scholarly journals Inhibition of mammalian target of rapamycin (mTOR) improves neurobehavioral deficit and modulates inflammatory response after traumatic brain injury

2020 ◽  
Author(s):  
Irene Paterniti ◽  
Michela Campolo ◽  
Giovanna Casili ◽  
Marika Lanza ◽  
Alessia Filippone ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Function ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Brain Parenchyma ◽  
Target Of Rapamycin ◽  
Mtor Inhibition ◽  
Secondary Damage ◽  
Effective Therapeutic Strategy

Abstract Traumatic brain injury (TBI) induce primary and secondary damage on endothelium and brain parenchyma, leading neurons die rapidly by necrosis. The mammalian target of rapamycin signalling pathway (mTOR) mediates many aspects of cell growth and regeneration and is up-regulated after moderate to severe traumatic brain injury (TBI). The significance of this increased signalling event for recovery of brain function is presently unclear, here we used two different selective inhibitors of mTOR activity to explore the functional role of mTOR inhibition in an validated model of TBI, the controlled cortical impact injury (CCI). We treated animals withKU0063794, a dual mTORC1 and mTORC2 inhibitor, and with rapamycin a well-known inhibitor of mTOR, 1 and 4 hours after TBI. Our results demonstrated that mTOR inhibitors, especially KU0063794, significantly improve motor and cognitive recovery after TBI as well as reduce lesion volumes. Moreover we observed that mTOR inhibitors treatment ameliorate the neuroinflammation associated to TBI and showed that this acute treatment significantly diminished the extent of neuronal death, astrogliosis and apoptotic process after trauma. Our findings suggest that the neuronal mTORC1/2 activity after TBI is deleterious to brain function and acute intervention with selective mTORC1/2 inhibitor may represent an effective therapeutic strategy to improve recovery after brain trauma.

scholarly journals Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro

2009 ◽  
Vol 16 (3) ◽  
pp. 1017-1027 ◽  
Author(s):  
Alexander Gorshtein ◽  
Hadara Rubinfeld ◽  
Efrat Kendler ◽  
Marily Theodoropoulou ◽  
Vesna Cerovac ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cyclin D1 ◽  
Pituitary Adenomas ◽  
Pituitary Tumor ◽  
Mammalian Target Of Rapamycin ◽  
Pituitary Tumors ◽  
Mtor Inhibitors ◽  
Target Of Rapamycin ◽  
Gh3 Cells ◽  
Mtor Inhibition

The effect of mammalian target of rapamycin (mTOR) inhibitors on pituitary tumors is unknown. Akt overexpression was demonstrated in pituitary adenomas, which may render them sensitive to the anti-proliferative effects of these drugs. The objective of the study was to evaluate the anti-proliferative efficacy of the mTOR inhibitor, rapamycin, and its orally bioavailable analog RAD001 on the GH-secreting pituitary tumor GH3 and MtT/S cells and in human GH-secreting pituitary adenomas (GH-omas) in primary cell cultures. Treatment with rapamycin or RAD001 significantly decreased the number of viable cells and cell proliferation in a dose- and time-dependent manner. This was reflected by decreased phosphorylation levels of the downstream mTOR target p70S6K. Rapamycin treatment of GH3 cells induced G0/G1 cell cycle arrest. In other tumor cell types, this was attributed to a decrease in cyclin D1 levels. However, rapamycin did not affect cyclin D1 protein levels in GH3 cells. By contrast, it decreased cyclin D3 and p21/CIP, which stabilizes cyclin D/cyclin-dependent kinase 4 (cdk4) complexes. Rapamycin inhibited FCS-induced retinoblastoma phosphorylation and subsequent E2F-transcriptional activity. In response to decreased E2F activity, the expression of the E2F-regulated genes cyclin E and cdk2 was reduced. Our results showed that mTOR inhibitors potently inhibit pituitary cell proliferation, suggesting that mTOR inhibition may be a promising anti-proliferative therapy for pituitary adenomas. This therapeutic manipulation may have beneficial effects particularly for patients harboring invasive pituitary tumors resistant to current treatments.

scholarly journals Is There a Role for Mammalian Target of Rapamycin Inhibition in Renal Failure due to Mesangioproliferative Nephrotic Syndrome?

