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International Journal of Molecular... May 2024The use of secondary metabolites of rice to control pests has become a research hotspot, but little is known about the mechanism of rice self-resistance. In this study,...
The use of secondary metabolites of rice to control pests has become a research hotspot, but little is known about the mechanism of rice self-resistance. In this study, metabolomics analysis was performed on two groups of rice (T1, with insect pests; T2, without pests), indicating that fatty acids, alkaloids, and phenolic acids were significantly up-regulated in T1. The up-regulated metabolites (-value < 0.1) were enriched in linoleic acid metabolism, terpene, piperidine, and pyridine alkaloid biosynthesis, α-linolenic acid metabolism, and tryptophan metabolism. Six significantly up-regulated differential metabolites in T1 were screened out: --feruloyl-3-methoxytyramine (), --feruloyltyramine (), N---coumaroyltyramine (), --feruloyltyramine (), -phenylacetyl-L-glutamine (), and benzamide (). The insect growth inhibitory activities of these six different metabolites were determined, and the results show that compound had the highest activity, which significantly inhibited the growth of by 59.63%. Compounds - also showed a good inhibitory effect on the growth of , while the other compounds had no significant effect. RNA-seq analyses showed that larval exposure to compound up-regulated the genes that were significantly enriched in ribosome biogenesis in eukaryotes, the cell cycle, ribosomes, and other pathways. The down-regulated genes were significantly enriched in metabolic pathways, oxidative phosphorylation, the citrate cycle (TCA cycle), and other pathways. Eighteen up-regulated genes and fifteen down-regulated genes from the above significantly enriched pathways were screened out and verified by real-time quantitative PCR. The activities of detoxification enzymes (glutathione S-transferase (GST); UDP-glucuronosyltransferase (UGT); and carboxylesterase (CarE)) under larval exposure to compound were measured, which indicated that the activity of GST was significantly inhibited by compound , while the activities of the UGT and CarE enzymes did not significantly change. As determined by UPLC-MS, the contents of compound in the T1 and T2 groups were 8.55 ng/g and 0.53 ng/g, respectively, which indicated that pest insects significantly induced the synthesis of compound . Compound may enhance rice insect resistance by inhibiting the detoxification enzyme activity and metabolism of , as well as promoting cell proliferation to affect its normal growth and development process. The chemical-ecological mechanism of the insect resistance of rice is preliminarily clarified in this paper.
Topics: Oryza; Animals; Metabolomics; Alkaloids; Gene Expression Regulation, Plant; Metabolome; Herbivory; Coumaric Acids; Tyramine
PubMed: 38892132
DOI: 10.3390/ijms25115946 -
International Journal of Molecular... May 2024With projections suggesting an increase in the global use of neonicotinoids, contemporary farmers can get caught on the "pesticide treadmill", thus creating ecosystem...
With projections suggesting an increase in the global use of neonicotinoids, contemporary farmers can get caught on the "pesticide treadmill", thus creating ecosystem side effects. The aim of this study was to investigate the sorption/desorption behavior of acetamiprid, imidacloprid, and thiacloprid that controls their availability to other fate-determining processes and thus could be useful in leveling the risk these insecticides or their structural analogues pose to the environment, animals, and human health. Sorption/desorption isotherms in four soils with different organic matter (OC) content were modelled by nonlinear equilibrium models: Freundlich's, Langmuir's, and Temkin's. Sorption/desorption parameters obtained by Freundlich's model were correlated to soil physico-chemical characteristics. Even though the OC content had the dominant role in the sorption of the three insecticides, the role of its nature as well as the chemical structure of neonicotinoids cannot be discarded. Insecticides sorbed in the glassy OC phase will be poorly available unlike those in the rubbery regions. Imidacloprid will fill the sorption sites equally in the rubbery and glassy phases irrespective of its concentration. The sorption of thiacloprid at low concentrations and acetamiprid at high concentrations is controlled by hydrophilic aromatic structures, "trapping" the insecticides in the pores of the glassy phase of OC.
Topics: Neonicotinoids; Insecticides; Nitro Compounds; Thiazines; Adsorption; Soil; Soil Pollutants; Pyridines; Imidazoles
PubMed: 38891887
DOI: 10.3390/ijms25115700 -
International Journal of Molecular... May 2024We present the case of a 70-year-old never-smoking female patient with () p.L858R-mutated metastatic non-small cell lung cancer (NSCLC). After three months of...
