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British Journal of Pharmacology Oct 2023Necroptosis plays an essential role in acute kidney injury and is mediated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3...
BACKGROUND AND PURPOSE
Necroptosis plays an essential role in acute kidney injury and is mediated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed lineage kinase domain-like pseudokinase (MLKL). A novel RIPK3 inhibitor, compound 42 (Cpd-42) alleviates the systemic inflammatory response. The current study was designed to investigate whether Cpd-42 exhibits protective effects on acute kidney injury and reveal the underlying mechanisms.
EXPERIMENTAL APPROACH
The effects of Cpd-42 were determined in vivo through cisplatin- and ischaemia/reperfusion (I/R)-induced acute kidney injury and in vitro through cisplatin- and hypoxia/re-oxygenation (H/R)-induced cell damage. Transmission electron microscopy and periodic acid-Schiff staining were used to identify renal pathology. Cellular thermal shift assay and RIPK3-knockout mouse renal tubule epithelial cells were used to explore the relationship between Cpd-42 and RIPK3. Molecular docking and site-directed mutagenesis were used to determine the binding site of RIPK3 with Cpd-42.
KEY RESULTS
Cpd-42 reduced human proximal tubule epithelial cell line (HK-2) cell damage, necroptosis and inflammatory responses in vitro. Furthermore, in vivo, cisplatin- and I/R-induced acute kidney injury was alleviated by Cpd-42 treatment. Cpd-42 inhibited necroptosis by interacting with two key hydrogen bonds of RIPK3 at Thr94 and Ser146, which further blocked the phosphorylation of RIPK3 and mitigated acute kidney injury.
CONCLUSION AND IMPLICATIONS
Acting as a novel RIPK3 inhibitor, Cpd-42 reduced kidney damage, inflammatory response and necroptosis in acute kidney injury by binding to sites Thr94 and Ser146 on RIPK3. Cpd-42 could be a promising treatment for acute kidney injury.
Topics: Mice; Animals; Humans; Cisplatin; Necroptosis; Molecular Docking Simulation; Acute Kidney Injury; Protein Kinases; Mice, Knockout; Apoptosis; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37248964
DOI: 10.1111/bph.16152 -
Biomedicine & Pharmacotherapy =... Dec 2023DNMT1 (DNA methyltransferase 1) is the predominant member of the DNMT family and the most abundant DNMT in various cell types. It functions as a maintenance DNMT and is... (Review)
Review
DNMT1 (DNA methyltransferase 1) is the predominant member of the DNMT family and the most abundant DNMT in various cell types. It functions as a maintenance DNMT and is involved in various diseases, including cancer and nervous system diseases. Programmed cell death (PCD) is a fundamental mechanism that regulates cell proliferation and maintains the development and homeostasis of multicellular organisms. DNMT1 plays a regulatory role in various types of PCD, including apoptosis, autophagy, necroptosis, ferroptosis, and others. DNMT1 is closely associated with the development of various diseases by regulating key genes and pathways involved in PCD, including caspase 3/7 activities in apoptosis, Beclin 1, LC3, and some autophagy-related proteins in autophagy, glutathione peroxidase 4 (GPX4) and nuclear receptor coactivator 4 (NCOA4) in ferroptosis, and receptor-interacting protein kinase 1-receptor-interacting protein kinase 3-mixed lineage kinase domain-like protein (RIPK1-RIPK3-MLKL) in necroptosis. Our study summarizes the regulatory relationship between DNMT1 and different types of PCD in various diseases and discusses the potential of DNMT1 as a common regulatory hub in multiple types of PCD, offering a perspective for therapeutic approaches in disease.
