المؤلفون: Cho, Ara¹ (AUTHOR), Park, Sunghae² (AUTHOR), Han, Ahram¹ (AUTHOR), Ha, Jongwon¹ (AUTHOR), Park, Jae Berm² (AUTHOR), Lee, Kyo Won² (AUTHOR), Min, Sangil¹ (AUTHOR) surgeonmsi@gmail.com

المصدر: Scientific Reports. 6/4/2024, Vol. 14 Issue 1, p1-10. 10p.

مصطلحات موضوعية: *KIDNEY transplantation, *MTOR inhibitors, *CALCINEURIN, *TREATMENT effectiveness, *TACROLIMUS, *RAPAMYCIN, *VIREMIA

مستخلص: BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols adds to the complexity of managing this condition. This study aimed to compare the two treatment approaches. The study population consisted of patients who underwent kidney transplantation between January 2016 and June 2020 at two tertiary hospitals in Korea. Patients diagnosed with BK viremia were evaluated based on their initial viral load and the treatment methods. The 'Reduction group' involved dose reduction of tacrolimus while the 'Conversion group' included tacrolimus discontinuation and conversion to sirolimus. A total of 175 patients with an initial viral load (iVL) ≥ 3 on the log10 scale were evaluated within two iVL intervals (3–4 and 4–5). In the iVL 4–5 interval, the Reduction group showed potential effectiveness in terms of viral clearance without statistically significant differences. However, within the iVL 3–4 interval, the Reduction group demonstrated superior viral clearance and a lower incidence of biopsy-proven acute rejection (BPAR) than the Conversion group. The renal function over 12 months after BKV diagnosis showed no statistically significant difference. Reducing tacrolimus compared to converting to mTORi would be a more appropriate treatment approach for BK viral clearance in kidney transplantation. Further research is warranted in a large cohort of patients. [ABSTRACT FROM AUTHOR]

المؤلفون: Marafie, Sulaiman K.¹ (AUTHOR) sulaiman.marafie@dasmaninstitute.org, Al-Mulla, Fahd² (AUTHOR) fahd.almulla@dasmaninstitute.org, Abubaker, Jehad¹ (AUTHOR) sulaiman.marafie@dasmaninstitute.org

المصدر: International Journal of Molecular Sciences. Jun2024, Vol. 25 Issue 11, p6141. 17p.

مصطلحات موضوعية: *METABOLIC disorders, *MTOR inhibitors, *AGING, *CELL physiology, *PROTEIN synthesis

مستخلص: The mammalian target of rapamycin (mTOR) is a pivotal regulator, integrating diverse environmental signals to control fundamental cellular functions, such as protein synthesis, cell growth, survival, and apoptosis. Embedded in a complex network of signaling pathways, mTOR dysregulation is implicated in the onset and progression of a range of human diseases, including metabolic disorders such as diabetes and cardiovascular diseases, as well as various cancers. mTOR also has a notable role in aging. Given its extensive biological impact, mTOR signaling is a prime therapeutic target for addressing these complex conditions. The development of mTOR inhibitors has proven advantageous in numerous research domains. This review delves into the significance of mTOR signaling, highlighting the critical components of this intricate network that contribute to disease. Additionally, it addresses the latest findings on mTOR inhibitors and their clinical implications. The review also emphasizes the importance of developing more effective next-generation mTOR inhibitors with dual functions to efficiently target the mTOR pathways. A comprehensive understanding of mTOR signaling will enable the development of effective therapeutic strategies for managing diseases associated with mTOR dysregulation. [ABSTRACT FROM AUTHOR]

المؤلفون: Xia, Jianhong¹ (AUTHOR) jhxia2006@163.com, Wang, Haiyun^1,2 (AUTHOR) sunny.haiyun@gmail.com, Zhong, Zhihang^3,4 (AUTHOR) zhongzhihanggood@163.com, Jiang, Jun^3,4 (AUTHOR) jiangjun@scau.edu.cn

المصدر: Cells (2073-4409). Jun2024, Vol. 13 Issue 11, p953. 18p.

