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Adipocyte Dec 2024Insulin resistance is caused by the abnormal secretion of proinflammatory cytokines in adipose tissue, which is induced by an increase in lipid accumulation in...
Insulin resistance is caused by the abnormal secretion of proinflammatory cytokines in adipose tissue, which is induced by an increase in lipid accumulation in adipocytes, hepatocytes, and myocytes. The inflammatory pathway involves multiple targets such as nuclear factor kappa B, inhibitor of nuclear factor κ-B kinase, and mitogen-activated protein kinase. Vitamins are micronutrients with anti-inflammatory activities that have unclear mechanisms. The present study aimed to describe the putative mechanisms of vitamins involved in the inflammatory pathway of insulin resistance. The strategy to achieve this goal was to integrate data mining and analysis, target prediction, and molecular docking simulation calculations to support our hypotheses. Our results suggest that the multitarget activity of vitamins A, B1, B2, B3, B5, B6, B7, B12, C, D3, and E inhibits nuclear factor kappa B and mitogen-activated protein kinase, in addition to vitamins A and B12 against inhibitor of nuclear factor κ-B kinase. The findings of this study highlight the pharmacological potential of using an anti-inflammatory and multitarget treatment based on vitamins and open new perspectives to evaluate the inhibitory activity of vitamins against nuclear factor kappa B, mitogen-activated protein kinase, and inhibitor of nuclear factor κ-B kinase in an insulin-resistant context.
Topics: Insulin Resistance; Humans; Vitamins; NF-kappa B; Molecular Docking Simulation; Animals; Anti-Inflammatory Agents; Mitogen-Activated Protein Kinases
PubMed: 38937879
DOI: 10.1080/21623945.2024.2369777 -
BMC Plant Biology Jun 2024Anthracnose, mainly caused by Colletotrichum fructicola, leads to severe losses in pear production. However, there is limited information available regarding the...
BACKGROUND
Anthracnose, mainly caused by Colletotrichum fructicola, leads to severe losses in pear production. However, there is limited information available regarding the molecular response to anthracnose in pears.
RESULTS
In this study, the anthracnose-resistant variety 'Seli' and susceptible pear cultivar 'Cuiguan' were subjected to transcriptome analysis following C. fructicola inoculation at 6 and 24 h using RNA sequencing. A total of 3186 differentially expressed genes were detected in 'Seli' and 'Cuiguan' using Illumina sequencing technology. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that the transcriptional response of pears to C. fructicola infection included responses to reactive oxygen species, phytohormone signaling, phenylpropanoid biosynthesis, and secondary metabolite biosynthetic processes. Moreover, the mitogen-activated protein kinase (MAPK) signaling pathway and phenylpropanoid biosynthesis were involved in the defense of 'Seli'. Furthermore, the gene coexpression network data showed that genes related to plant-pathogen interactions were associated with C. fructicola resistance in 'Seli' at the early stage.
CONCLUSION
Our results showed that the activation of specific genes in MAPK, calcium signaling pathways and phenylpropanoid biosynthesis was highly related to C. fructicola resistance in 'Seli' and providing several potential candidate genes for breeding anthracnose-resistant pear varieties.
Topics: Pyrus; Colletotrichum; Plant Diseases; Disease Resistance; Gene Expression Profiling; Transcriptome; Gene Expression Regulation, Plant
PubMed: 38937683
DOI: 10.1186/s12870-024-05077-6 -
Neurocritical Care Jun 2024Hypoxic-ischemic brain injury is a common cause of mortality after cardiac arrest (CA) and cardiopulmonary resuscitation; however, the specific underlying mechanisms are...
BACKGROUND
Hypoxic-ischemic brain injury is a common cause of mortality after cardiac arrest (CA) and cardiopulmonary resuscitation; however, the specific underlying mechanisms are unclear. This study aimed to explore postresuscitation changes based on multi-omics profiling.
METHODS
A CA swine model was established, and the neurological function was assessed at 24 h after resuscitation, followed by euthanizing animals. Their fecal, blood, and hippocampus samples were collected to analyze gut microbiota, metabolomics, and transcriptomics.
RESULTS
The 16S ribosomal DNA sequencing showed that the microbiota composition and diversity changed after resuscitation, in which the abundance of Akkermansia and Muribaculaceae_unclassified increased while the abundance of Bifidobacterium and Romboutsia decreased. A relationship was observed between CA-related microbes and metabolites via integrated analysis of gut microbiota and metabolomics, in which Escherichia-Shigella was positively correlated with glycine. Combined metabolomics and transcriptomics analysis showed that glycine was positively correlated with genes involved in apoptosis, interleukin-17, mitogen-activated protein kinases, nuclear factor kappa B, and Toll-like receptor signal pathways.
CONCLUSIONS
Our results provided novel insight into the mechanism of hypoxic-ischemic brain injury after resuscitation, which is envisaged to help identify potential diagnostic and therapeutic markers.
PubMed: 38937417
DOI: 10.1007/s12028-024-02038-7 -
In Vivo (Athens, Greece) 2024Diabetic retinopathy is a leading cause of blindness worldwide, characterized by neurovascular dysfunction. This study aimed to investigate the impact of brimonidine, a...
