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Cellular and Molecular Life Sciences :... Jun 2024Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) patients receiving targeted therapy. However, the mechanism that causes...
Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) patients receiving targeted therapy. However, the mechanism that causes cetuximab resistance, especially microRNA (miRNA) regulation, remains unclear. Growing evidence suggests that miRNAs may act as "nuclear activating miRNAs" for targeting promoter regions or enhancers related to target genes. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, quantitative real-time polymerase chain reaction (qRT‒PCR) and fluorescence in situ hybridization (FISH) results provided compelling evidence of miR-451a nuclear enrichment in response to cetuximab treatment. Chromatin isolation via RNA purification, microarray analysis, and bioinformatic analysis revealed that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It has also been demonstrated that the activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Logistic regression analyses of 87 HNSCC samples indicated the significance of miR-451a and KDM7A in the development of cetuximab resistance. These discoveries support the potential of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear-activating miRNAs.
Topics: Humans; MicroRNAs; Cetuximab; Drug Resistance, Neoplasm; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Jumonji Domain-Containing Histone Demethylases; Argonaute Proteins; Animals; Mice; Cell Nucleus; Female; Mice, Nude
PubMed: 38943031
DOI: 10.1007/s00018-024-05324-x -
Cardiovascular Drugs and Therapy Jun 2024Heme oxygenase-1 (HO-1) is a crucial enzyme in heme metabolism, facilitating the breakdown of heme into biliverdin, carbon monoxide, and free iron. Renowned for its... (Review)
Review
PURPOSE
Heme oxygenase-1 (HO-1) is a crucial enzyme in heme metabolism, facilitating the breakdown of heme into biliverdin, carbon monoxide, and free iron. Renowned for its potent cytoprotective properties, HO-1 showcases notable antioxidant, anti-inflammatory, and anti-apoptotic effects. In this review, the authors aim to explore the profound impact of HO-1 on cardiac senescence and its potential implications in myocardial infarction (MI).
RESULTS
Recent research has unveiled the intricate role of HO-1 in cellular senescence, characterized by irreversible growth arrest and functional decline. Notably, cardiac senescence has emerged as a pivotal factor in the development of various cardiovascular conditions, including MI. Notably, cardiac senescence has emerged as an important factor in the development of various cardiovascular conditions, including myocardial infarction (MI). The accumulation of senescent cells, spanning vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes, and progenitor cells, poses a significant risk for cardiovascular diseases such as vascular aging, atherosclerosis, myocardial infarction, and ventricular remodeling. Inhibition of cardiomyocyte senescence not only reduces senescence-associated inflammation but also impacts other myocardial lineages, hinting at a broader mechanism of propagation in pathological remodeling. HO-1 has been shown to improve heart function and mitigate cardiomyocyte senescence induced by ischemic injury and aging. Furthermore, HO-1 induction has been found to alleviate HO-induced cardiomyocyte senescence. As we grow in our understanding of antiproliferative, antiangiogenic, anti-aging, and vascular effects of HO-1, we see the potential to exploit potential links between individual susceptibility to cardiac senescence and myocardial infarction.
CONCLUSIONS
This review investigates strategies for upregulating HO-1, including gene targeting and pharmacological agents, as potential therapeutic approaches. By synthesizing compelling evidence from diverse experimental models and clinical investigations, this study elucidates the therapeutic potential of targeting HO-1 as an innovative strategy to mitigate cardiac senescence and improve outcomes in myocardial infarction, emphasizing the need for further research in this field.
PubMed: 38940935
DOI: 10.1007/s10557-024-07590-0 -
Microbiology Spectrum Jun 2024The majority of the nearly 10,000 described species of green algae are photoautotrophs; however, some species have lost their ability to photosynthesize and become...
UNLABELLED
The majority of the nearly 10,000 described species of green algae are photoautotrophs; however, some species have lost their ability to photosynthesize and become obligate heterotrophs that rely on parasitism for survival. Two high-quality genomes of the heterotrophic algae Pz20 and Pz23 were obtained using short- and long-read genomic as well as transcriptomic data. The genome sizes were 31.2 Mb and 31.3 Mb, respectively, and contig N50 values of 1.99 Mb and 1.26 Mb. Although maintained its plastid genome, the transition to heterotrophy led to a reduction in both plastid and nuclear genome size, including the loss of photosynthesis-related genes from both the nuclear and plastid genomes and the elimination of genes encoding for carotenoid oxygenase and pheophorbide an oxygenase. The loss of genes, including basic leucine-zipper (bZIP) transcription factors, flavin adenine dinucleotide-linked oxidase, and helicase, could have played a role in the transmission of autotrophy to heterotrophs and in the processes of abiotic stress resistance and pathogenicity. A total of 66 (1.37%) and 73 (1.49%) genes were identified as potential horizontal gene transfer events in the two genomes, respectively. Genes for malate synthase and isocitrate lyase, which are horizontally transferred from bacteria, may play a pivotal role in carbon and nitrogen metabolism as well as the pathogenicity of and non-photosynthetic organisms. The two high-quality genomes provide new insights into their evolution as obligate heterotrophs and pathogenicity.