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Hernán Trimarchi ◽  
Mariano Forrester ◽  
Fernando Lombi ◽  
Vanesa Pomeranz ◽  
Romina Iriarte ◽  
...  
Keyword(s):  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Target Of Rapamycin ◽  
Mtor Inhibition ◽  
Primary Glomerulonephritis ◽  
Glomerular Proteinuria ◽  
Mesangioproliferative Glomerulonephritis ◽  
Stage Renal Disease ◽  
End Stage

Primary glomerulonephritis stands as the third most important cause of end-stage renal disease, suggesting that appropriate treatment may not be as effective as intended to be. Moreover, proteinuria, the hallmark of glomerular damage and a prognostic marker of renal damage progression, is frequently resistant to thorough control. In addition, proteinuria may be the common end pathway in which different pathogenetic mechanisms may converge. This explains why immunosuppressive and nonimmunosuppressive approaches are partly not sufficient to halt disease progression. One of the commonest causes of primary glomerulonephritis is mesangioproliferative glomerulonephritis. Among the triggered intracellular pathways involved in mesangial cell proliferation, the mammalian target of rapamycin (mTOR) plays a critical role in cell growth, in turn regulated by many cytokines, disbalanced by the altered glomerulopathy itself. However, when inhibition of mTOR was studied in rodents and in humans with primary glomerulonephritis the results were contradictory. In light of these controversial data, we propose an explanation for these results, to dilucidate under which circumstances mTOR inhibition should be considered to treat glomerular proteinuria and finally to propose mTOR inhibitors to be prospectively assessed in clinical trials in patients with primary mesangioproliferative glomerulonephritis, for which a satisfactory standard immunosuppressive regimen is still pending.

scholarly journals Traumatic brain injury in dogs and cats: a systematic review

2018 ◽  
Vol 63 (No. 8) ◽  
pp. 345-357 ◽  
Author(s):  
LO Dos Santos ◽  
GG Caldas ◽  
CRO Santos ◽  
DB Junior
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Motor Vehicle ◽  
Brain Parenchyma ◽  
Irreversible Damage ◽  
Vehicle Accidents ◽  
Secondary Damage ◽  
Therapeutic Measures ◽  
Crush Injuries ◽  
The Brain

Traumatic brain injury occurs frequently in dogs and cats due to motor vehicle accidents, falls and crush injuries. The primary lesion occurs at the time of injury and causes direct, irreversible damage to the brain parenchyma and vasculature. Secondary lesions occur in the minutes following the trauma due to a combination of physical and biochemical changes that lead to intracranial hypertension. Therefore, knowing the pathophysiology of the cranioencephalic trauma is essential for treatment directed at minimising secondary damage. The approach to the patient affected by traumatic brain injury is based on the ABCD of trauma, guided by the neurological examination with the aid of imaging exams and adequate therapeutic measures. The treatment of patients with cranioencephalic trauma is still in many ways controversial. For that reason, this literature review aims to address the main points regarding the pathophysiology of this disease and to describe the clinical and surgical therapeutic options currently available.

Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas

2008 ◽  
Vol 10 ◽  
Author(s):  
Elias Drakos ◽  
George Z. Rassidakis ◽  
L. Jeffrey Medeiros
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Central Element ◽  
Mtor Inhibitors ◽  
Chemotherapeutic Agents ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Mtor Inhibition

AbstractThe mammalian target of rapamycin mTOR is a central element in an evolutionary conserved signalling pathway that regulates cell growth, survival and proliferation, orchestrating signals originating from growth factors, nutrients or particular stress stimuli. Two important modulators of mTOR activity are the AKT and ERK/MAPK signalling pathways. Many studies have shown that mTOR plays an important role in the biology of malignant cells, including deregulation of the cell cycle, inactivation of apoptotic machinery and resistance to chemotherapeutic agents. The development of several mTOR inhibitors, in addition to rapamycin, has facilitated studies of the role of mTOR in cancer, and verified the antitumour effect of mTOR inhibition in many types of neoplasms, including lymphomas. Clinical trials of rapamycin derivatives in lymphoma patients are already in development and there are encouraging preliminary results, such as the substantial response of a subset of mantle cell lymphoma patients to the rapamycin analogue temsirolimus. Based on results obtained from in vitro and in vivo studies of the mTOR pathway in lymphomas, it seems that better understanding of mTOR regulation will reveal aspects of lymphomagenesis and contribute to the development of more powerful, targeted therapies for lymphoma patients.

Inhibition of the Mammalian Target of Rapamycin May Augment the Increase in Soluble Klotho Levels in Renal Transplantation Recipients

2019 ◽  
Vol 47 (Suppl. 2) ◽  
pp. 12-18 ◽  
Author(s):  
Kosuke Mizusaki ◽  
Yukiko Hasuike ◽  
Tomoko Kimura ◽  
Yasuyuki Nagasawa ◽  
Takahiro Kuragano ◽  
...  
Keyword(s):  
Renal Transplantation ◽  
Mammalian Target Of Rapamycin ◽  
Vascular Complications ◽  
Mtor Inhibitors ◽  
Target Of Rapamycin ◽  
Soluble Form ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Mtor Inhibition ◽  
Before And After