مصطلحات موضوعية: *LYSOSOMAL storage diseases, *MTOR inhibitors, *CELL culture, *BRACHYDANIO, *HOMEOSTASIS

مستخلص: PIKfyve is an endosomal lipid kinase that synthesizes phosphatidylinositol 3,5-biphosphate from phosphatidylinositol 3-phsphate. Inhibition of PIKfyve activity leads to lysosomal enlargement and cytoplasmic vacuolation, attributed to impaired lysosomal fission processes and homeostasis. However, the precise molecular mechanisms underlying these effects remain a topic of debate. In this study, we present findings from PIKfyve-deficient zebrafish embryos, revealing enlarged macrophages with giant vacuoles reminiscent of lysosomal storage disorders. Treatment with mTOR inhibitors or effective knockout of mTOR partially reverses these abnormalities and extend the lifespan of mutant larvae. Further in vivo and in vitro mechanistic investigations provide evidence that PIKfyve activity is essential for mTOR shutdown during early zebrafish development and in cells cultured under serum-deprived conditions. These findings underscore the critical role of PIKfyve activity in regulating mTOR signaling and suggest potential therapeutic applications of PIKfyve inhibitors for the treatment of lysosomal storage disorders. [ABSTRACT FROM AUTHOR]

المؤلفون: Johnson, Jan¹ (AUTHOR), Somerfield, Wendy² (AUTHOR), Johnson, Simon R.^1,2,3 (AUTHOR) simon.johnson@nottingham.ac.uk

المصدر: Orphanet Journal of Rare Diseases. 3/26/2024, Vol. 19 Issue 1, p1-8. 8p.

مصطلحات موضوعية: *TUBEROUS sclerosis, *MTOR inhibitors, *LUNG transplantation, *TREATMENT delay (Medicine)

مصطلحات جغرافية: UNITED Kingdom

مستخلص: Background: Lymphangioleiomyomatosis (LAM) is common in tuberous sclerosis complex (TSC) yet under recognised with management mostly based upon evidence obtained from patients with sporadic LAM. We performed a prospective audit of patients with TSC-LAM attending a national referral centre to inform management guidelines. Methods: The UK LAM Centre was established in 2011 and conducts a prospective audit of pre-defined quality outcomes for all subjects. Audit data are reported on all patients with TSC-LAM and a comparator population of patients with sporadic LAM. Results: Between 2011 and 2022, 73 patients were seen with TSC-LAM. All were women with a mean (SD) age of 39 (12) years. Referral rates were similar over the study period including after the introduction of CT screening. Median age of diagnosis with TSC was 11 years (range 0–70) with one third diagnosed with TSC as adults. Compared with all TSC patients in the 'TOSCA' registry, TSC-LAM patients tended to have been diagnosed with TSC at an older age, had fewer neuro-cognitive manifestations and were more likely to have angiomyolipoma. The most common presentations of TSC-LAM were following workup for angiomyolipoma, pneumothorax or dyspnoea with only one fifth detected after CT screening. Baseline FEV1 and DLCO at first assessment were reduced to 77 and 63% predicted respectively and were similar to patients with sporadic LAM. During follow-up, FEV1 fell by a mean of 81 ml/year and DLCO fell by 0.309 mmol/ml/kPa/year in patients not being treated with an mTOR inhibitor. 55% required treatment with either sirolimus or Everolimus for LAM or angiomyolipoma respectively. For those treated with an mTOR inhibitor, mean FEV1 fell by 3 ml/year and DLCO increased by 0.032 mmol/ml/kPa/year and was similar to sporadic LAM. Risk of death due to LAM or need for lung transplant in patients with TSC-LAM was 0.67%/year. Conclusions: Despite screening recommendations, LAM is often diagnosed in TSC after symptoms develop which may delay treatment. Complications including pneumothorax and loss of lung function are significant and similar to sporadic LAM. Work is needed to implement the recommended CT screening for LAM and improve respiratory care for TSC-LAM. [ABSTRACT FROM AUTHOR]

المؤلفون: Shaw, Suman¹ (AUTHOR), Dey, Rajdeep¹ (AUTHOR), Bhatt, Hardik¹ (AUTHOR), Patel, Bhumika¹ (AUTHOR), Patel, Saumya² (AUTHOR), Dixit, Nandan² (AUTHOR), Chaube, Udit¹ (AUTHOR) uditchoube@gmail.com

المصدر: ChemistrySelect. Feb2024, Vol. 9 Issue 7, p1-15. 15p.

