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Veterinary Sciences Jun 2024African swine fever virus (ASFV) is a double-stranded DNA virus with an envelope. ASFV has almost the largest genome among all DNA viruses, and its mechanisms of immune...
African swine fever virus (ASFV) is a double-stranded DNA virus with an envelope. ASFV has almost the largest genome among all DNA viruses, and its mechanisms of immune evasion are complex. Better understanding of the molecular mechanisms of ASFV genes will improve vaccine design. A238L, a nonstructural protein of ASFV, inhibits NF-κB activation by suppressing the HAT activity of p300. Whether A238L also affects the transcriptional activity of IRF3 remains unexplored. Here we first confirmed the ability of A238L to suppress NF-κB-activity in L929 cells. A238L inhibits the expression of proinflammatory cytokine genes. In contrast, A238L increased the phosphorylation levels of TBK1 and IRF3 in three different cell lines. A238L increases the IRF3-driven promoter activity and induces IRF3 nuclear translocation. Furthermore, A238L enhanced innate antiviral immunity in the absence or presence of poly d (A:T) or poly (I:C) stimulation, or herpes simplex virus type 1 (HSV-1) or Sendai virus (SeV) infection. This study reveals a previously unrecognized role of A238L in promoting antiviral immune responses by TBK1-IRF3 pathway activation.
PubMed: 38921999
DOI: 10.3390/vetsci11060252 -
ELife Jun 2024mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAF drives tumorigenesis through constitutive downstream extracellular signal-regulated...
mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAF drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a 'just-right' level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in -mutant adenomas/polyps in mice and patients. In ; mice, deletion maximized BRAF's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAF-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a 'just-right' ERK signaling optimal for -induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.
Topics: Animals; Proto-Oncogene Proteins B-raf; Phosphorylation; Mice; Humans; Cecal Neoplasms; Focal Adhesion Kinase 1; Extracellular Signal-Regulated MAP Kinases; MAP Kinase Signaling System; ErbB Receptors; Carcinogenesis; Receptors, G-Protein-Coupled; Male
PubMed: 38921956
DOI: 10.7554/eLife.94605 -
Neurology International Jun 2024The tau protein is a microtubule-associated protein that promotes microtubule stabilization. The phosphorylation of the tau protein has been linked to its dissociation...
The tau protein is a microtubule-associated protein that promotes microtubule stabilization. The phosphorylation of the tau protein has been linked to its dissociation from microtubules. Here, we examined the relationship between neuronal depolarization activity and tau protein phosphorylation by employing model systems in culture as well as in vivo. The KCl-evoked depolarization of cultured neurons has often been used to investigate the effects of neuronal activity. We found dephosphorylation at AT8 sites (S202, T205), T212, AT180 sites (T231, S235), and S396 in KCl-simulated cultured neurons. We also found that the KCl-induced tau protein dephosphorylation increases the level of the tau protein fractionated with stable microtubules. In an in vivo experiment, we demonstrated that the exposure of mice to a new environment activates protein phosphatase 1 in the mouse hippocampus and induces tau protein dephosphorylation. We also found an increased amount of the tau protein in a stable microtubule fraction, suggesting that the dephosphorylation of the tau protein may lead to its increased microtubule association in vivo. These results suggest that the association of microtubules with tau proteins may be regulated by the tau protein phosphorylation status affected by neuronal electrical activity.
PubMed: 38921953
DOI: 10.3390/neurolint16030049 -
Pathogens (Basel, Switzerland) Jun 2024(1) : Peptides are appealing as pharmacological materials because they are easily produced, safe, and tolerable. Despite increasing gum-care awareness, periodontitis is...
(1) : Peptides are appealing as pharmacological materials because they are easily produced, safe, and tolerable. Despite increasing gum-care awareness, periodontitis is still prevalent and is influenced by factors like high sugar consumption, smoking, and aging. is considered a major etiologic agent of periodontitis and activates the NLR family pyrin domain containing 3 (NLRP3) but is absent in melanoma 2 (AIM2) inflammasomes, resulting in pro-inflammatory cytokine release. (2) : We examined the anti-inflammatory effects of 18 peptides derived from human stromal cell-derived factor-1 (SDF-1) on THP-1 macrophages. Inflammation was induced by , and the anti-inflammatory effects were analyzed using molecular biological techniques. In a mouse periodontitis model, alveolar bone resorption was assessed using micro-CT. (3) : Of the 18 SDF-1-derived peptides, S10 notably reduced IL-1β and TNF-α secretion. S10 also diminished the -induced expression of NLRP3, AIM2, ASC (apoptosis-associated speck-like protein), caspase-1, and IL-1β. Furthermore, S10 attenuated the enhanced TLR (toll-like receptor) signaling pathway and decreased the phosphorylation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). In addition, S10 mitigated alveolar bone loss in our -induced mouse model of periodontitis. (4) : S10 suppressed TLR/NF-κB/NLRP3 inflammasome signaling and the AIM2 inflammasome in our -induced murine periodontitis model, which suggests that it has potential use as a therapeutic treatment for periodontitis.