Background/Aims: α-Klotho is mainly expressed in the kidneys, and its soluble form can prevent vascular calcifications. Inhibition of the mammalian target of rapamycin (mTOR) upregulates Klotho. We assessed serial changes in the levels of soluble Klotho (sKlotho) in recipients before and after renal transplantation and investigated the effects of an mTOR inhibitor. Methods: Serum sKlotho levels were measured in 36 recipients before and 1 year after transplantation and compared between those taking everolimus and those not taking everolimus. Results: sKlotho levels were higher after transplantation than before transplantation (369.3 vs. 211.8 pg/mL). After transplantation, sKlotho levels were significantly higher in recipients taking everolimus than in those not taking everolimus (536.7 vs. 332.4 pg/mL). Conclusion: Our results suggest that mTOR inhibition may augment the increase in sKlotho levels in transplant recipients. Further studies are needed to examine whether mTOR inhibitors suppress the development of vascular complications via upregulation of Klotho expression in renal transplant recipients.

scholarly journals Alterations in Mammalian Target of Rapamycin Signaling Pathways after Traumatic Brain Injury

2006 ◽  
Vol 27 (5) ◽  
pp. 939-949 ◽  
Author(s):  
Shaoyi Chen ◽  
Coleen M Atkins ◽  
Chunli L Liu ◽  
Ofelia F Alonso ◽  
W Dalton Dietrich ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Signaling Pathways ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin

scholarly journals Creatine Supplementation and Brain Health

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 586 ◽  
Author(s):  
Hamilton Roschel ◽  
Bruno Gualano ◽  
Sergej M. Ostojic ◽  
Eric S. Rawson
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Function ◽  
Cognitive Processing ◽  
Brain Function ◽  
Creatine Supplementation ◽  
Short Review ◽  
Future Research ◽  
Brain Health

There is a robust and compelling body of evidence supporting the ergogenic and therapeutic role of creatine supplementation in muscle. Beyond these well-described effects and mechanisms, there is literature to suggest that creatine may also be beneficial to brain health (e.g., cognitive processing, brain function, and recovery from trauma). This is a growing field of research, and the purpose of this short review is to provide an update on the effects of creatine supplementation on brain health in humans. There is a potential for creatine supplementation to improve cognitive processing, especially in conditions characterized by brain creatine deficits, which could be induced by acute stressors (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g., creatine synthesis enzyme deficiencies, mild traumatic brain injury, aging, Alzheimer’s disease, depression). Despite this, the optimal creatine protocol able to increase brain creatine levels is still to be determined. Similarly, supplementation studies concomitantly assessing brain creatine and cognitive function are needed. Collectively, data available are promising and future research in the area is warranted.

scholarly journals Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung

2010 ◽  
Vol 17 (4) ◽  
pp. 977-987 ◽  
Author(s):  
Luisella Righi ◽  
Marco Volante ◽  
Ida Rapa ◽  
Veronica Tavaglione ◽  
Frediano Inzani ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Differential Sensitivity ◽  
Initiation Factor ◽  
Target Of Rapamycin ◽  
Low Grade ◽  
Mtor Inhibition ◽  
Signaling Activation ◽  
Activation Status

Among alternative therapeutic strategies in clinically aggressive neuroendocrine tumors (NETs) of the lung, promising results have been obtained in experimental clinical trials with mammalian target of rapamycin (mTOR) inhibitors, though in the absence of a proven mTOR signaling activation status. This study analyzed the expression of phosphorylated mTOR (p-mTOR) and its major targets, the ribosomal p70S6-kinase (S6K) and the eukaryotic initiation factor 4E-binding protein 1 (4EBP1) in a large series of 218 surgically resected, malignant lung NETs, including 24 metastasizing typical carcinoids, 73 atypical carcinoids, 60 large cell neuroendocrine carcinomas (LCNECs), and 61 small cell carcinomas (SCLCs). By immunohistochemistry, low-to-intermediate-grade tumors as compared with high-grade tumors showed higher levels of p-mTOR and phosphorylated S6K (p-S6K) (P<0.001), at variance with phosphorylated 4EBP1 (p-4EBP1), which was mainly expressed in LCNECs and SCLCs (P<0.001). The activated status of mTOR pathway was proved by the strong correlation of p-mTOR with p-S6K and somatostatin receptor(s). Western blot analysis of NET tumor samples confirmed such findings, and differential sensitivity to mTOR inhibition according to mTOR pathway activation characteristics was determined in two lung carcinoid cell lines in vitro. None of the investigated molecules had an impact on survival. However, in low-grade tumors, low p-mTOR expression correlated with lymph node metastases (P=0.016), recurrent disease, and survival (P=0.005). In conclusion, these data demonstrate a differential mTOR activation status in the spectrum of pulmonary NETs, possibly suggesting that mTOR pathway profiling might play a predictive role in candidate patients for mTOR-targeted therapies.

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