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International Journal of Molecular... Sep 2023The mechanistic/mammalian target of rapamycin (mTOR), a member of the phosphoinositide 3-kinase (PI3K) related kinase family, integrates intracellular and environmental...
The mechanistic/mammalian target of rapamycin (mTOR), a member of the phosphoinositide 3-kinase (PI3K) related kinase family, integrates intracellular and environmental cues that coordinate a diverse set of cellular/tissue functions, such as cell growth, proliferation, metabolism, autophagy, apoptosis, longevity, protein/lipid/nucleotide synthesis, and tissue regeneration and repair [...].
Topics: Humans; Cardiovascular Diseases; Phosphatidylinositol 3-Kinases; TOR Serine-Threonine Kinases; Diabetes Mellitus; Neoplasms
PubMed: 37686434
DOI: 10.3390/ijms241713628 -
ChemMedChem Oct 2023Kinases are prominent drug targets in the pharmaceutical and research community due to their involvement in signal transduction, physiological responses, and upon... (Review)
Review
Kinases are prominent drug targets in the pharmaceutical and research community due to their involvement in signal transduction, physiological responses, and upon dysregulation, in diseases such as cancer, neurological and autoimmune disorders. Several FDA-approved small-molecule drugs have been developed to combat human diseases since Gleevec was approved for the treatment of chronic myelogenous leukemia. Kinases were considered "undruggable" in the beginning. Several FDA-approved small-molecule drugs have become available in recent years. Most of these drugs target ATP-binding sites, but a few target allosteric sites. Among kinases that belong to the same family, the catalytic domain shows high structural and sequence conservation. Inhibitors of ATP-binding sites can cause off-target binding. Because members of the same family have similar sequences and structural patterns, often complex relationships between kinases and inhibitors are observed. To design and develop drugs with desired selectivity, it is essential to understand the target selectivity for kinase inhibitors. To create new inhibitors with the desired selectivity, several experimental methods have been designed to profile the kinase selectivity of small molecules. Experimental approaches are often expensive, laborious, time-consuming, and limited by the available kinases. Researchers have used computational methodologies to address these limitations in the design and development of effective therapeutics. Many computational methods have been developed over the last few decades, either to complement experimental findings or to forecast kinase inhibitor activity and selectivity. The purpose of this review is to provide insight into recent advances in theoretical/computational approaches for the design of new kinase inhibitors with the desired selectivity and optimization of existing inhibitors.
Topics: Humans; Protein Kinase Inhibitors; Phosphotransferases; Signal Transduction; Binding Sites; Adenosine Triphosphate
PubMed: 37442809
DOI: 10.1002/cmdc.202200693 -
Communications Biology Oct 2023CDK4/6 are important regulators of cell cycle and their inhibitors have been approved as anti-cancer drugs. Here, we report a STING-dependent anti-tumor immune mechanism...
CDK4/6 are important regulators of cell cycle and their inhibitors have been approved as anti-cancer drugs. Here, we report a STING-dependent anti-tumor immune mechanism responsible for tumor suppression by CDK4/6 blockade. Clinical datasets show that in human tissues, CDK4 and CDK6 are over-expressed and their expressions are negatively correlated with patients' overall survival and T cell infiltration. Deletion of Cdk4 or Cdk6 in tumor cells significantly reduce tumor growth. Mechanistically, we find that Cdk4 or Cdk6 deficiency contributes to an increased level of endogenous DNA damage, which triggers the cGAS-STING signaling pathway to activate type I interferon response. Knockout of Sting is sufficient to reverse and partially reverse the anti-tumor effect of Cdk4 and Cdk6 deficiency respectively. Therefore, our findings suggest that CDK4/6 inhibitors may enhance anti-tumor immunity through the STING-dependent type I interferon response.
Topics: Humans; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Immunity; Interferon Type I; Neoplasms; Nucleotidyltransferases; Signal Transduction
PubMed: 37833461
DOI: 10.1038/s42003-023-05412-x -
Trends in Biochemical Sciences Jun 2024Autophagy - a highly regulated intracellular degradation process - is pivotal in maintaining cellular homeostasis. Liquid-liquid phase separation (LLPS) is a fundamental... (Review)
Review
Autophagy - a highly regulated intracellular degradation process - is pivotal in maintaining cellular homeostasis. Liquid-liquid phase separation (LLPS) is a fundamental mechanism regulating the formation and function of membrane-less compartments. Recent research has unveiled connections between LLPS and autophagy, suggesting that phase separation events may orchestrate the spatiotemporal organization of autophagic machinery and cargo sequestration. The Unc-51-like kinase (ULK)/autophagy-related 1 (Atg1) family of proteins is best known for its regulatory role in initiating autophagy, but there is growing evidence that the functional spectrum of ULK/Atg1 extends beyond autophagy regulation. In this review, we explore the spatial and temporal regulation of the ULK/Atg1 family of kinases, focusing on their recruitment to LLPS-driven compartments, and highlighting their multifaceted functions beyond their traditional role.