BACKGROUND/AIM
Diabetic retinopathy is a leading cause of blindness worldwide, characterized by neurovascular dysfunction. This study aimed to investigate the impact of brimonidine, a selective adrenoceptor agonist, on diabetic retinal neurodegeneration, recognizing the critical role of neurodegeneration in diabetic retinopathy.
MATERIALS AND METHODS
Streptozotocin-induced diabetes was established in adult male Sprague-Dawley rats to mimic diabetic retinopathy. Rats, except non-diabetic control rats, received topical applications of 0.15% brimonidine tartrate (treatment group) or balanced salt solution (diabetic control group) twice daily following diabetes induction. Each group comprised six randomly assigned animals. Retinal samples were analyzed using immunofluorescence staining, apoptosis assay, and western blot.
RESULTS
Topical brimonidine treatment reduced apoptosis of retinal ganglion cells at 8 weeks after induction of diabetes (p<0.05). Glial activation induced by diabetes was reduced by brimonidine treatment. Immunoblot and immunofluorescence assay revealed that the decrease in phospho- protein kinase B (AKT) level resulting from diabetes was also attenuated by brimonidine (p<0.05). Furthermore, brimonidine alleviated the decrease in anti-apoptotic proteins [BCL2 apoptosis regulator (BCL2) and BCL-xl] induced by diabetes (p<0.05). Elevation of phospho-p38 mitogen-activated protein kinase (p38MAPK) and p53 in diabetic rats were reduced by brimonidine (p<0.05). Additionally, brimonidine treatment attenuated the upregulation of the pro-apoptotic molecule BCL-2 associated X in retinas of diabetic rats (p<0.05).
CONCLUSION
These findings suggest that topical brimonidine treatment may protect retinal ganglion cells in experimental diabetes by modulating the AKT pathway and reducing pro-apoptotic p38MAPK levels. This presents a potential neuroprotective approach in diabetes, offering the advantage of localized treatment without the added burden of oral medication.
Topics: Animals; Diabetic Retinopathy; Brimonidine Tartrate; Neuroprotective Agents; Rats; Apoptosis; Diabetes Mellitus, Experimental; Male; Retinal Ganglion Cells; Administration, Topical; Disease Models, Animal; Rats, Sprague-Dawley; Proto-Oncogene Proteins c-akt; Retina
PubMed: 38936912
DOI: 10.21873/invivo.13611 -
Clinical Immunology (Orlando, Fla.) Jun 2024Adult orbital xanthogranulomatous disease (AOXGD) is a spectrum of histiocytoses with four subtypes. Mitogen-activated protein kinase (MAPK) pathway mutations have been...
Adult orbital xanthogranulomatous disease (AOXGD) is a spectrum of histiocytoses with four subtypes. Mitogen-activated protein kinase (MAPK) pathway mutations have been detected in various histiocytic neoplasms, little is known about this in AOXGD. Targeted regions of cancer- and histiocytosis-related genes were analyzed and immunohistochemical staining of phosphorylated ERK (pERK), cyclin D1 and PU.1 was performed in 28 AOXGD and 10 control xanthelasma biopsies to assess MAPK pathway activation. Mutations were detected in 7/28 (25%) patients. Positive staining for pERK and/or cyclin D1 was found across all subtypes in 17/27 (63%) patients of whom 12/17 (71%) did not harbour a mutation. Xanthelasma tissue stained negative for pERK and cyclin D1. Relapse occurred in 5/7 (71%) patients with a MAPK pathway mutation compared to 8/21 (38%) patients in whom no mutation could be detected. Molecular analysis and evaluation for systemic disease is warranted to identify patients at risk of recurrent xanthomatous disease.
PubMed: 38936524
DOI: 10.1016/j.clim.2024.110299 -
Pathology, Research and Practice Jun 2024Phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt) signaling pathways contribute to the development of several... (Review)
Review
Phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt) signaling pathways contribute to the development of several cancers, including multiple myeloma (MM). PTEN is a tumor suppressor that influences the PI3K/Akt/mTOR pathway, which in turn impacts vital cellular processes like growth, survival, and treatment resistance. The current study aims to present the role of PTEN and PI3K/Akt/mTOR signaling in the development of MM and its response to treatment. In addition, the molecular interactions in MM that underpin the PI3K/Akt/mTOR pathway and address potential implications for the development of successful treatment plans are also discussed in detail. We investigate their relationship to both upstream and downstream regulators, highlighting new developments in combined therapies that target the PTEN/PI3K/Akt axis to overcome drug resistance, including the use of PI3K and mitogen-activated protein kinase (MAPK) inhibitors. We also emphasize that PTEN/PI3K/Akt pathway elements may be used in MM diagnosis, prognosis, and therapeutic targets.
PubMed: 38936094
DOI: 10.1016/j.prp.2024.155401 -
Marine Pollution Bulletin Jun 2024In this study, we investigated the acute toxicity, in vivo effects, oxidative stress, and gene expression changes caused by hypoxia on the brackish water flea...