مصطلحات موضوعية: *MTOR inhibitors, *MTOR protein, *MOLECULAR dynamics, *QSAR models, *LUNG cancer

مستخلص: There is a need to develop innovative, safe, and more effective treatment methods for lung cancer due to obstacles including resistance, side effects, and low bioavailability, among others related to present medicines. Our previous research findings gave some promising results of tetrahydroquinoline (THQ) derivatives as mTOR inhibitors for the treatment of lung cancer. The current research has employed certain integrated computational techniques to enhance the effectiveness of THQ derivatives. Various computational methods, like the generation of the pharmacophore model, virtual screening, and QSAR modeling were employed to achieve the goal, and their results were connected to develop novel THQ analogues. This study revealed that among 48 newly designed THQ derivatives, the compound UC_1 indicated the XP Gscore of −9.378 kcal/mol and also showed the key amino acid interactions with the mTOR protein viz. Gln2167, Val2240. Interestingly, compound UC_1 showed a better binding affinity with the mTOR protein compared to the clinical trial molecules viz. AZD‐8055 and AZD‐2014. The molecular dynamics simulations (100 ns) along with each output give a shred of strong evidence that the designed THQ derivative (UC_1) has all the required features in terms of inhibiting mTOR protein for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

المؤلفون: Sonis, Stephen T.^1,2,3 (AUTHOR) ssonis@biomodels.com, Villa, Alessandro^4,5 (AUTHOR)

المصدر: Cancers. Jan2024, Vol. 16 Issue 1, p68. 11p.

مصطلحات موضوعية: *CANKER sores, *MTOR inhibitors, *ORAL diseases, *HYPOTHESIS, *ORAL mucosa

مستخلص: Simple Summary: The mammalian/mechanistic target of the rapamycin (mTOR) pathway is made up of many components that have far-reaching biological consequences, such as cell division, growth, and metabolism. The results of experiments performed years ago showed that inhibitors of the mTOR pathway have a negative effect on tumor cells, which sparked interest in the development of a class of drugs called mTOR inhibitors as anti-cancer therapies. mTOR inhibitors are now part of oncologists' armamentarium for various types of cancers, but patients who use these drugs are at a high risk of developing painful mouth sores. In this paper, we provide a hypothesis as to why these sores develop, how their development compares to other common mouth sores such as canker sores, why other parts of the body are not affected, and how treatment may work. It has been 24 years since rapamycin (sirolimus) was approved to mitigate solid organ transplant rejection and 16 years since mTOR (mammalian/mechanistic target of rapamycin) inhibitors reached patients as a cancer therapy. While the clinical benefits of mTOR inhibitors (mTORi) are robust, so too are their toxicities. Among the most common issues is the development of ulcers of the oral mucosa (mTOR-inhibitor associated stomatitis; mIAS). These lesions are distinct from those of other anti-cancer agents, occur with regularity, and impact patient outcomes. mIAS' pathogenesis has been the subject of speculation, and its similar presentation to recurrent aphthous stomatitis (RAS) has led to the hypothesis that it might serve as a surrogate to better understand RAS. Based on a review of the literature, the current manuscript provides a hypothesis regarding the mechanisms by which mTORis uniquely initiate mucosal injury and an explanation for the observation that steroids (also an immunosuppressive) are effective in its treatment through a non-immunologic mechanism. Unexplained unique features of mIAS are discussed in this review in the context of future investigation. [ABSTRACT FROM AUTHOR]

المؤلفون: Asghari, F.¹, Karimi, M. H.^2,3, Pourfathollah, A. A.¹ pourfa@modares.ac.ir

المصدر: Immunopharmacology & Immunotoxicology. Dec2023, Vol. 45 Issue 6, p719-729. 11p.

مصطلحات موضوعية: *T cells, *MTOR inhibitors, *OXIDATIVE stress, *GENE expression, *CELL proliferation, *CD28 antigen, *IMMUNOSENESCENCE