We present the case of a 70-year-old never-smoking female patient with () p.L858R-mutated metastatic non-small cell lung cancer (NSCLC). After three months of first-line treatment with erlotinib, progression occurred and platinum/pemetrexed was initiated, followed by a response for more than two years. After the progression, the molecular testing of a vertebral metastasis revealed a () translocation and a (2) p.S310F mutation, in addition to the known p.L858R mutation. Crizotinib then led to a durable response of 17 months. The molecular retesting of the tumour cells obtained from the recurrent pleural effusion revealed the absence of the translocation, whereas the and mutations were still present. Afatinib was added to the crizotinib, and the combination treatment resulted in another durable response of more than two years. The patient died more than 7 years after the initial diagnosis of metastatic NSCLC. This case demonstrates that the repeated molecular testing of metastatic NSCLC may identify new druggable genomic alterations that can impact the patient management and improve the patient outcome.
Topics: Humans; Crizotinib; Female; Afatinib; Aged; Proto-Oncogene Mas; Receptor, ErbB-2; ErbB Receptors; Lung Neoplasms; Proto-Oncogene Proteins; Protein-Tyrosine Kinases; Adenocarcinoma of Lung; Proto-Oncogene Proteins c-met; Mutation; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38891886
DOI: 10.3390/ijms25115698 -
AIDS Research and Therapy Jun 2024Scholars recommend providing migrants living with HIV (MLWH) with free treatment, rapidly, once linked to care to optimize their HIV-related experiences and health...
BACKGROUND
Scholars recommend providing migrants living with HIV (MLWH) with free treatment, rapidly, once linked to care to optimize their HIV-related experiences and health outcomes. Quantitative evaluations of patient-reported measures for MLWH in such models are necessary to explore the viability of these recommendations.
METHODS
Within a 96-week prospective cohort study at a multidisciplinary HIV clinic, participants received bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for free and rapidly following care linkage. Eight patient-reported measures were administered at weeks 4, 24, and 48: (1) mMOS-SS to measure perceived social support; (2) IA-RSS to measure internalized stigma; (3) K6 to measure psychological distress; (4) PROMIS to measure self-efficacy with treatment taking; (5) G-MISS to measure perceived compliance with clinicians' treatment plans; (6) HIVTSQ to measure treatment satisfaction; (7) CARE to measure perceived provider empathy; and (8) PRPCC to measure perceived clinician cultural competence. Linear mixed modelling with bootstrapping was conducted to identify significant differences by sociodemographics and time.
RESULTS
Across weeks 4, 24, and 48, results suggest that MLWH enrolled in this study experienced moderate levels of social support; elevated levels of HIV-related stigma; moderate levels of distress; high self-efficacy with daily medication self-management; great compliance with clinicians' treatment plans; high treatment satisfaction; high perceived empathy; and high perceived cultural competence. Experience of social support (i.e., mMOS-SS scores) differed significantly by birth region. Experience of HIV-related stigma (i.e., IA-RSS scores) differed significantly by birth region, age, and language. Experience of distress (i.e., K6 scores) differed significantly by sexual orientation. Experience of treatment satisfaction (i.e., HIVTSQ scores) differed significantly by birth region and age. No significant differences were identified by time for any measure.
CONCLUSION
Overall, participants expressed positive experiences around treatment and care, alongside comparably lower perceptions of social support, internalized stigma, and distress, potentially underscoring a need to embed targeted, well-funded, and accessible mental health support within HIV care models.
Topics: Humans; HIV Infections; Male; Patient Reported Outcome Measures; Female; Adult; Prospective Studies; Anti-HIV Agents; Social Stigma; Middle Aged; Transients and Migrants; Social Support; Heterocyclic Compounds, 4 or More Rings; Tenofovir; Emtricitabine; Piperazines; Medication Adherence; Pyridones; Drug Combinations; Patient Satisfaction; Young Adult; Self Efficacy; Amides; Heterocyclic Compounds, 3-Ring
PubMed: 38890671
DOI: 10.1186/s12981-024-00632-5 -
Journal of Cancer Research and Clinical... Jun 2024Hepatocellular carcinoma (HCC) is a prevalent malignant tumor, often arising from hepatitis induced by the hepatitis B virus (HBV) in China. However, effective...
PURPOSE
Hepatocellular carcinoma (HCC) is a prevalent malignant tumor, often arising from hepatitis induced by the hepatitis B virus (HBV) in China. However, effective biomarkers for early diagnosis are lacking, leading to a 5-year overall survival rate of less than 20% among patients with advanced HCC. This study aims to identify serum biomarkers for early HCC diagnosis to enhance patient survival rates.