In this study, we investigated the acute toxicity, in vivo effects, oxidative stress, and gene expression changes caused by hypoxia on the brackish water flea Diaphanosoma celebensis. The no-observed-effect concentration (NOEC) of 48 h of hypoxia exposure was found to be 2 mg/L O. Chronic exposure to NOEC caused a significant decline in lifespan but had no effect on total fecundity. The induction of reactive oxygen species increased in a time-dependent manner over 48 h, whereas the content of antioxidant enzymes (superoxide dismutase and catalase) decreased. The transcription and translation levels were modulated by hypoxia exposure. In particular, a significant increase in hemoglobin level was followed by up-regulation of hypoxia-inducible factor 1α gene expression and activation of the mitogen-activated protein kinase pathway. In conclusion, our findings provide a better understanding of the molecular mechanism of the adverse effects of hypoxia in brackish water zooplankton.
PubMed: 38936003
DOI: 10.1016/j.marpolbul.2024.116633 -
JCO Precision Oncology Jun 2024The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II...
Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.
PURPOSE
The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor.
METHODS
As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS).
RESULTS
Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with -altered CNS tumors achieved stable disease >6 months.
CONCLUSION
Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.
Topics: Humans; Adolescent; Child; Female; Male; Young Adult; Child, Preschool; Neoplasms; Infant; United States; Mitogen-Activated Protein Kinases; National Cancer Institute (U.S.); MAP Kinase Signaling System; Aminopyridines; Pyrroles
PubMed: 38935895
DOI: 10.1200/PO.24.00103 -
Current Pain and Headache Reports Jun 2024The purpose of this narrative review is to summarize pain symptomatology and mechanisms in neurofibromatosis type 1 (NF1), discuss the pain related quality of life... (Review)
Review
PURPOSE OF REVIEW
The purpose of this narrative review is to summarize pain symptomatology and mechanisms in neurofibromatosis type 1 (NF1), discuss the pain related quality of life impacts of NF1, and discuss the literature exploring interventions to improve quality of life.
RECENT FINDINGS
Chronic pain in NF1 is described as headache and non-headache pain. The literature describes mechanisms contributing to neuronal hyperexcitability in the setting of reduced neurofibromin as key contributors to pain in NF1. Pain in NF1 negatively impacts quality of life with pain interference, depression, anxiety, and cognitive functioning acting as important mediators. Mitogen-activated protein kinase (MEK) inhibitors are pharmacologic agents that interfere with pain mechanisms. Mind-body interventions improve coping skills to improve quality of life. Chronic pain in NF1 is heterogeneous with negative impacts on quality of life. New developments in pharmacological and non-pharmacological interventions offer promising approaches to pain management and quality of life improvement. Additional research is necessary to validate the use of MEK inhibitors and mind-body interventions in the treatment of NF1.
PubMed: 38935244
DOI: 10.1007/s11916-024-01283-x -
Gynecologic and Obstetric Investigation Jun 2024Endometriosis (EMs) commonly occurs in reproductive women. We explored the mechanism of methyltransferase-like 14 (METTL14) on human endometriotic stromal cell (ESC;...
OBJECTIVE
Endometriosis (EMs) commonly occurs in reproductive women. We explored the mechanism of methyltransferase-like 14 (METTL14) on human endometriotic stromal cell (ESC; HEM15A) proliferation, migration and invasion, to provide novel therapy for EMs.
METHODS
HEM15A and human endometrial stromal cells (HESCs) were cultured in vitro. HEM15A cells were treated with oe-METTL14 and oe-zinc finger E-box-binding protein 1 (ZEB1) plasmids, N6-methyladenosine (m6A) inhibitor 3-deazaadenosine (3-DAA) and the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway inhibitor isoprenaline (ISO). After identifying HEM15A and HESCs, METTL14, ZEB1, p-ERK1/2/ERK1/2 and p-MEK/MEK levels, and cell proliferation, migration and invasion were assessed. The modification sites of ZEB1 and m6A were predicted using SRAMP database, with m6A modification level assessed by MeRIP. The binding of YT521-B homology domain 2 (YTHDF2) to ZEB1 messenger RNA (mRNA), and ZEB1 stability and mRNA level were tested.
RESULTS
Compared with HESCs, METTL14 level in HEM15A was significantly reduced. METTL14 overexpression in HEM15A prominently increased its proliferation, migration and invasion. METTL14 overexpression notably elecated m6A-methylated ZEB1 mRNA level and reduced the stability and expression of ZEB1 mRNA. Further m6A modification inhibition increased ZEB1 mRNA stability and mRNA and protein levels, and decreased ZEB1 m6A modification level. ZEB1 upregulation partially reversed METTL14 overexpression-inhibited HEM15A proliferation, migration and invasion. METTL14 inhibited the MEK/ERK signaling activation by regulating ZEB1, and the MEK/ERK signaling activation partly averted METTL14-suppressed proliferation, migration and invasion.
CONCLUSION
METTL14 lowered ZEB1 expression by regulating ZEB1 m6A modification levels, thereby inhibiting the MEK/ERK pathway activation and ESC proliferation, migration and invasion.
PubMed: 38934184
DOI: 10.1159/000539656