مستخلص: Background: Due to the increase of the elderly's population and related social and economic problems, it is very important to provide strategies on health. In this regard, induction of T lymphocytes responses, the most important cells of the immune system, may be a good approach. Among different agents considered as antiaging factors, mTORC1 pathway inhibitors are significant. So, the purpose of this study was to evaluate the effect of two mTORC1 inhibitors, Everolimus and Metformin, on age-related features of activated T cells. Materials and Methods: Optimum doses of drugs was determined with evaluating the effect of treatments on IL-2 gene expression. T cells isolated from old and young mice were treated with drugs and PHA. IL-2 production was evaluated by ELISA. Also, the expression of CD28, PD-1, and KLRG-1, proliferation, and intracellular oxidative stress were assessed by flow cytometry-based assays, phenotyping, CFSE, and DCF-DA assay respectively. Results: Both drugs increased IL-2 production in the T cells of old mice. Also, using drugs especially Metformin could improve age-related phenotypical markers and increase the proliferation of T cells of old mice significantly. In addition, Metformin and Everolimus reduced intracellular oxidative stress in aged cells. However, the effect of both drugs on the T cells of young mice wasn't significant or was in opposite to the results of old mice T cells. Discussion: In line with studies noting mTOR inhibitors as antiaging drugs, Metformin and Everolimus may improve T cells affected from aging in vitro, and a decrease in intracellular oxidative stress may be one of their mechanism of function. [ABSTRACT FROM AUTHOR]

المؤلفون: Wang, Jiani¹ (AUTHOR), Gui, Lin¹ (AUTHOR), Mu, Yuxin¹ (AUTHOR), Wang, Jiayu¹ (AUTHOR), Chi, Yihebali¹ (AUTHOR), Liu, Zhenteng² (AUTHOR), Li, Qing¹ (AUTHOR) cheryliqing@126.com, Xu, Binghe^1,3 (AUTHOR) xubinghebm@163.com

المصدر: BMC Cancer. 12/6/2023, Vol. 23 Issue 1, p1-12. 12p.

مصطلحات موضوعية: *MTOR inhibitors, *ORAL drug administration, *ALANINE aminotransferase, *CHINESE people, *ASPARTATE aminotransferase, *RAPAMYCIN

مستخلص: Background: The mammalian target of rapamycin (mTOR) kinase, a central component of the PI3K/AKT/mTOR pathway, plays a critical role in tumor biology as an attractive therapeutic target. We conducted this first-in-human study to investigate the safety, pharmacokinetics (PK), and pilot efficacy of LXI-15029, an mTORC1/2 dual inhibitor, in Chinese patients with advanced malignant solid tumors. Methods: Eligible patients with advanced, unresectable malignant solid tumors after failure of routine therapy or with no standard treatment were enrolled to receive ascending doses (10, 20, 40, 60, 80, 110, and 150 mg) of oral LXI-15029 twice daily (BID) (3 + 3 dose-escalation pattern) until disease progression or intolerable adverse events (AEs). The primary endpoints were safety and tolerability. Results: Between June 2017 and July 2021, a total of 24 patients were enrolled. LXI-15029 was well tolerated at all doses. Only one dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in the 150 mg group, and the maximum tolerated dose was 110 mg BID. The most common treatment-related AEs were leukocytopenia (41.7%), increased alanine aminotransferase (20.8%), increased aspartate aminotransferase (20.8%), prolonged electrocardiogram QT interval (20.8%), and hypertriglyceridemia (20.8%). No other serious treatment-related AEs were reported. LXI-15029 was absorbed rapidly after oral administration. The increases in the peak concentration and the area under the curve were greater than dose proportionality over the dose range. Eight patients had stable disease. The disease control rate was 40.0% (8/20; 95% CI 21.7–60.6). In evaluable patients, the median progression-free survival was 29 days (range 29–141). Conclusions: LXI-15029 demonstrated reasonable safety and tolerability profiles and encouraging preliminary antitumor activity in Chinese patients with advanced malignant solid tumors, which warranted further validation in phase II trials. Trial registration: NCT03125746(24/04/2017),http://ClinicalTrials.gov/show/NCT03125746Test [ABSTRACT FROM AUTHOR]

المؤلفون: Zhou, Huakang¹ (AUTHOR) sajjad.muhammad@med.uni-duesseldorf.de, Li, Xuanchen¹ (AUTHOR), Rana, Majeed² (AUTHOR), Cornelius, Jan Frederick¹ (AUTHOR), Khan, Dilaware¹ (AUTHOR) dilaware.khan@med.uni-duesseldorf.de, Muhammad, Sajjad^1,3,4 (AUTHOR)

المصدر: Cells (2073-4409). Nov2023, Vol. 12 Issue 22, p2609. 13p.