METHODS
We established an independent cohort comprising 27 healthy individuals, 13 patients with HBV-induced cirrhosis, 13 patients with hepatitis B-type HCC, and 8 patients who progressed from cirrhosis to hepatocellular carcinoma during follow-up. Serum metabolic abnormalities during the progression from cirrhosis to HCC were studied using untargeted metabolomics. Liquid chromatography-mass spectrometry-based metabolomics methods characterized the subjects' serum metabolic profiles. Partial least squares discriminant analysis (PLS-DA) was employed to elucidate metabolic profile changes during the progression from cirrhosis to HCC. Differentially expressed metabolites (DEMs) between cirrhosis and HCC groups were identified using the LIMMA package in the R language. Two machine learning algorithms, Least Absolute Shrinkage and Selection Operator (LASSO), and Random Forest Classifier (RF), were used to identify key metabolic biomarkers involved in the progression from cirrhosis to HCC. Key metabolic biomarkers were further validated using targeted metabolomics in a new independent validation cohort comprising 25 healthy individuals and 25 patients with early-stage hepatocellular carcinoma.
RESULTS
A total of 155 serum metabolites were identified, of which 21/54 metabolites exhibited significant changes in HCC patients compared with cirrhosis patients and healthy individuals, respectively. PLS-DA clustering results demonstrated a significant change trend in the serum metabolic profile of patients with HBV-induced cirrhosis during the progression to HCC. Utilizing LASSO regression and RF algorithms, we confirmed 10 key metabolic biomarkers. Notably, 1-Methylnicotinamide (1-MNAM) exhibited a persistent and significant decrease in healthy individuals, cirrhosis, and HCC patients. Moreover, 1-MNAM levels in developing patients were significantly higher during the cirrhosis stage than in the HCC stage. Targeted metabolomic validation in an external cohort further confirmed the good diagnostic performance of 1-MNAM in early HCC detection.
CONCLUSION
Our findings imply that 1-MNAM may be a specific biomarker for the progression of cirrhosis to HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Liver Cirrhosis; Disease Progression; Male; Biomarkers, Tumor; Female; Middle Aged; Niacinamide; Adult; Metabolomics; Cohort Studies; Aged
PubMed: 38890166
DOI: 10.1007/s00432-024-05848-6 -
EuroIntervention : Journal of EuroPCR... Jun 2024
Topics: Humans; Platelet Aggregation Inhibitors; Clopidogrel; Percutaneous Coronary Intervention; Treatment Outcome
PubMed: 38887879
DOI: 10.4244/EIJ-E-24-00009 -
Molecular Brain Jun 2024Areca nut, the seed of Areca catechu L., is one of the most widely consumed addictive substances in the world after nicotine, ethanol, and caffeine. The major effective...
Areca nut, the seed of Areca catechu L., is one of the most widely consumed addictive substances in the world after nicotine, ethanol, and caffeine. The major effective constituent of A. catechu, arecoline, has been reported to affect the central nervous system. Less is known if it may affect pain and its related emotional responses. In this study, we found that oral application of arecoline alleviated the inflammatory pain and its induced anxiolytic and anti-depressive-like behavior. Arecoline also increased the mechanical nociceptive threshold and alleviated depression-like behavior in naïve mice. In the anterior cingulate cortex (ACC), which acts as a hinge of nociception and its related anxiety and depression, by using the multi-electrode field potential recording and whole-cell patch-clamp recording, we found that the evoked postsynaptic transmission in the ACC of adult mice has been inhibited by the application of arecoline. The muscarinic receptor is the major receptor of the arecoline in the ACC. Our results suggest that arecoline alleviates pain, anxiety, and depression-like behavior in both physiological and pathological conditions, and this new mechanism may help to treat patients with chronic pain and its related anxiety and disorder in the future.
Topics: Animals; Synaptic Transmission; Anxiety; Arecoline; Male; Depression; Behavior, Animal; Nociception; Mice, Inbred C57BL; Gyrus Cinguli; Mice; Cerebral Cortex
PubMed: 38886822
DOI: 10.1186/s13041-024-01106-5 -
Alzheimer's Research & Therapy Jun 2024Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a...
BACKGROUND
Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer's disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine's neuroprotective effects, potentially compromising the neuronal integrity of LC's cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.
METHODS
A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.
RESULTS
Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.
CONCLUSIONS
Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.
Topics: Humans; Locus Coeruleus; Female; Alzheimer Disease; Male; Aged; Magnetic Resonance Imaging; tau Proteins; Aged, 80 and over; Cohort Studies; Amyloid beta-Peptides; Positron-Emission Tomography; Cerebral Cortex; Carbolines; Thiazoles; Aniline Compounds; Brain Cortical Thickness
PubMed: 38886798
DOI: 10.1186/s13195-024-01500-0 -
Journal of Experimental & Clinical... Jun 2024The cyclin D1-cyclin dependent kinases (CDK)4/6 inhibitor palbociclib in combination with endocrine therapy shows remarkable efficacy in the management of estrogen...