PubMed: 38921772
DOI: 10.3390/pathogens13060474 -
Marine Drugs Jun 2024Cadmium (Cd) is a toxic heavy metal that causes nephrosis, including acute kidney injury. To prevent and treat acute kidney injury (AKI) following Cd exposure, a...
Cadmium (Cd) is a toxic heavy metal that causes nephrosis, including acute kidney injury. To prevent and treat acute kidney injury (AKI) following Cd exposure, a tripeptide, Ser-Arg-Pro (SRP), from L. was employed, and its potential efficacy in AKI was assessed. Oral administration of SRP significantly alleviated Cd-induced kidney damage, leading to improved renal function and the attenuation of structural abnormalities. A network pharmacology analysis revealed the potential of SRP in renal protection by targeting various pathways, including mitogen-activated protein kinase (MAPK) signaling, inflammatory response, and apoptosis pathways. Mechanistic studies indicated that SRP achieves renal protection by inhibiting the activation of MAPK pathways (phosphorylation of p38, p56, ERK, and JNK) in the oxidative stress cascade, suppressing inflammatory responses (iNOS, Arg1, Cox2, TNF-α, IL-1β, and IL-6), and restoring altered apoptosis factors (caspase-9, caspase-3, Bax, and Bcl-2). Hence, SRP has the potential to be used as a therapeutic agent for the treatment of Cd-induced nephrotoxicity.
Topics: Animals; Acute Kidney Injury; Apoptosis; Mice; Cadmium; Oxidative Stress; Male; Oligopeptides; MAP Kinase Signaling System; Kidney; Inflammation; Disease Models, Animal; Network Pharmacology
PubMed: 38921597
DOI: 10.3390/md22060286 -
Marine Drugs Jun 2024SeviL, a galactoside-binding lectin previously isolated from the mussel , was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this...
SeviL, a galactoside-binding lectin previously isolated from the mussel , was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this lectin can promote the polarization of macrophage cell lines toward an M1 functional phenotype at low concentrations. The administration of SeviL to monocyte and basophil cell lines reduced their growth in a dose-dependent manner. However, low lectin concentrations induced proliferation in the RAW264.7 macrophage cell line, which was supported by the significant up-regulation of TOM22, a component of the mitochondrial outer membrane. Furthermore, the morphology of lectin-treated macrophage cells markedly changed, shifting from a spherical to an elongated shape. The ability of SeviL to induce the polarization of RAW264.7 cells to M1 macrophages at low concentrations is supported by the secretion of proinflammatory cytokines and chemokines, as well as by the enhancement in the expression of IL-6- and TNF-α-encoding mRNAs, both of which encode inflammatory molecular markers. Moreover, we also observed a number of accessory molecular alterations, such as the activation of MAP kinases and the JAK/STAT pathway and the phosphorylation of platelet-derived growth factor receptor-α, which altogether support the functional reprogramming of RAW264.7 following SeviL treatment. These results indicate that this mussel β-trefoil lectin has a concentration-dependent multifunctional role in regulating cell proliferation, phenotype, and death in macrophages, suggesting its possible involvement in regulating hemocyte activity in vivo.
Topics: Animals; Mice; Macrophages; RAW 264.7 Cells; Lectins; Bivalvia; Cell Proliferation; Humans; Cytokines; Phenotype; Signal Transduction
PubMed: 38921580
DOI: 10.3390/md22060269 -
Cells Jun 2024[...].
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PubMed: 38920703
DOI: 10.3390/cells13121026 -
Cells Jun 2024We have designed cell-penetrating peptides that target the leucine zipper transcription factors ATF5, CEBPB and CEBPD and that promote apoptotic death of a wide range of...
