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GeroScience Oct 2023Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan...
Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with "off-target" inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans.
Topics: Humans; Sirolimus; Senotherapeutics; Mechanistic Target of Rapamycin Complex 1; MTOR Inhibitors; Mechanistic Target of Rapamycin Complex 2
PubMed: 37801202
DOI: 10.1007/s11357-023-00935-x -
The Biochemical Journal Jan 2024The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two... (Review)
Review
The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.
Topics: Signal Transduction; TOR Serine-Threonine Kinases; Mechanistic Target of Rapamycin Complex 2; Mechanistic Target of Rapamycin Complex 1; Sirolimus
PubMed: 38270460
DOI: 10.1042/BCJ20220325 -
Journal of Translational Medicine Jan 2024Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase... (Review)
Review
Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase (PI3K) pathway has emerged as a crucial contributor to the development, advancement, and resistance to treatment. This review article explores the implications of the PI3K pathway in predictive, preventive, and personalized medicine for BC. It emphasizes the identification of predictive biomarkers, such as PIK3CA mutations, and the utility of molecular profiling in guiding treatment decisions. The review also discusses the potential of targeting the PI3K pathway for preventive strategies and the customization of therapy based on tumor stage, molecular subtypes, and genetic alterations. Overcoming resistance to PI3K inhibitors and exploring combination therapies are addressed as important considerations. While this field holds promise in improving patient outcomes, further research and clinical trials are needed to validate these approaches and translate them into clinical practice.
Topics: Humans; Female; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Breast Neoplasms; Precision Medicine; Phosphoinositide-3 Kinase Inhibitors; Mutation; Class I Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt
PubMed: 38172946
DOI: 10.1186/s12967-023-04841-w -
Cell Reports Aug 2023Cellular stress in the form of disrupted transcription, loss of organelle integrity, or damage to nucleic acids can elicit inflammatory responses by activating signaling...
Cellular stress in the form of disrupted transcription, loss of organelle integrity, or damage to nucleic acids can elicit inflammatory responses by activating signaling cascades canonically tasked with controlling pathogen infections. These stressors must be kept in check to prevent unscheduled activation of interferon, which contributes to autoinflammation. This study examines the role of the transcription factor myocyte enhancing factor 2A (MEF2A) in setting the threshold of transcriptional stress responses to prevent R-loop accumulation. Increases in R-loops lead to the induction of interferon and inflammatory responses in a DEAD-box helicase 41 (DDX41)-, cyclic GMP-AMP synthase (cGAS)-, and stimulator of interferon genes (STING)-dependent manner. The loss of MEF2A results in the activation of ATM and RAD3-related (ATR) kinase, which is also necessary for the activation of STING. This study identifies the role of MEF2A in sustaining transcriptional homeostasis and highlights the role of ATR in positively regulating R-loop-associated inflammatory responses.
Topics: Signal Transduction; Nucleotidyltransferases; RNA Helicases; Interferons; Immunity, Innate
PubMed: 37467105
DOI: 10.1016/j.celrep.2023.112805 -
European Journal of Pharmacology Oct 2023Acute kidney injury (AKI) is a clinically serious disorder associated with high mortality rates and an increased risk of progression to end-stage renal disease. As an...
Acute kidney injury (AKI) is a clinically serious disorder associated with high mortality rates and an increased risk of progression to end-stage renal disease. As an essential supportive treatment for patients with respiratory failure, mechanical ventilation not only save many critically ill patients, but also affect glomerular filtration function by changing renal hemodynamics, neurohumoral and positive end-expiratory pressure, eventually leading to AKI. AMP-activated protein kinase (AMPK), a crucial energy homeostasis regulator, could enhance macrophage phagocytic ability and inhibit inflammation, but whether it can engulf neutrophil extracellular traps (NETs) and alleviate mechanical ventilation-associated AKI is still unclear. In this study, we found that geniposide significantly ameliorated histopathological damage, reduced serum Cre and BUN levels. Besides, geniposide can also induce AMPK activation and enhance macrophage phagocytic ability toward NETs. Moreover, geniposide can markedly reduce the levels of high mobility group box 1 (HMGB1), and these effects were dependent on AMPK-PI3K/Akt signaling. Altogether, these results indicated that geniposide promoted macrophage efferocytosis by inducing AMPK-PI3K/Akt signaling activation, clearing NETs and ameliorating AKI.
Topics: Humans; Extracellular Traps; AMP-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Macrophages; Acute Kidney Injury
PubMed: 37634840
DOI: 10.1016/j.ejphar.2023.176018 -
Brain : a Journal of Neurology Mar 2024There are 78 loci associated with Parkinson's disease in the most recent genome-wide association study (GWAS), yet the specific genes driving these associations are...
There are 78 loci associated with Parkinson's disease in the most recent genome-wide association study (GWAS), yet the specific genes driving these associations are mostly unknown. Herein, we aimed to nominate the top candidate gene from each Parkinson's disease locus and identify variants and pathways potentially involved in Parkinson's disease. We trained a machine learning model to predict Parkinson's disease-associated genes from GWAS loci using genomic, transcriptomic and epigenomic data from brain tissues and dopaminergic neurons. We nominated candidate genes in each locus and identified novel pathways potentially involved in Parkinson's disease, such as the inositol phosphate biosynthetic pathway (INPP5F, IP6K2, ITPKB and PPIP5K2). Specific common coding variants in SPNS1 and MLX may be involved in Parkinson's disease, and burden tests of rare variants further support that CNIP3, LSM7, NUCKS1 and the polyol/inositol phosphate biosynthetic pathway are associated with the disease. Functional studies are needed to further analyse the involvements of these genes and pathways in Parkinson's disease.