BACKGROUND
The cyclin D1-cyclin dependent kinases (CDK)4/6 inhibitor palbociclib in combination with endocrine therapy shows remarkable efficacy in the management of estrogen receptor (ER)-positive and HER2-negative advanced breast cancer (BC). Nevertheless, resistance to palbociclib frequently arises, highlighting the need to identify new targets toward more comprehensive therapeutic strategies in BC patients.
METHODS
BC cell lines resistant to palbociclib were generated and used as a model system. Gene silencing techniques and overexpression experiments, real-time PCR, immunoblotting and chromatin immunoprecipitation studies as well as cell viability, colony and 3D spheroid formation assays served to evaluate the involvement of the G protein-coupled estrogen receptor (GPER) in the resistance to palbociclib in BC cells. Molecular docking simulations were also performed to investigate the potential interaction of palbociclib with GPER. Furthermore, BC cells co-cultured with cancer-associated fibroblasts (CAFs) isolated from mammary carcinoma, were used to investigate whether GPER signaling may contribute to functional cell interactions within the tumor microenvironment toward palbociclib resistance. Finally, by bioinformatics analyses and k-means clustering on clinical and expression data of large cohorts of BC patients, the clinical significance of novel mediators of palbociclib resistance was explored.
RESULTS
Dissecting the molecular events that characterize ER-positive BC cells resistant to palbociclib, the down-regulation of ERα along with the up-regulation of GPER were found. To evaluate the molecular events involved in the up-regulation of GPER, we determined that the epidermal growth factor receptor (EGFR) interacts with the promoter region of GPER and stimulates its expression toward BC cells resistance to palbociclib treatment. Adding further cues to these data, we ascertained that palbociclib does induce pro-inflammatory transcriptional events via GPER signaling in CAFs. Of note, by performing co-culture assays we demonstrated that GPER contributes to the reduced sensitivity to palbociclib also facilitating the functional interaction between BC cells and main components of the tumor microenvironment named CAFs.
CONCLUSIONS
Overall, our results provide novel insights on the molecular events through which GPER may contribute to palbociclib resistance in BC cells. Additional investigations are warranted in order to assess whether targeting the GPER-mediated interactions between BC cells and CAFs may be useful in more comprehensive therapeutic approaches of BC resistant to palbociclib.
Topics: Humans; Pyridines; Breast Neoplasms; Piperazines; Female; Receptors, Estrogen; Drug Resistance, Neoplasm; Cyclin-Dependent Kinase 4; Cell Line, Tumor; Receptors, G-Protein-Coupled; Cyclin-Dependent Kinase 6; Protein Kinase Inhibitors; Tumor Microenvironment
PubMed: 38886784
DOI: 10.1186/s13046-024-03096-7 -
Scientific Reports Jun 2024Demyelination is generated in several nervous system illnesses. Developing strategies for effective clinical treatments requires the discovery of promyelinating drugs....
Demyelination is generated in several nervous system illnesses. Developing strategies for effective clinical treatments requires the discovery of promyelinating drugs. Increased GABAergic signaling through γ-aminobutyric acid type A receptor (GABAR) activation in oligodendrocytes has been proposed as a promyelinating condition. GABAR expressed in oligodendroglia is strongly potentiated by n-butyl-β-carboline-3-carboxylate (β-CCB) compared to that in neurons. Here, mice were subjected to 0.3% cuprizone (CPZ) added in the food to induce central nervous system demyelination, a well-known model for multiple sclerosis. Then β-CCB (1 mg/Kg) was systemically administered to analyze the remyelination status in white and gray matter areas. Myelin content was evaluated using Black-Gold II (BGII) staining, immunofluorescence (IF), and magnetic resonance imaging (MRI). Evidence indicates that β-CCB treatment of CPZ-demyelinated animals promoted remyelination in several white matter structures, such as the fimbria, corpus callosum, internal capsule, and cerebellar peduncles. Moreover, using IF, it was observed that CPZ intake induced an increase in NG2 and a decrease in CC1 cell populations, alterations that were importantly retrieved by β-CCB treatment. Thus, the promyelinating character of β-CCB was confirmed in a generalized demyelination model, strengthening the idea that it has clinical potential as a therapeutic drug.
Topics: Animals; Cuprizone; Remyelination; Mice; Demyelinating Diseases; Disease Models, Animal; Carbolines; Myelin Sheath; Male; Mice, Inbred C57BL; Oligodendroglia; Multiple Sclerosis; White Matter; Magnetic Resonance Imaging
PubMed: 38886527
DOI: 10.1038/s41598-024-64501-x