMCs are also detectable in maternal blood and tissues after pregnancy. In cases where the maternal tissue is damaged, it is thought that FMCs head towards to damaged tissues, turn into functional cells and contributes to the repair of the damaged area. Ischemic stroke is the leading causes of death in the world, and it leads to deterioration in functional and psychological activities. Although the only applicable treatment is tissue plasminogen activator (tPA), most of the patients are not eligible for this treatment because of time limitation of it. This suggests that FMCs can be a new approach in the treatment of ischemic stroke. In order to understand the effects of FMCs on ischemic stroke, the middle cerebral artery occlusion model, in which up to 80% of human stroke patients are affected, was used. It has been observed that FMCs applied as treatment can cross the blood-brain barrier and have therapeutic potential by increasing neuronal survival and reducing edema in ischemic damage in the short term (72 hours) outside the maternal environment. In addition, it has been observed that FMCs can survive in the long term (30 days) by hiding from the immune system. Migration of FMCs to the ischemic brain region was shown via bioluminescent tomography technique in the long-term after ischemia. Moreover, it was detected that FMCs were differentiated into neurons in the damaged brain area by immunofluorescent staining. The long-term survival of FMCs by exceeding the immune system of another organism other than fetal and maternal tissue, their ability to cross the blood-brain barrier and tend to migrate damaged area are promising for their use in cell therapy-based translational studies

Interaction of melatonin and Bmal1 in the regulation of PI3K/AKT pathway components and cellular survival

The circadian rhythm is driven by a master clock within the suprachiasmatic nucleus which regulates the rhythmic secretion of melatonin. Bmal1 coordinates the rhythmic expression of transcriptome and regulates biological activities, involved in cell metabolism and aging. However, the role of Bmal1 in cellular- survival, signaling, its interaction with intracellular proteins, and how melatonin regulates its expression is largely unclear. Here we observed that melatonin increases the expression of Bmal1 and both melatonin and Bmal1 increase cellular survival after oxygen glucose deprivation (OGD) while the inhibition of Bmal1 resulted in the decreased cellular survival without affecting neuroprotective effects of melatonin. By using a planar surface immunoassay for PI3K/AKT signaling pathway components, we revealed that both melatonin and Bmal1 increased phosphorylation of AKT, ERK-1/2, PDK1, mTOR, PTEN, GSK-3 alpha beta, and p70S6K. In contrast, inhibition of Bmal1 resulted in decreased phosphorylation of these proteins, which the effect of melatonin on these signaling molecules was not affected by the absence of Bmal1 . Besides, the inhibition of PI3K/AKT decreased Bmal1 expression and the effect of melatonin on Bmal1 after both OGD in vitro and focal cerebral ischemia in vivo. Our data demonstrate that melatonin controls the expression of Bmal1 via PI3K/AKT signaling, and Bmal1 plays critical roles in cellular survival via activation of survival kinases

The role of phosphatidylinositol-3 kinase/AKT and ERK-1/2 pathways in the neuroprotective activity of lithium

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The protein expression profile of old and young mice after cerebral ischemia

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Regulation of E3 ligase Nedd4-1 under oxidative stress

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Acute and post-acute neuromodulation induces stroke recovery by promoting survival signaling, neurogenesis, and pyramidal tract plasticity

WOS: 000464493200003PubMed ID: 31031599Repetitive transcranial magnetic stimulation (rTMS) has gained interest as a non-invasive treatment for stroke based on the data promoting its effects on functional recovery. However, the exact action mechanisms by which the rTMS exert beneficial effects in cellular and molecular aspect are largely unknown. To elucidate the effects of high- and low-frequency rTMS in the acute-ischemic brain, we examined how rTMS influences injury development, cerebral blood flow (CBF), DNA fragmentation, neuronal survival, pro- and anti-apoptotic protein activations after 30 and 90 min of focal cerebral ischemia. In addition, inflammation, angiogenesis, growth factors and axonal outgrowth related gene expressions, were analyzed. Furthermore, we have investigated the effects of rTMS on post-acute ischemic brain, particularly on spontaneous locomotor activity, perilesional tissue remodeling, axonal sprouting of corticobulbar tracts, glial scar formation and cell proliferation, in which rTMS was applied starting 3 days after the stroke onset for 28 days. In the high-frequency rTMS received animals reduced DNA fragmentation, infarct volume and improved CBF were observed, which were associated with increased Bcl-xL activity and reduced Bax, caspase-1, and caspase-3 activations. Moreover, increased angiogenesis, growth factors; and reduced inflammation and axonal sprouting related gene expressions were observed. These results correlated with reduced microglial activation, neuronal degeneration, glial scar formation and improved functional recovery, tissue remodeling, contralesional pyramidal tract plasticity and neurogenesis in the subacute rTMS treated animals. Overall, we propose that high-frequency rTMS in stroke patients can be used to promote functional recovery by inducing the endogenous repair and recovery mechanisms of the brain.Turkish Academy of Sciences (TUBA); Necmettin Erbakan University [161318006]This work was funded by Turkish Academy of Sciences (TUBA) and Necmettin Erbakan University (Scientific Research Project No. 161318006)

Role of normobaric oxygen treatment on newborn hypoxia-ischemia

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The role of solute carrier oatp1a4 in brain injury pharmacotherapy

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Effect of circadian rhythm protein BMAL1 on neuronal damage

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Short-term diet restriction but not alternate day fasting prevents cisplatin-induced nephrotoxicity in mice

Cisplatin (CP) is one of the most preferred platinum-containing antineoplastic drugs. However, even in nontoxic plasma concentrations, it may cause kidney injury. To be able to increase its effective pharmacological dose, its side effects need to be regarded. Diet restriction (DR) has been demonstrated to improve cellular survival in a number of disorders. In this context, we investigated the role of DR in CP-induced nephrotoxicity (CPN). Besides alternate DR, animals were exposed to DR for 3 days prior or after CP treatment. Here, we observed that both 3 days of DR reverses the nephrotoxic effect of CP, which was associated with improved physiological outcomes, such as serum creatine, blood-urea nitrogen and urea. These treatments significantly increased phosphorylation of survival kinases PI3K/Akt and ERK-1/2 and decreased the level of stress kinase JNK were noted. In addition, the activation level of signal transduction mediator p38 MAPK phosphorylation was higher particularly in both three-day DR groups. Next, animals were fed with carbohydrate-, protein- or fat-enriched diets in the presence of CP. Results indicated that not only fasting but also dietary content itself may play a determinant role in the severity of CPN. Our data suggest that DR is a promising approach to reduce CPN by regulating metabolism and cell signaling pathways.Turkish Academy of Science