Topics: Humans; Genome-Wide Association Study; Parkinson Disease; Inositol Phosphates; Dopaminergic Neurons; Machine Learning; Phosphotransferases (Phosphate Group Acceptor)
PubMed: 37804111
DOI: 10.1093/brain/awad345 -
Biochemistry. Biokhimiia Jan 2024Nucleic acids (NAs) are important components of living organisms responsible for the storage and transmission of hereditary information. They form complex structures... (Review)
Review
Nucleic acids (NAs) are important components of living organisms responsible for the storage and transmission of hereditary information. They form complex structures that can self-assemble and bind to various biological molecules. DNAzymes are NAs capable of performing simple chemical reactions, which makes them potentially useful elements for creating DNA nanomachines with required functions. This review focuses on multicomponent DNA-based nanomachines, in particular on DNAzymes as their main functional elements, as well as on the structure of DNAzyme nanomachines and their application in the diagnostics and treatment of diseases. The article also discusses the advantages and disadvantages of DNAzyme-based nanomachines and prospects for their future applications. The review provides information about new technologies and the possibilities of using NAs in medicine.
Topics: DNA, Catalytic; DNA; Biosensing Techniques
PubMed: 38621754
DOI: 10.1134/S0006297924140141 -
Journal of Translational Medicine Nov 2023The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a crucial role in the pathogenesis of cancer. The dysregulation of this pathway has been linked to the... (Review)
Review
The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a crucial role in the pathogenesis of cancer. The dysregulation of this pathway has been linked to the development and initiation of various types of cancer. Recently, epigenetic modifications, particularly N6-methyladenosine (m6A), have been recognized as essential contributors to mRNA-related biological processes and translation. The abnormal expression of m6A modification enzymes has been associated with oncogenesis, tumor progression, and drug resistance. Here, we review the role of m6A modification in regulating the PI3K/AKT pathway in cancer and its implications in the development of novel strategies for cancer treatment.
Topics: Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Neoplasms; Phosphatidylinositol 3-Kinase; Signal Transduction
PubMed: 37915034
DOI: 10.1186/s12967-023-04651-0 -
Molecular Cell Jan 2024Cellular homeostasis is continuously challenged by environmental cues and cellular stress conditions. In their defense, cells need to mount appropriate stress responses... (Review)
Review
Cellular homeostasis is continuously challenged by environmental cues and cellular stress conditions. In their defense, cells need to mount appropriate stress responses that, dependent on the cellular context, signaling intensity, and duration, may have diverse outcomes. The stress- and mitogen-activated protein kinase (SAPK/MAPK) system consists of well-characterized signaling cascades that sense and transduce an array of different stress stimuli into biological responses. However, the physical and chemical nature of stress signals and how these are sensed by individual upstream MAP kinase kinase kinases (MAP3Ks) remain largely ambiguous. Here, we review the existing knowledge of how individual members of the large and diverse group of MAP3Ks sense specific stress signals through largely non-redundant mechanisms. We emphasize the large knowledge gaps in assigning function and stress signals for individual MAP3K family members and touch on the potential of targeting this class of proteins for clinical benefit.
Topics: Animals; MAP Kinase Kinase Kinases; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Signal Transduction; Phosphorylation; p38 Mitogen-Activated Protein Kinases; Calcium-Calmodulin-Dependent Protein Kinases; Mammals
PubMed: 38118452
DOI: 10.1016/j.molcel.2023.11.028 -
International Journal of Molecular... Dec 2023Apoptosis signal-regulating kinase 1 (ASK1) is a serine-threonine kinase that is ubiquitously expressed in nucleated cells and is responsible for the activation of... (Review)
Review
Apoptosis signal-regulating kinase 1 (ASK1) is a serine-threonine kinase that is ubiquitously expressed in nucleated cells and is responsible for the activation of multiple mitogen-activated protein kinases (MAPK) to regulate cell stress. Activation of ASK1 via cellular stress leads to activation of downstream signaling components, activation of transcription factors, and proinflammatory cytokine production. ASK1 is also expressed in anucleate platelets and is a key player in platelet activation as it is important for signaling. Interestingly, the mechanism of ASK1 activation is cell type-dependent. In this review we will explore how ASK1 regulates a variety of cellular processes from innate immune function to thrombosis and hemostasis. We will discuss how ASK1 influences FcγRIIA-mediated platelet reactivity and how that reactivity drives platelet clearance. Furthermore, we will explore the role of ASK1 in thromboxane (TxA) generation, which highlights differences in the way ASK1 functions in mouse and human platelets.
Topics: Humans; Animals; Mice; MAP Kinase Kinase Kinase 5; Sepsis; Blood Platelets; Kinetics; Mitogen-Activated Protein Kinases
PubMed: 38203381
DOI: 10.3390/ijms25010213