Topics: Apoptosis; Ferroptosis; Protein Kinases; Transcription Factors; Humans; DNA (Cytosine-5-)-Methyltransferase 1
PubMed: 37871559
DOI: 10.1016/j.biopha.2023.115753 -
Experimental Cell Research Jul 2023Cells are programmed to favorably respond towards the nutrient availability by adapting their metabolism to meet energy demands. AMP-activated protein kinase (AMPK) is a... (Review)
Review
Cells are programmed to favorably respond towards the nutrient availability by adapting their metabolism to meet energy demands. AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine energy-sensing kinase. It gets activated upon a decrease in the cellular energy status as reflected by an increased AMP/ATP ratio, ADP, and also during the conditions of glucose starvation without change in the adenine nucelotide ratio. AMPK functions as a centralized regulator of metabolism, acting at cellular and physiological levels to circumvent the metabolic stress by restoring energy balance. This review intricately highlights the integrated signaling pathways by which AMPK gets activated allosterically or by multiple non-canonical upstream kinases. AMPK activates the ATP generating processes (e.g., fatty acid oxidation) and inhibits the ATP consuming processes that are non-critical for survival (e.g., cell proliferation, protein and triglyceride synthesis). An integrated signaling network with AMPK as the central effector regulates all the aspects of enhanced stress resistance, qualified cellular housekeeping, and energy metabolic homeostasis. Importantly, the AMPK mediated amelioration of cellular stress and inflammatory responses are mediated by stimulation of transcription factors such as Nrf2, SIRT1, FoxO and inhibition of NF-κB serving as main downstream effectors. Moreover, many lines of evidence have demonstrated that AMPK controls autophagy through mTOR and ULK1 signaling to fine-tune the metabolic pathways in response to different cellular signals. This review also highlights the critical involvement of AMPK in promoting mitochondrial health, and homeostasis, including mitophagy. Loss of AMPK or ULK1 activity leads to aberrant accumulation of autophagy-related proteins and defective mitophagy thus, connecting cellular energy sensing to autophagy and mitophagy.
Topics: AMP-Activated Protein Kinases; Protein Serine-Threonine Kinases; Signal Transduction; Energy Metabolism; Homeostasis; Autophagy; Adenosine Triphosphate
PubMed: 37127064
DOI: 10.1016/j.yexcr.2023.113614 -
European Journal of Medicinal Chemistry Dec 2023Alzheimer's disease (AD) is a serious neurodegenerative disease characterized by memory impairment, mental retardation, impaired motor balance, loss of self-care and... (Review)
Review
Alzheimer's disease (AD) is a serious neurodegenerative disease characterized by memory impairment, mental retardation, impaired motor balance, loss of self-care and even death. Among the complex and diverse pathological changes in AD, protein kinases are deeply involved in abnormal phosphorylation of Tau proteins to form intracellular neuronal fiber tangles, neuronal loss, extracellular β-amyloid (Aβ) deposits to form amyloid plaques, and synaptic disturbances. As a disease of the elderly, the growing geriatric population is directly driving the market demand for AD therapeutics, and protein kinases are potential targets for the future fight against AD. This perspective provides an in-depth look at the role of the major protein kinases (GSK-3β, CDK5, p38 MAPK, ERK1/2, and JNK3) in the pathogenesis of AD. At the same time, the development of different protein kinase inhibitors and the current state of clinical advancement are also outlined.
Topics: Aged; Humans; Alzheimer Disease; Protein Kinases; Neurodegenerative Diseases; Glycogen Synthase Kinase 3 beta; Brain; tau Proteins; Amyloid beta-Peptides; Phosphorylation
PubMed: 37722288
DOI: 10.1016/j.ejmech.2023.115817 -
Nature Communications Aug 2023Pathogen-associated molecular patterns (PAMPs) trigger plant innate immunity that acts as the first line of inducible defense against pathogen infection. A receptor-like...
Pathogen-associated molecular patterns (PAMPs) trigger plant innate immunity that acts as the first line of inducible defense against pathogen infection. A receptor-like cytoplasmic kinase BOTRYTIS-INDUCED KINASE 1 (BIK1) functions as a signaling hub immediately downstream of multiple pattern recognition receptors (PRRs). It is known that PLANT U-BOX PROTEIN 25 (PUB25) and PUB26 ubiquitinate BIK1 and mediate BIK1 degradation. However, how BIK1 homeostasis is maintained is not fully understood. Here, we show that two closely related ubiquitin ligases, RING DOMAIN LIGASE 1 (RGLG1) and RGLG2, preferentially associate with the hypo-phosphorylated BIK1 and promote the association of BIK1 with the co-receptor for several PRRs, BRI1-ASSOCIATED RECEPTOR KINASE1 (BAK1). PUB25 interacts with RGLG2 and mediates its degradation. In turn, RGLG2 represses the ubiquitin ligase activity of PUB25. RGLG1/2 suppress PUB25-mediated BIK1 degradation, promote BIK1 protein accumulation, and positively regulate immune signaling in a ubiquitin ligase activity-dependent manner. Our work reveals how BIK1 homeostasis is maintained by the interplay of different ubiquitin ligases.