Topics: Autophagy; Humans; Autophagy-Related Protein-1 Homolog; Animals; Protein Serine-Threonine Kinases
PubMed: 38565496
DOI: 10.1016/j.tibs.2024.03.004 -
Molecular Cancer Jul 2023The mechanistic/mammalian target of rapamycin (mTOR), a protein discovered in 1991, integrates a complex pathway with a key role in maintaining cellular homeostasis. By... (Review)
Review
The mechanistic/mammalian target of rapamycin (mTOR), a protein discovered in 1991, integrates a complex pathway with a key role in maintaining cellular homeostasis. By comprising two functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2, it is a central cellular hub that integrates intra- and extracellular signals of energy, nutrient, and hormone availability, modulating the molecular responses to acquire a homeostatic state through the regulation of anabolic and catabolic processes. Accordingly, dysregulation of mTOR pathway has been implicated in a variety of human diseases. While major advances have been made regarding the regulators and effectors of mTOR signaling pathway, insights into the regulation of mTOR gene expression are beginning to emerge. Here, we present the current available data regarding the mTOR expression regulation at the level of transcription, translation and mRNA stability and systematize the current knowledge about the fluctuations of mTOR expression observed in several diseases, both cancerous and non-cancerous. In addition, we discuss whether mTOR expression changes can be used as a biomarker for diagnosis, disease progression, prognosis and/or response to therapeutics. We believe that our study will contribute for the implementation of new disease biomarkers based on mTOR as it gives an exhaustive perspective about the regulation of mTOR gene expression in both normal and pathological conditions.
Topics: Humans; Multiprotein Complexes; Sirolimus; TOR Serine-Threonine Kinases; Mechanistic Target of Rapamycin Complex 1; Signal Transduction; Mechanistic Target of Rapamycin Complex 2
PubMed: 37454139
DOI: 10.1186/s12943-023-01820-z -
Journal of Nanobiotechnology Sep 2023Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia and insulin resistance. Mung bean sprouts are traditionally considered a...
BACKGROUND
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia and insulin resistance. Mung bean sprouts are traditionally considered a "folk" hypoglycemic food and their pharmacological effects and underlying mechanisms warrant further investigation.
PURPOSE
This study aimed to investigate the anti-diabetic effects of the exosomes-like nanoparticles in mung bean sprouts (MELNs) and explore the related molecular mechanisms.
RESULTS
MELNs were isolated using a differential centrifugation-polyethylene glycol (PEG) method, and the identification of MELNs were confirmed by PAGE gel electrophoresis, agarose gel electrophoresis, thin-layer chromatography (TLC), and transmission electron microscopy (TEM). In the high-fat diet/streptozotocin (HFD/STZ) mouse model, MELNs ameliorated the progression of T2DM by increasing oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) results, decreasing the fasting blood glucose level, and reducing the serum triglycerides (TG) and total cholesterol (TC). Histopathological examinations indicated MELNs diminished inflammatory infiltration of hepatocytes and amplified the area of islet B cells. In addition, MELNs decreased the oxidative stress levels in liver tissue and had good biocompatibility. In vitro experiments verified that MELNs improved the viability of glucosamine (GlcN) induced insulin-resistant hepatocytes. Furthermore, this study also revealed that MELNs upregulated GLUT4 & Nrf2 and down-regulated GSK-3β via activating the PI3K/Akt signaling pathway, promoting the production of antioxidant enzymes, such as HO-1 and SOD, to reduce oxidative stress.
CONCLUSION
MELNs mitigated the progression of type 2 diabetes in HFD/STZ mouse model. The underlying molecular mechanism is related to PI3K/Akt/GLUT4/GSK-3β signaling pathway.