مصطلحات موضوعية: *ENDOTHELIAL cells, *MTOR inhibitors, *GENE expression, *MTOR protein, *CARDIOVASCULAR diseases risk factors, *DNA damage

مستخلص: The cardiovascular risk factors, including smoking, ethanol, and oxidative stress, can induce cellular senescence. The senescent cells increase the expression and release of pro-inflammatory molecules and matrix metalloproteinase (MMPs). These pro-inflammatory molecules and MMPs promote the infiltration and accumulation of inflammatory cells in the vascular tissue, exacerbating vascular tissue inflammation. MMPs damage vascular tissue by degenerating the extracellular matrix. Consequently, these cellular and molecular events promote the initiation and progression of cardiovascular diseases. We used Rapalink-1, an mTOR inhibitor, to block ethanol-induced senescence. Rapalink-1 inhibited oxidative-stress-induced DNA damage and senescence in endothelial cells exposed to ethanol. It attenuated the relative protein expression of senescence marker P21 and improved the relative protein expression of DNA repair protein KU70 and aging marker Lamin B1. It inhibited the activation of NF-κB, MAPKs (P38 and ERK), and mTOR pathway proteins (mTOR, 4EBP-1, and S6). Moreover, Rapalink-1 suppressed ethanol-induced mRNA expression of ICAM-1, E-selectin, MCP-1, IL-8, MMP-2, and TIMP-2. Rapalink-1 also reduced the relative protein expression of MMP-2. In summary, Rapalink-1 prevented senescence, inhibited pro-inflammatory pathway activation, and ameliorated pro-inflammatory molecule expression and MMP-2. [ABSTRACT FROM AUTHOR]

المؤلفون: Wiese, Wojciech¹ (AUTHOR) wojciech.wiese@stud.umed.lodz.pl, Barczuk, Julia¹ (AUTHOR) julia.barczuk@stud.umed.lodz.pl, Racinska, Olga¹ (AUTHOR) olga.racinska@stud.umed.lodz.pl, Siwecka, Natalia¹ (AUTHOR) natalia.siwecka@stud.umed.lodz.pl, Rozpedek-Kaminska, Wioletta¹ (AUTHOR) wioletta.rozpedek@umed.lodz.pl, Slupianek, Artur² (AUTHOR) aslupian@temple.edu, Sierpinski, Radoslaw³ (AUTHOR) r.sierpinski@uksw.edu.pl, Majsterek, Ireneusz¹ (AUTHOR) ireneusz.majsterek@umed.lodz.pl

المصدر: Cancers. Nov2023, Vol. 15 Issue 21, p5297. 18p.

مصطلحات موضوعية: *PHOSPHOTRANSFERASES, *MTOR inhibitors, *LEUKEMIA, *CELLULAR signal transduction, *CELL cycle, *HEMATOLOGIC malignancies, *CELL proliferation

مستخلص: Simple Summary: The PI3K/Akt/mTOR pathway plays a crucial role in cancer, including leukemia. Abnormalities in this pathway drive carcinogenesis by inducing uncontrolled growth, increased survival, and treatment resistance. The abovementioned pathway is also disrupted in various types of leukemia, which makes it a potential therapeutic target for this disease. Current treatment approaches for leukemia are limited and fraught with numerous side effects. This review article aims to summarize recent research data on inhibitors of the PI3K/Akt/mTOR pathway. Inhibition of this pathway may potentially provide improved treatment outcomes for leukemia. Blood malignancies remain a therapeutic challenge despite the development of numerous treatment strategies. The phosphatidylinositol-3 kinase (PI3K)/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway plays a central role in regulating many cellular functions, including cell cycle, proliferation, quiescence, and longevity. Therefore, dysregulation of this pathway is a characteristic feature of carcinogenesis. Increased activation of PI3K/Akt/mTOR signaling enhances proliferation, growth, and resistance to chemo- and immunotherapy in cancer cells. Overactivation of the pathway has been found in various types of cancer, including acute and chronic leukemia. Inhibitors of the PI3K/Akt/mTOR pathway have been used in leukemia treatment since 2014, and some of them have improved treatment outcomes in clinical trials. Recently, new inhibitors of PI3K/Akt/mTOR signaling have been developed and tested both in preclinical and clinical models. In this review, we outline the role of the PI3K/Akt/mTOR signaling pathway in blood malignancies' cells and gather information on the inhibitors of this pathway that might provide a novel therapeutic opportunity against leukemia. [ABSTRACT FROM AUTHOR]