Topics: Protein Serine-Threonine Kinases; Botrytis; Arabidopsis Proteins; Phosphorylation; Arabidopsis; Ligases; Ubiquitin; Proteostasis; Protein Kinases; Plant Proteins; Receptors, Pattern Recognition; Homeostasis; Ubiquitin-Protein Ligases; Plant Immunity
PubMed: 37532719
DOI: 10.1038/s41467-023-40364-0 -
Biochimica Et Biophysica Acta.... Oct 2023Macroautophagy is a health-modifying process of engulfing misfolded or aggregated proteins or damaged organelles, coating these proteins or organelles into vesicles,... (Review)
Review
Macroautophagy is a health-modifying process of engulfing misfolded or aggregated proteins or damaged organelles, coating these proteins or organelles into vesicles, fusion of vesicles with lysosomes to form autophagic lysosomes, and degradation of the encapsulated contents. It is also a self-rescue strategy in response to harsh environments and plays an essential role in cancer cells. AMP-activated protein kinase (AMPK) is the central pathway that regulates autophagy initiation and autophagosome formation by phosphorylating targets such as mTORC1 and unc-51 like activating kinase 1 (ULK1). AMPK is an evolutionarily conserved serine/threonine protein kinase that acts as an energy sensor in cells and regulates various metabolic processes, including those involved in cancer. The regulatory network of AMPK is complicated and can be regulated by multiple upstream factors, such as LKB1, AKT, PPAR, SIRT1, or noncoding RNAs. Currently, AMPK is being investigated as a novel target for anticancer therapies based on its role in macroautophagy regulation. Herein, we review the effects of AMPK-dependent autophagy on tumor cell survival and treatment strategies targeting AMPK.
Topics: AMP-Activated Protein Kinases; Protein Serine-Threonine Kinases; Autophagy; Mechanistic Target of Rapamycin Complex 1; Neoplasms
PubMed: 37463638
DOI: 10.1016/j.bbamcr.2023.119537 -
PeerJ 2023The Protein Kinase Ontology (ProKinO) is an integrated knowledge graph that conceptualizes the complex relationships among protein kinase sequence, structure, function,...
The Protein Kinase Ontology (ProKinO) is an integrated knowledge graph that conceptualizes the complex relationships among protein kinase sequence, structure, function, and disease in a human and machine-readable format. In this study, we have significantly expanded ProKinO by incorporating additional data on expression patterns and drug interactions. Furthermore, we have developed a completely new browser from the ground up to render the knowledge graph visible and interactive on the web. We have enriched ProKinO with new classes and relationships that capture information on kinase ligand binding sites, expression patterns, and functional features. These additions extend ProKinO's capabilities as a discovery tool, enabling it to uncover novel insights about understudied members of the protein kinase family. We next demonstrate the application of ProKinO. Specifically, through graph mining and aggregate SPARQL queries, we identify the p21-activated protein kinase 5 (PAK5) as one of the most frequently mutated dark kinases in human cancers with abnormal expression in multiple cancers, including a previously unappreciated role in acute myeloid leukemia. We have identified recurrent oncogenic mutations in the PAK5 activation loop predicted to alter substrate binding and phosphorylation. Additionally, we have identified common ligand/drug binding residues in PAK family kinases, underscoring ProKinO's potential application in drug discovery. The updated ontology browser and the addition of a web component, ProtVista, which enables interactive mining of kinase sequence annotations in 3D structures and Alphafold models, provide a valuable resource for the signaling community. The updated ProKinO database is accessible at https://prokino.uga.edu.
Topics: Humans; Protein Kinases; Ligands; Proteins; Phosphorylation; Neoplasms
PubMed: 38077442
DOI: 10.7717/peerj.16087 -
Biochemical Pharmacology Oct 2023Nonalcoholic fatty liver disease (NAFLD) has been linked to fat accumulation in the liver and lipid metabolism imbalance. Sesamin, a lignan commonly found in sesame seed...
Nonalcoholic fatty liver disease (NAFLD) has been linked to fat accumulation in the liver and lipid metabolism imbalance. Sesamin, a lignan commonly found in sesame seed oil, possesses antioxidant, anti-inflammatory, and anticancer properties. However, the precise mechanisms by which sesamin prevents hepatic steatosis are not well understood. This study aimed to explore the molecular mechanisms by which sesamin may improve lipid metabolism dysregulation. A in vitro hepatic steatosis model was established by exposing HepG2 cells to palmitate sodium. The results showed that sesamin effectively mitigated lipotoxicity and reduced reactive oxygen species production. Additionally, sesamin suppressed lipid accumulation by regulating key factors involved in lipogenesis and lipolysis, such as fatty acid synthase (FASN), sterol regulatory element-binding protein 1c (SREBP-1c), forkhead box protein O-1, and adipose triglyceride lipase. Molecular docking results indicated that sesamin could bind to estrogen receptor α (ERα) and reduce FASN and SREBP-1c expression via the Ca/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMP-activated protein kinase (AMPK) signaling pathway. Sesamin attenuated palmitate-induced lipotoxicity and regulated hepatic lipid metabolism in HepG2 cells by activating the ERα/CaMKKβ/AMPK signaling pathway. These findings suggest that sesamin can improve lipid metabolism disorders and is a promising candidate for treating hepatic steatosis.