We have designed cell-penetrating peptides that target the leucine zipper transcription factors ATF5, CEBPB and CEBPD and that promote apoptotic death of a wide range of cancer cell types, but not normal cells, in vitro and in vivo. Though such peptides have the potential for clinical application, their mechanisms of action are not fully understood. Here, we show that one such peptide, Dpep, compromises glucose uptake and glycolysis in a cell context-dependent manner (in about two-thirds of cancer lines assessed). These actions are dependent on induction of tumor suppressor TXNIP (thioredoxin-interacting protein) mRNA and protein. Knockdown studies show that TXNIP significantly contributes to apoptotic death in those cancer cells in which it is induced by Dpep. The metabolic actions of Dpep on glycolysis led us to explore combinations of Dpep with clinically approved drugs metformin and atovaquone that inhibit oxidative phosphorylation and that are in trials for cancer treatment. Dpep showed additive to synergistic activities in all lines tested. In summary, we find that Dpep induces TXNIP in a cell context-dependent manner that in turn suppresses glucose uptake and glycolysis and contributes to apoptotic death of a range of cancer cells.
Topics: Humans; Glycolysis; Carrier Proteins; Glucose; Cell Line, Tumor; Cell Survival; Up-Regulation; Apoptosis; Neoplasms; Peptides
PubMed: 38920655
DOI: 10.3390/cells13121025 -
Cells Jun 2024Neurodegenerative disorders are affecting millions of people worldwide, impacting the healthcare system of our society. Among them, Alzheimer's disease (AD) is the most...
Neurodegenerative disorders are affecting millions of people worldwide, impacting the healthcare system of our society. Among them, Alzheimer's disease (AD) is the most common form of dementia, characterized by severe cognitive impairments. Neuropathological hallmarks of AD are β-amyloid (Aβ) plaques and neurofibrillary tangles, as well as endoplasmic reticulum and mitochondria dysfunctions, which finally lead to apoptosis and neuronal loss. Since, to date, there is no definitive cure, new therapeutic and prevention strategies are of crucial importance. In this scenario, cannabinoids are deeply investigated as promising neuroprotective compounds for AD. In this study, we evaluated the potential neuroprotective role of cannabinerol (CBNR) in an in vitro cellular model of AD via next-generation sequencing. We observed that CBNR pretreatment counteracts the Aβ-induced loss of cell viability of differentiated SH-SY5Y cells. Moreover, a network-based transcriptomic analysis revealed that CBNR restores normal mitochondrial and endoplasmic reticulum functions in the AD model. Specifically, the most important genes regulated by CBNR are related mainly to oxidative phosphorylation (, , , ), protein folding () and degradation (, , ), and glucose () and lipid (, , ) metabolism. Therefore, these results suggest that CBNR could be a new neuroprotective agent helpful in the prevention of AD dysfunctions.
Topics: Humans; Alzheimer Disease; Mitochondria; Endoplasmic Reticulum; Cannabinoids; Amyloid beta-Peptides; Endoplasmic Reticulum Chaperone BiP; Cell Line, Tumor; Gene Expression Profiling; Transcriptome; Cell Survival; Neuroprotective Agents; Models, Biological; Gene Regulatory Networks
PubMed: 38920643
DOI: 10.3390/cells13121012 -
Open Medicine (Warsaw, Poland) 2024The malfunction of endothelial progenitor cells (EPCs) due to ox-LDL is a risk contributor for arteriosclerotic disease. Meanwhile, lycopene possesses anti-inflammatory...
The malfunction of endothelial progenitor cells (EPCs) due to ox-LDL is a risk contributor for arteriosclerotic disease. Meanwhile, lycopene possesses anti-inflammatory and antioxidative qualities. This investigation aimed to determine if lycopene can protect EPCs from ox-LDL-induced damage and to elucidate the underlying mechanism. The effects of lycopene on the survival, migration, and tube-forming capacity of EPCs were determined via assays. Expression of proteins related to pyroptosis and cellular proteins related to AMPK/mTOR/NLRP3 signaling was determined by western blot/flow cytometry. Our results demonstrated that lycopene treatment significantly enhanced proliferation, tube formation, and migration of EPCs stimulated by ox-LDL. Additionally, lycopene was found to suppress pyroptosis in ox-LDL-induced EPCs through the activation of AMPK, which led to the inhibition of mTOR phosphorylation and subsequent downregulation of the downstream NLRP3 inflammasome. In summary, our study suggests that lycopene mitigates ox-LDL-induced dysfunction in EPCs and inhibits pyroptosis via AMPK/mTOR/NLRP3 signaling. Our study suggests that lycopene may act as promising therapies for preventing atherosclerosis.
PubMed: 38919547
DOI: 10.1515/med-2024-0973