Topics: Animals; Mice; Diabetes Mellitus, Type 2; Glycogen Synthase Kinase 3 beta; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Vigna; Exosomes; Insulin; Nanoparticles; Disease Models, Animal; Signal Transduction
PubMed: 37759297
DOI: 10.1186/s12951-023-02120-w -
The Plant Cell Sep 2023DNA-dependent RNA polymerases (Pols) transfer the genetic information stored in genomic DNA to RNA in all organisms. In eukaryotes, the typical products of nuclear Pol...
DNA-dependent RNA polymerases (Pols) transfer the genetic information stored in genomic DNA to RNA in all organisms. In eukaryotes, the typical products of nuclear Pol I, Pol II, and Pol III are ribosomal RNAs, mRNAs, and transfer RNAs, respectively. Intriguingly, plants possess two additional Pols, Pol IV and Pol V, which produce small RNAs and long noncoding RNAs, respectively, mainly for silencing transposable elements. The five plant Pols share some subunits, but their distinct functions stem from unique subunits that interact with specific regulatory factors in their transcription cycles. Here, we summarize recent advances in our understanding of plant nucleus-localized Pols, including their evolution, function, structures, and transcription cycles.
Topics: DNA-Directed RNA Polymerases; Plants; RNA Polymerase II; DNA; DNA Methylation
PubMed: 37453082
DOI: 10.1093/plcell/koad195 -
European Journal of Medicinal Chemistry Feb 2024Polo-like kinase 4 (PLK4), a highly conserved serine/threonine kinase, masterfully regulates centriole duplication in a spatiotemporal manner to ensure the fidelity of... (Review)
Review
Polo-like kinase 4 (PLK4), a highly conserved serine/threonine kinase, masterfully regulates centriole duplication in a spatiotemporal manner to ensure the fidelity of centrosome duplication and proper mitosis. Abnormal expression of PLK4 contributes to genomic instability and associates with a poor prognosis in cancer. Inhibition of PLK4 is demonstrated to exhibit significant efficacy against various types of human cancers, further highlighting its potential as a promising therapeutic target for cancer treatment. As such, numerous small-molecule inhibitors with distinct chemical scaffolds targeting PLK4 have been extensively investigated for the treatment of different human cancers, with several undergoing clinical evaluation (e.g., CFI-400945). Here, we review the structure, distribution, and biological functions of PLK4, encapsulate its intricate regulatory mechanisms of expression, and highlighting its multifaceted roles in cancer development and metastasis. Moreover, the recent advancements of PLK4 inhibitors in patent or literature are summarized, and their therapeutic potential as monotherapies or combination therapies with other anticancer agents are also discussed.
Topics: Humans; Cell Cycle; Mitosis; Neoplasms; Polo-like Kinases; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases
PubMed: 38199166
DOI: 10.1016/j.ejmech.2023.116115 -
Journal of Hepatology Dec 2023
Topics: Humans; Macrophages; Receptor Protein-Tyrosine Kinases; Cholestasis; Liver Diseases; c-Mer Tyrosine Kinase; Phagocytosis
PubMed: 37821021
DOI: 10.1016/j.jhep.2023.09.022 -
Biomolecules Aug 2023Ovarian clear cell (OCCC) and endometrioid (EnOC) carcinomas are often subsumed under the umbrella term "endometriosis-associated ovarian cancer" (EAOC), since they... (Review)
Review
Ovarian clear cell (OCCC) and endometrioid (EnOC) carcinomas are often subsumed under the umbrella term "endometriosis-associated ovarian cancer" (EAOC), since they frequently arise from ectopic endometrium settled in the ovaries. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is known to be aberrantly activated both in endometriosis and EAOC; however, its role in the progression of endometriosis to ovarian cancer remains unclear. In fact, cancer-associated alterations in the mTOR pathway may be found in normal uterine epithelium, likely acting as a first step towards ovarian cancer, through the intermediary stage of endometriosis. This review aims to summarize the current knowledge regarding mTOR signaling dysregulation in the uterine endometrium, endometriosis, and EAOC while focusing on the interconnections between the PI3K/AKT/mTOR pathway and other signaling molecules that give rise to synergistic molecular mechanisms triggering ovarian cancer development in the presence of endometriosis.
Topics: Female; Humans; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Endometriosis; Ovarian Neoplasms; TOR Serine-Threonine Kinases; Phosphatidylinositol 3-Kinase; Carcinoma
PubMed: 37627318
DOI: 10.3390/biom13081253