Topics: Humans; Estrogen Receptor alpha; Sterol Regulatory Element Binding Protein 1; AMP-Activated Protein Kinases; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Molecular Docking Simulation; Liver; Non-alcoholic Fatty Liver Disease; Lignans; Lipid Metabolism; Hep G2 Cells; Signal Transduction; Palmitates
PubMed: 37652106
DOI: 10.1016/j.bcp.2023.115768 -
Cells Dec 2023The serine/threonine protein kinase CK2 is implicated in the regulation of fundamental processes in eukaryotic cells. CK2 consists of two catalytic α or α' isoforms... (Review)
Review
The serine/threonine protein kinase CK2 is implicated in the regulation of fundamental processes in eukaryotic cells. CK2 consists of two catalytic α or α' isoforms and two regulatory CK2β subunits. These three proteins exist in a free form, bound to other cellular proteins, as tetrameric holoenzymes composed of CK2α/β, CK2αα'/β, or CK2α'/β as well as in higher molecular forms of the tetramers. The catalytic domains of CK2α and CK2α' share a 90% identity. As CK2α contains a unique C-terminal sequence. Both proteins function as protein kinases. These properties raised the question of whether both isoforms are just backups of each other or whether they are regulated differently and may then function in an isoform-specific manner. The present review provides observations that the regulation of both CK2α isoforms is partly different concerning the subcellular localization, post-translational modifications, and aggregation. Up to now, there are only a few isoform-specific cellular binding partners. The expression of both CK2α isoforms seems to vary in different cell lines, in tissues, in the cell cycle, and with differentiation. There are different reports about the expression and the functions of the CK2α isoforms in tumor cells and tissues. In many cases, a cell-type-specific expression and function is known, which raises the question about cell-specific regulators of both isoforms. Another future challenge is the identification or design of CK2α'-specific inhibitors.
Topics: Humans; Animals; Casein Kinase II; Isoenzymes; Holoenzymes
PubMed: 38132153
DOI: 10.3390/cells12242834 -
Free Radical Biology & Medicine Aug 2023AMP-activated protein kinase (AMPK) is a crucial energy sensor of cellular metabolism under various metabolic stresses, such as oxidative stress and inflammation. AMPK...
AMP-activated protein kinase (AMPK) is a crucial energy sensor of cellular metabolism under various metabolic stresses, such as oxidative stress and inflammation. AMPK deficiency increases osteoclast numbers and reduces bone mass; however, the precise mechanisms remain unclear. This study aimed to clarify the mechanistic connection between AMPK and osteoclast differentiation, and the potential role of AMPK in the anti-resorptive effects of several phytochemicals. We found that receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL)-induced osteoclast differentiation, osteoclastic gene expression, and activation of mitogen-activated protein kinase (MAPK) and NF-κB were promoted in cells transfected with AMPK siRNA. AMPK knockdown led to defective synthesis of heme oxygenase-1, an antioxidant enzyme, and the upstream mediator, nuclear factor erythroid-2-related factor 2. Furthermore, treatment with N-acetyl-l-cysteine, an antioxidant, abolished osteoclast differentiation and MAPK/NF-κB activation induced by AMPK knockdown. AMPK activators, hesperetin, gallic acid, resveratrol, and curcumin, suppressed osteoclast differentiation via the activation of AMPK. These results suggest that AMPK inhibits RANKL-induced osteoclast differentiation by enhancing antioxidant defense system and regulating oxidative stress. AMPK activation by dietary-derived phytochemicals may be effective for the treatment of bone diseases.
Topics: Osteoclasts; NF-kappa B; Antioxidants; AMP-Activated Protein Kinases; Cell Differentiation; Oxidative Stress; Mitogen-Activated Protein Kinases; RANK Ligand
PubMed: 37270032
DOI: 10.1016/j.freeradbiomed.2023.05.033