IMPORTANCE
The genus , characterized by its heterotrophic nature and pathogenicity, serves as an exemplary model for investigating pathobiology. The limited understanding of the protothecosis infectious disease is attributed to the lack of genomic resources. Using HiFi long-read sequencing, both nuclear and plastid genomes were generated for two strains of . The findings revealed a concurrent reduction in both plastid and nuclear genome size, accompanied by the loss of genes associated with photosynthesis, carotenoid oxygenase, basic leucine-zipper (bZIP) transcription factors, and others. The analysis of horizontal gene transfer revealed the presence of 1.37% and 1.49% bacterial genes, including malate synthase and isocitrate lyase, which play crucial roles in carbon and nitrogen metabolism, as well as pathogenicity and obligate heterotrophy. The two high-quality genomes represent valuable resources for investigating their adaptation and evolution as obligate heterotrophs, as well as for developing future prevention and treatment strategies against protothecosis.
PubMed: 38940543
DOI: 10.1128/spectrum.04148-23 -
Frontiers in Bioscience (Landmark... May 2024Phosphine resistance in challenges grain storage. This study investigates the impact of cytochrome P450 (CYP) enzymes and CYP346 family genes on phosphine resistance in...
BACKGROUND
Phosphine resistance in challenges grain storage. This study investigates the impact of cytochrome P450 (CYP) enzymes and CYP346 family genes on phosphine resistance in Indian Tribolium castaneum populations.
METHODS
Seven field populations of were compared with Lab- susceptible population for their resistance to phosphine. The levels of cytochrome P450 enzyme and expression of certain CYP346 family genes were tracked in these populations.
RESULTS
The highly resistant Patiala population showed significantly increased CYP450 activity (11.26 ± 0.14 nmol/min/mg protein, 7.41-fold higher) compared to the lab-susceptible population (1.52 ± 0.09 nmol/min/mg protein) when assayed using 8 mM p-nitroanisole as the substrate. The mRNA expression was measured relative to the standard gene and revealed significant upregulation of and in highly resistant populations Moga and Patiala (: 12.09 ± 2.19 to 21.74 ± 3.82; : 59.097 ± 10.265 to 50.148 ± 8.272). Patiala's exhibited an impressive 685.76-fold change, and Moga's showed a 361.893-fold change compared to lab-susceptible. Linear regression confirmed robust fits for each gene (R2: 0.693 to 0.756). Principal component analysis (PCA) demonstrated a strong positive correlation between genes expression; and cytochrome P450 activity. Patiala, Moga, and Hapur populations showed conformity, associating higher resistance with increased P450 activity and CYP346 gene expression. Cluster analysis highlighted a potential correlation between , , and and P450 activity, with Patiala and Moga clustering together.
CONCLUSIONS
Variability in and in strong resistance populations may contribute to adaptation and resistance mechanisms. The study provides insights into specific CYP346 family genes associated with phosphine resistance, emphasizing the intricate interaction between CYP450 detoxifying enzymes, CYP346 family genes, and resistance mechanisms. The upregulation of genes suggests a survival advantage for against phosphine, diminishing phosphine's efficacy as a pest control measure.
Topics: Tribolium; Cytochrome P-450 Enzyme System; Insecticide Resistance; Phosphines; Insecticides; India; Animals
PubMed: 38940033
DOI: 10.31083/j.fbl2906203 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2024The role of the aryl hydrocarbon receptor (AhR) in regulating oxidative stress and immune responses has been increasingly recognized. However, its involvement in...
