mTOR

From the beginning, humankind has been wondering why we aged and if there was any way to avoid it. Several animal models have been studied and several theories have been postulated about the process of aging. The main goal of these studies has been to modulate the process of aging and it has been demonstrated how nutritional interventions are able to delay the effects of aging and the development of age-related diseases. Caloric restriction (CR) has been widely studied, as well as protein restriction; moreover, just methionine restriction has been proven to achieve almost the same effects as CR. The mechanism by which these interventions increase life expectancy still remains unknown, although several metabolic pathways are involved or affected such as mTOR and insulin-like growth factor (IGF)-I signalling pathways. Likewise, and in concordance with the free radical theory, methionine restriction can be translated in a decrease in oxidative damage. This review collects those studies focused on nutritional restriction, mainly on methionine restriction, and its implications in the aging process.

Study Guide and Exercises for Human Microbiome and Dysbiosis in Clinical Disease: Textbook and Presentation Slides

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Major depression and chronic pain are significant health problems that seriously impact the quality of life of affected individuals. These diseases that individually are difficult to treat often co-exist, thereby compounding the patient's disability and impairment as well as the challenge of successful treatment. The development of efficacious treatments for these comorbid disorders requires a more comprehensive understanding of their linked associations through common neuromodulators, such as tumor necrosis factor-α (TNFα), and various neurotransmitters, as well as common neuroanatomical pathways and structures, including the hippocampal brain region. This review discusses the interaction between depression and chronic pain, emphasizing the fundamental role of the hippocampus in the development and maintenance of both disorders. The focus of this review addresses the hypothesis that hippocampal expressed TNFα serves as a therapeutic target for management of chronic pain and maj...

Mammalian target of rapamycin (mTOR) is a PI3K (phosphatidylinositol-3-kinase)-related kinase, via two distinct forms – mTOR complex 1 (mTORC1) and mTORC2 coordinates various extracellular and intracellular signals like growth factors, nutrients, amino acids, energy levels in order to achieve optimum cell growth. mTORC1 regulates protein synthesis, lipid biogenesis, oxygen homeostasis, proliferation, autophagy; mTORC2 plays role in cell survival. Since this pathway controls major cellular processes, its dysregulation is associated with pathological conditions like cancer, obesity, type 2 diabetes mellitus. Rapamycin, a naturally occurring mTOR inhibitor, along with synthetically derived compounds of rapamycin – rapamycin analogs (rapalogs), produced by chemical modification of parent drug have achieved clinical success in certain tumor subtypes. Rapalogs have shown their own limitations due to development of resistance and activation of feedback pathways, focusing on the need for efficient mTOR inhibition. In this regard, mTORC1/mTORC2 (mTOR Kinase) inhibitors and dual mTOR/PI3K inhibitors have shown promising results in various in-vitro tumor models, and are currently in phase I/II of clinical trials. With the better understanding of dynamics of mTOR signaling pathway and its function in tumor microenvironment, mTOR inhibitors may provide a good alternative against advanced and refractory cancers.

Cell death is a crucial process during development, homeostasis and immune regulation of multicellular organisms, and its dysregulation is associated with numerous pathologies. Cell death is often induced upon pathogen infection as part of the defense mechanism, and pathogens have evolved strategies to modulate host cell death. In this review, we will discuss the molecular mechanisms and physiological relevance of four major types of programmed cell death, namely apoptosis, necrosis, autophagic cell death and pyroptosis.

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors.

C. Peter Verrijzer, Jan A. van der Knaap et al., from Department of Biochemistry and Center for Biomedical Genetics at Erasmus University Medical Center, in collaboration with other institutes, have shown the importance of the formation of GMPS-USP7 deubiquitylating complex in the nucleus under stress conditions and focused on the regulation of p53 tumor suppressor pathway, which is strongly related to cell proliferation and therefore to carcinogenesis. As for the GMPS (Guanine Monophosphate Synthase), which converts XMP (xanthosine 5’-monophoshate) to GMP, they have also pointed out its function as a target gene regulator through USP7-mediated deubiquitylation of H2B histone. Based on de novo synthesis of GMP pathway, there is an enzyme upstream of GMPS, which is of great interest; IMPDH (Inosine-5′-Monophosphate Dehydrogenase) which is responsible for the oxidation of IMP to XMP and also involved in transcription regulation through sequence-specific DNA binding. While identifying GMPS-associated factors in human cells, they have noticed IMPDH2 (one of the two isoforms of IMPDH in humans) and the DUB (deubiquitylating enzyme) USP11. In order to study further the GMPS-USP7 complex’s function under cell stress conditions and the cells’ reaction, we also focused on GMPR (GMP Reductase) and USP11 which proteins were expressed for later antibody production. SNF4, the Drosophilla homologue of mammalian AMPK γ-subunit was also produced to be used for antibody production, as it contains a CBS domain, just like IMPDH. To investigate additional pathways that are regulated by GMPS/USP7, apart from the stabilization of p53 and deubiquitylation of H2B, we treated U2OS and HEK293 cells with different drugs. After immunofluorescence experiments, we concluded that GMPS also regulates PTEN and PML, which both are tumor suppressors.

A novel hybrid class of telmisartan–rosiglitazone molecules was synthesized in an attempt to discover a dual peroxisome proliferator-activated receptor gamma (PPARγ) agonist/angiotensin II antagonist for treatment for metabolic syndrome. Almost all the synthesized molecules showed moderate PPARγ activity. However, none of the hybrid analogs showed binding affinity toward the AT1 receptor.

Abstract: The levels of protein tyrosine phosphorylation within a cell is regulated by protein tyrosine kinases and protein tyrosine phosphatases. These protein tyrosine phosphatases (PTP) can act both as positive and negative regulators during cell cycle progression and signal transduction. Phosphatase activity is shown by Phosphatase and Tensin homolog (PTEN) protein encoded by PTEN gene localized on human chromosome 10. Earlier findings established the role of PTEN as a tumor suppressor in Cowden’s disease, where PTEN mutations resulted in disease outcomes. Subsequent studies found the role of PTEN mutations in various human cancers, making it one of the vastly studied tumor suppressor genes. The current review has been planned to get a deeper insight into the potential role of PTEN in a variety of physiological processes involved in normal development like cell growth, migration, and differentiation along with the factors, regulation, and underlying mechanism.

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have been investigated in pre-clinical and clinical investigations and then discuss how cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance.