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Science (New York, N.Y.) Sep 2023Neuronal cell loss is a defining feature of Alzheimer's disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain...
Neuronal cell loss is a defining feature of Alzheimer's disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA was strongly up-regulated in human neurons This neuron-specific long noncoding RNA is also up-regulated in AD patients. expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD.
Topics: Animals; Humans; Mice; Alzheimer Disease; Heterografts; Necroptosis; Neurons; RNA, Long Noncoding; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37708272
DOI: 10.1126/science.abp9556 -
Science (New York, N.Y.) Jun 2023Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress...
Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid -deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.
Topics: Animals; Mice; AMP-Activated Protein Kinases; Phosphorylation; Necroptosis; Stress, Physiological; Energy Metabolism; Receptor-Interacting Protein Serine-Threonine Kinases; Inflammation; Ischemia
PubMed: 37384704
DOI: 10.1126/science.abn1725 -
Pharmacological Research Feb 2024Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st... (Review)
Review
Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st century. There are 80 FDA-approved therapeutic agents that target about two dozen different protein kinases and seven of these drugs were approved in 2023. Of the approved drugs, thirteen target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), twenty block nonreceptor protein-tyrosine kinases, and 43 inhibit receptor protein-tyrosine kinases. The data indicate that 69 of these drugs are prescribed for the treatment of neoplasms. Six drugs (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis). Of the 80 approved drugs, nearly two dozen are used in the treatment of multiple diseases. The following seven drugs received FDA approval in 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal cancer), momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung cancer), and ritlecitinib (alopecia areata). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 80 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, and ligand efficiency.
Topics: Humans; Adult; Protein Kinase Inhibitors; Alopecia Areata; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Protein Serine-Threonine Kinases; Protein Kinases; Neoplasms
PubMed: 38216005
DOI: 10.1016/j.phrs.2024.107059 -
Cell Research Dec 2023Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear....
Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDME or GSDME knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.
Topics: Humans; Animals; Mice; Pyroptosis; Mannose; AMP-Activated Protein Kinases; Gasdermins
PubMed: 37460805
DOI: 10.1038/s41422-023-00848-6 -
Autophagy Sep 2023The skeletal system is the basis of the vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions,...
The skeletal system is the basis of the vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions, supplies places to the hematopoietic system, and participates in complex endocrine and immune system. Not surprisingly, bones are constantly reabsorbed, formed, and remodeled under physiological conditions. Once bone metabolic homeostasis is interrupted (including inflammation, tumors, fractures, and bone metabolic diseases), the body rapidly initiates bone regeneration to maintain bone tissue structure and quality. Macroautophagy/autophagy is an essential metabolic process in eukaryotic cells, which maintains metabolic energy homeostasis and plays a vital role in bone regeneration by controlling molecular degradation and organelle renewal. One relatively new observation is that mesenchymal cells, osteoblasts, osteoclasts, osteocytes, chondrocytes, and vascularization process exhibit autophagy, and the molecular mechanisms and targets involved are being explored and updated. The role of autophagy is also emerging in degenerative diseases (intervertebral disc degeneration [IVDD], osteoarthritis [OA], etc.) and bone metabolic diseases (osteoporosis [OP], osteitis deformans, osteosclerosis). The use of autophagy regulators to modulate autophagy has benefited bone regeneration, including MTOR (mechanistic target of rapamycin kinase) inhibitors, AMPK activators, and emerging phytochemicals. The application of biomaterials (especially nanomaterials) to trigger autophagy is also an attractive research direction, which can exert superior therapeutic properties from the material-loaded molecules/drugs or the material's properties such as shape, roughness, surface chemistry, etc. All of these have essential clinical significance with the discovery of autophagy associated signals, pathways, mechanisms, and treatments in bone diseases in the future. Δψm: mitochondrial transmembrane potential AMPK: AMP-activated protein kinase ARO: autosomal recessive osteosclerosis ATF4: activating transcription factor 4 ATG: autophagy-related β-ECD: β-ecdysone BMSC: bone marrow mesenchymal stem cell ER: endoplasmic reticulum FOXO: forkhead box O GC: glucocorticoid HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha HSC: hematopoietic stem cell HSP: heat shock protein IGF1: insulin like growth factor 1 IL1B/IL-1β: interleukin 1 beta IVDD: intervertebral disc degradation LPS: lipopolysaccharide MAPK: mitogen-activated protein kinase MSC: mesenchymal stem cell MTOR: mechanistic target of rapamycin kinase NP: nucleus pulposus NPWT: negative pressure wound therapy OA: osteoarthritis OP: osteoporosis PTH: parathyroid hormone ROS: reactive oxygen species SIRT1: sirtuin 1 SIRT3: sirtuin 3 SQSTM1/p62: sequestosome 1 TNFRSF11B/OPG: TNF receptor superfamily member 11b TNFRSF11A/RANK: tumor necrosis factor receptor superfamily, member 11a TNFSF11/RANKL: tumor necrosis factor (ligand) superfamily, member 11 TSC1: tuberous sclerosis complex 1 ULK1: unc-51 like autophagy activating kinase 1.
Topics: Humans; Autophagy; Signal Transduction; AMP-Activated Protein Kinases; Clinical Relevance; Osteoarthritis; TOR Serine-Threonine Kinases; Osteoporosis; Metabolic Diseases
PubMed: 36858962
DOI: 10.1080/15548627.2023.2186112 -
Nature Reviews. Immunology Dec 2023Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death... (Review)
Review
Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death and in the production of inflammatory mediators, targeting kinases has proven to be an effective treatment strategy, initially as anticancer therapies, but shortly thereafter in immune-mediated diseases. Herein, we provide an overview of the status of small molecule inhibitors specifically generated to target protein kinases relevant to immune cell function, with an emphasis on those approved for the treatment of immune-mediated diseases. The development of inhibitors of Janus kinases that target cytokine receptor signalling has been a particularly active area, with Janus kinase inhibitors being approved for the treatment of multiple autoimmune and allergic diseases as well as COVID-19. In addition, TEC family kinase inhibitors (including Bruton's tyrosine kinase inhibitors) targeting antigen receptor signalling have been approved for haematological malignancies and graft versus host disease. This experience provides multiple important lessons regarding the importance (or not) of selectivity and the limits to which genetic information informs efficacy and safety. Many new agents are being generated, along with new approaches for targeting kinases.
Topics: Humans; Protein Kinases; Protein Kinase Inhibitors; Signal Transduction; Immune System Diseases
PubMed: 37188939
DOI: 10.1038/s41577-023-00877-7 -
Redox Biology Jul 2023Cancer cells and ischemic diseases exhibit unique metabolic responses and adaptations to energy stress. Forkhead box O 3a (FoxO3a) is a transcription factor that plays...
Cancer cells and ischemic diseases exhibit unique metabolic responses and adaptations to energy stress. Forkhead box O 3a (FoxO3a) is a transcription factor that plays an important role in cell metabolism, mitochondrial dysfunction and oxidative stress response. Although the AMP-activated protein kinase (AMPK)/FoxO3a signaling pathway plays a pivotal role in maintaining energy homeostasis under conditions of energy stress, the role of AMPK/FoxO3a signaling in mitochondria-associated ferroptosis has not yet been fully elucidated. We show that glucose starvation induced AMPK/FoxO3a activation and inhibited ferroptosis induced by erastin. Inhibition of AMPK or loss of FoxO3a in cancer cells under the glucose starvation condition can sensitize these cells to ferroptosis. Glucose deprivation inhibited mitochondria-related gene expression, reduced mitochondrial DNA(mtDNA) copy number, decreased expression of mitochondrial proteins and lowered the levels of respiratory complexes by inducing FoxO3a. Loss of FoxO3a promoted mitochondrial membrane potential hyperpolarization, oxygen consumption, lipid peroxide accumulation and abolished the protective effects of energy stress on ferroptosis in vitro. In addition, we identified a FDA-approved antipsychotic agent, the potent FoxO3a agonist trifluoperazine, which largely reduced ferroptosis-associated cerebral ischemia-reperfusion (CIR) injuries in rats through AMPK/FoxO3a/HIF-1α signaling and mitochondria-dependent mechanisms. We found that FoxO3a binds to the promoters of SLC7A11 and reduces CIR-mediated glutamate excitotoxicity through inhibiting the expression of SLC7A11. Collectively, these results suggest that energy stress modulation of AMPK/FoxO3a signaling regulates mitochondrial activity and alters the ferroptosis response. The regulation of FoxO3a by AMPK may play a crucial role in mitochondrial gene expression that controls energy balance and confers resistance to mitochondria-associated ferroptosis and CIR injuries.
Topics: Rats; Animals; AMP-Activated Protein Kinases; Ferroptosis; Forkhead Box Protein O3; Mitochondria; Signal Transduction; DNA, Mitochondrial; Glucose
PubMed: 37267686
DOI: 10.1016/j.redox.2023.102760 -
Circulation Research Feb 2024The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors....
BACKGROUND
The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear.
METHODS
Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice.
RESULTS
(1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss of endogenous PKIα (PKA inhibition peptide α), and the stimulation by noncanonical PKA activators; (3) cPKAi ameliorated PaCH induced by TAC and increased Ca influxes and blunted neonatal rat cardiomyocyte hypertrophy by isoproterenol and phenylephrine; (4) cPKAi prevented TAC-induced protein synthesis by inhibiting mTOR (mammalian target of rapamycin) signaling through reducing Akt (protein kinase B) activity, but enhancing inhibitory GSK-3α (glycogen synthase kinase-3α) and GSK-3β signals; (5) cPKAi reduced protein degradation by the ubiquitin-proteasome system via decreasing RPN6 phosphorylation; (6) cPKAi increased the expression of antihypertrophic atrial natriuretic peptide (ANP); (7) cPKAi ameliorated established PaCH and improved animal survival.
CONCLUSIONS
Cardiomyocyte PKA is a master regulator of PhCH and PaCH through regulating protein synthesis and degradation. cPKAi can be a novel approach to treat PaCH.
Topics: Mice; Rats; Animals; Proteasome Endopeptidase Complex; Cyclic AMP-Dependent Protein Kinases; Glycogen Synthase Kinase 3 beta; Cardiomegaly; Myocytes, Cardiac; Mice, Transgenic; Peptides; Mammals
PubMed: 38275112
DOI: 10.1161/CIRCRESAHA.123.322729 -
Signal Transduction and Targeted Therapy Dec 2023Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular... (Review)
Review
Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis, chemoresistance, and the mechanistic backgrounds of individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway, encompassing the RAS-RAF-MAPK kinase (MEK)-extracellular signal-related kinase (ERK) pathway. RAF kinase is a primary mediator of the MAPK pathway, responsible for the sequential activation of downstream targets, such as MEK and the transcription factor ERK, which control numerous cellular and physiological processes, including organism development, cell cycle control, cell proliferation and differentiation, cell survival, and death. Defects in this signaling cascade are associated with diseases such as cancer. RAF inhibitors (RAFi) combined with MEK blockers represent an FDA-approved therapeutic strategy for numerous RAF-mutant cancers, including melanoma, non-small cell lung carcinoma, and thyroid cancer. However, the development of therapy resistance by cancer cells remains an important barrier. Autophagy, an intracellular lysosome-dependent catabolic recycling process, plays a critical role in the development of RAFi resistance in cancer. Thus, targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers. In this review, we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance. Furthermore, we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles. Additionally, this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.
Topics: Humans; Mitogen-Activated Protein Kinase Kinases; Extracellular Signal-Regulated MAP Kinases; raf Kinases; Melanoma; Lung Neoplasms
PubMed: 38105263
DOI: 10.1038/s41392-023-01705-z -
Cell Death & Disease Jul 2023Polymerase 1 and transcript release factor (PTRF, encoding by Cavin-1) regulates interleukin 33 (IL-33) release, which is implicated in asthma development. Z-DNA binding...
Polymerase 1 and transcript release factor (PTRF, encoding by Cavin-1) regulates interleukin 33 (IL-33) release, which is implicated in asthma development. Z-DNA binding protein 1 (ZBP1)-sensing Z-RNAs induces necroptosis which causes inflammatory diseases. House dust mite (HDM) is the major source of allergen in house dust and is strongly associated with the development of asthma. Whether PTRF via IL-33 and ZBP1 mediates HDM-induced macrophage necroptosis and airway inflammation remains unclear. Here, we found that deficiency of PTRF could reduce lung IL-33, ZBP1, phosphor-receptor-interacting protein kinase 3 (p-RIPK3), and phosphor-mixed lineage kinase domain-like (p-MLKL) (necroptosis executioner), and airway inflammation in an HDM-induced asthma mouse model. In HDM-treated macrophages, ZBP1, p-RIPK3, and p-MLKL levels were markedly increased, and these changes were reversed by deletion of Cavin-1. Deletion of Il33 also reduced expression of ZBP1, p-RIPK3, and p-MLKL in HDM-challenged lungs. Moreover, IL-33 synergizing with HDM boosted expression of ZBP1, p-RIPK3, and p-MLKL in macrophages. In bronchial epithelial cells rather than macrophages and vascular endothelial cells, PTRF positively regulates IL-33 expression. Therefore, we conclude that PTRF mediates HDM-induced macrophage ZBP1/necroptosis and airway inflammation, and this effect could be boosted by bronchial epithelial cell-derived IL-33. Our findings suggest that PTRF-IL33-ZBP1 signaling pathway might be a promising target for dampening airway inflammation.
Topics: Animals; Mice; Interleukin-33; Pyroglyphidae; Necroptosis; Endothelial Cells; Asthma; Macrophages; Protein Kinases; Signal Transduction; Inflammation
PubMed: 37454215
DOI: 10.1038/s41419-023-05971-1