The role of the aryl hydrocarbon receptor (AhR) in regulating oxidative stress and immune responses has been increasingly recognized. However, its involvement in depression and the underlying mechanisms remain poorly understood. This study aimed to investigate the effect of 6-formylindolo[3,2-b]carbazole (FICZ), an endogenous AhR ligand, on a lipopolysaccharide (LPS)-induced depression model and the underlying mechanism. After being treated with FICZ (50 mg/kg), male C57BL/6J mice received intraperitoneal injection of LPS and underwent behavioral tests 24 h later. The levels of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, were measured in the hippocampus and serum using enzyme-linked immunosorbent assay (ELISA). The expression levels of CYP1A1, AhR and NLRP3 were analyzed using qPCR and Western blot. The results showed that, compared with control group, LPS alone significantly down-regulated the expression levels of CYP1A1 mRNA and AhR protein in the hippocampus of mice, reduced glucose preference, prolonged immobility time in forced swimming test, increased IL-6 and IL-1β levels in the hippocampus, increased serum IL-1β level, and up-regulated NLRP3 mRNA and protein expression levels in mouse hippocampus, while FICZ significantly reversed the aforementioned effects of LPS. These findings suggest that AhR activation attenuates the inflammatory response associated with depression and modulates the expression of NLRP3. The present study provides novel insights into the role of AhR in the development of depression, and presents AhR as a potential therapeutic target for the treatment of depression.
Topics: Animals; Receptors, Aryl Hydrocarbon; Male; Mice; Lipopolysaccharides; Depression; Mice, Inbred C57BL; Cytochrome P-450 CYP1A1; Hippocampus; Carbazoles; NLR Family, Pyrin Domain-Containing 3 Protein; Interleukin-1beta; Interleukin-6; Tumor Necrosis Factor-alpha; Behavior, Animal; Cytokines
PubMed: 38939930
DOI: No ID Found -
Experimental and Therapeutic Medicine Aug 2024Inflammation serves as a multifaceted defense mechanism activated by pathogens, cellular damage and irritants, aiming to eliminate primary causes of injury and promote...
Inflammation serves as a multifaceted defense mechanism activated by pathogens, cellular damage and irritants, aiming to eliminate primary causes of injury and promote tissue repair. Miq (), prevalent in Vietnam and southern China, has a history of traditional use for treating cough, fever and asthma. Previous studies on its phytochemicals have shown their potential as anti-inflammatory agents, yet underlying mechanisms remain to be elucidated. The present study investigated the regulatory effects of on the anti-inflammatory pathways. The methanol extracts of (PDME) were found to inhibit nitric oxide (NO) production and induce heme oxygenase-1 (HO-1) expression in murine macrophages. While MAPKs inhibitors, such as SP600125, SB203580 and U0126 did not regulate HO-1 expression, the treatment of cycloheximide, a translation inhibitor, reduced HO-1. Furthermore, PDME inhibited lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and TNF-α expression at both the mRNA and protein levels. The activity of NOS and the expression of TNF-α, iNOS and COX-2 decreased in LPS-stimulated Raw 264.7 cells treated with PDME and this effect was regulated by inhibition of HO-1 activity. These findings suggested that PDME functions as an HO-1 inducer and serves as an effective natural anti-inflammatory agent in LPS-induced inflammation.
PubMed: 38939180
DOI: 10.3892/etm.2024.12606 -
PeerJ 2024White-rot fungi and bacteria communities are unique ecosystems with different types of symbiotic interactions occurring during wood decomposition, such as cooperation,...
Sequence and structure analyses of lytic polysaccharide monooxygenases mined from metagenomic DNA of humus samples around white-rot fungi in Cuc Phuong tropical forest, Vietnam.
BACKGROUND
White-rot fungi and bacteria communities are unique ecosystems with different types of symbiotic interactions occurring during wood decomposition, such as cooperation, mutualism, nutritional competition, and antagonism. The role of chitin-active lytic polysaccharide monooxygenases (LPMOs) in these symbiotic interactions is the subject of this study.
METHOD
In this study, bioinformatics tools were used to analyze the sequence and structure of putative LPMOs mined by hidden Markov model (HMM) profiles from the bacterial metagenomic DNA database of collected humus samples around white-rot fungi in Cuc Phuong primary forest, Vietnam. Two genes encoding putative LPMOs were expressed in and purified for enzyme activity assay.
RESULT
Thirty-one full-length proteins annotated as putative LPMOs according to HMM profiles were confirmed by amino acid sequence comparison. The comparison results showed that although the amino acid sequences of the proteins were very different, they shared nine conserved amino acids, including two histidine and one phenylalanine that characterize the H1-Hx-Yz motif of the active site of bacterial LPMOs. Structural analysis of these proteins revealed that they are multidomain proteins with different functions. Prediction of the catalytic domain 3-D structure of these putative LPMOs using Alphafold2 showed that their spatial structures were very similar in shape, although their protein sequences were very different. The results of testing the activity of proteins GL0247266 and GL0183513 show that they are chitin-active LPMOs. Prediction of the 3-D structures of these two LPMOs using Alphafold2 showed that GL0247266 had five functional domains, while GL0183513 had four functional domains, two of which that were similar to the GbpA_2 and GbpA_3 domains of protein GbpA of bacteria. The GbpA_2 - GbpA_3 complex was also detected in 11 other proteins. Based on the structural characteristics of functional domains, it is possible to hypothesize the role of chitin-active GbpA-like LPMOs in the relationship between fungal and bacterial communities coexisting on decomposing trees in primary forests.
Topics: Vietnam; Mixed Function Oxygenases; Forests; Chitin; Metagenomics; Metagenome; Amino Acid Sequence
PubMed: 38938609
DOI: 10.7717/peerj.17553 -
Scientific Reports Jun 2024The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use...
The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use the maximum a posterior Bayesian method to construct a warfarin individualized dose prediction model in line with the Chinese Han population. Finally, the built model is compared and analyzed with the widely used models at home and abroad. In this study, a total of 5467 INR measurements are collected from 646 eligible subjects in our hospital, and the maximum a posterior Bayesian method is used to construct a warfarin dose prediction that conforms to the Chinese Han population on the basis of the Hamberg model. The model is verified and compared with foreign models. This study finds that body weight and concomitant use of amiodarone have a significant effect on the anticoagulant effect of warfarin. The model can provide an effective basis for individualized and rational dosing of warfarin in Han population more accurately. In the performance of comparison with different warfarin dose prediction models, the new model has the highest prediction accuracy, and the prediction percentage is as high as 72.56%. The dose predicted by the Huang model is the closest to the actual dose of warfarin. The population pharmacokinetics and pharmacodynamics model established in this study can better reflect the distribution characteristics of INR values after warfarin administration in the Han population, and performs better than the models reported in the literature.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Anticoagulants; Bayes Theorem; China; Cytochrome P-450 CYP2C9; International Normalized Ratio; Vitamin K Epoxide Reductases; Warfarin; East Asian People
PubMed: 38937509
DOI: 10.1038/s41598-024-65048-7 -
Nature Communications Jun 2024Global warming has a severe impact on the flowering time and yield of crops. Histone modifications have been well-documented for their roles in enabling plant plasticity...
Global warming has a severe impact on the flowering time and yield of crops. Histone modifications have been well-documented for their roles in enabling plant plasticity in ambient temperature. However, the factor modulating histone modifications and their involvement in habitat adaptation have remained elusive. In this study, through genome-wide pattern analysis and quantitative-trait-locus (QTL) mapping, we reveal that BrJMJ18 is a candidate gene for a QTL regulating thermotolerance in thermotolerant B. rapa subsp. chinensis var. parachinensis (or Caixin, abbreviated to Par). BrJMJ18 encodes an H3K36me2/3 Jumonji demethylase that remodels H3K36 methylation across the genome. We demonstrate that the BrJMJ18 allele from Par (BrJMJ18) influences flowering time and plant growth in a temperature-dependent manner via characterizing overexpression and CRISPR/Cas9 mutant plants. We further show that overexpression of BrJMJ18 can modulate the expression of BrFLC3, one of the five BrFLC orthologs. Furthermore, ChIP-seq and transcriptome data reveal that BrJMJ18 can regulate chlorophyll biosynthesis under high temperatures. We also demonstrate that three amino acid mutations may account for function differences in BrJMJ18 between subspecies. Based on these findings, we propose a working model in which an H3K36me2/3 demethylase, while not affecting agronomic traits under normal conditions, can enhance resilience under heat stress in Brassica rapa.
Topics: Brassica rapa; Flowers; Gene Expression Regulation, Plant; Histones; Quantitative Trait Loci; Jumonji Domain-Containing Histone Demethylases; Plant Proteins; Temperature; Thermotolerance; Methylation; Plants, Genetically Modified; Chlorophyll
PubMed: 38937441
DOI: 10.1038/s41467-024-49721-z -
Journal of Molecular Medicine (Berlin,... Jun 2024The global incidence and prevalence of arrhythmias are continuously increasing. However, the precise mechanisms of underlying arrhythmogenesis and the optimal measures... (Review)
Review
The global incidence and prevalence of arrhythmias are continuously increasing. However, the precise mechanisms of underlying arrhythmogenesis and the optimal measures for effective treatment remain incompletely understood. The inducible form of heme oxygenase, known as heme oxygenase-1 (HO-1), is recognized as a potent antioxidant molecule capable of exerting anti-inflammatory and anti-apoptotic effects. Recent research indicates that HO-1 plays a role in preventing arrhythmias by mitigating cardiac remodeling, including electrical remodeling, ion remodeling, and structural remodeling. This review aimed to consolidate current knowledge regarding the involvement of HO-1 in arrhythmias and elucidate its underlying mechanisms of action.
PubMed: 38937302
DOI: 10.1007/s00109-024-02462-4