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Asian Pacific Journal of Cancer... Jun 2024Lung cancer is the most common malignancy and among the leading cause of cancer death worldwide. Therefore, there is an important need for biomarkers that can be used in...
OBJECTIVE
Lung cancer is the most common malignancy and among the leading cause of cancer death worldwide. Therefore, there is an important need for biomarkers that can be used in the early diagnosis of the disease and in the follow-up of treatment. Circular RNAs (circRNAs) have a covalently closed circular structure that lacks 3' and 5' polar ends and is resistant to RNAase enzymes. Due to these properties, they can be stably found in body fluids. Therefore, they can serve as potential biomarkers in the diagnosis, monitoring of therapeutic response and prognosis of cancer. In our study, we aimed to investigate the expression levels of circRNA molecules in the treatment of lung cancer and to determine those that have the potential to be biomarkers.
METHODS
In this in vitro study, expression levels of 163 circRNAs were investigated in A549 cells, a non-small cell lung cancer cell line, before and after treatment with carboplatin and pemetrexed. Total RNA isolation and cDNA synthesis were performed after treatments. Expression levels of circRNA genes were determined by RT-qPCR method with the designed divergent primer sequences.
RESULTS
The study revealed the characterisation of differentially expressed circRNAs by treatment in lung cancer cells. Of them, hsa_circ_0001320 is not expressed in cancer cells, is expressed only after treatment, and increased the level of its expression in response to combination therapy.
CONCLUSION
As a result, while carboplatin, pemetrexed, and combined drug applications changed the expression levels of some circRNAs in lung cancer cells, some circRNAs were expressed only after treatment. In treatment follow-up and management, hsa_circ_0001320 has been identified as potential biomarker candidate.
Topics: Humans; RNA, Circular; Lung Neoplasms; Biomarkers, Tumor; Prognosis; Carcinoma, Non-Small-Cell Lung; Carboplatin; Pemetrexed; Gene Expression Regulation, Neoplastic; Tumor Cells, Cultured
PubMed: 38918678
DOI: 10.31557/APJCP.2024.25.6.2147 -
Reumatismo Jun 2024The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory...
The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory abnormalities, such as an increase in creatine kinase (CK). Data from randomized controlled trials suggest that concomitant myalgia is rare in RA and does not lead to drug discontinuation. We describe the case of a 68-year-old Caucasian female with longstanding, multi-failure RA who started BARI and achieved disease remission. However, she developed a symptomatic CK increase, as well as a parallel increase in total cholesterol, low-density lipoprotein, and triglycerides. Dechallenge-rechallenge demonstrated a plausible relationship between the clinical/laboratory abnormalities and BARI. In fact, when the drug was withdrawn, CK returned to normal and myalgia disappeared, whereas symptoms returned and CK levels increased when BARI was restarted. BARI may be rarely associated with symptomatic CK elevation, and this may pose clinical challenges, particularly for patients with multi-failure RA who achieved good disease control with BARI but required drug discontinuation due to intolerance.
Topics: Humans; Arthritis, Rheumatoid; Female; Purines; Aged; Azetidines; Pyrazoles; Sulfonamides; Creatine Kinase; Myalgia; Antirheumatic Agents; Janus Kinase Inhibitors
PubMed: 38916168
DOI: 10.4081/reumatismo.2024.1620 -
Frontiers in Veterinary Science 2024High temperature induces heat stress, adversely affecting the growth and lactation performance of cows. Research has shown the protective effect of taurine against...
High temperature induces heat stress, adversely affecting the growth and lactation performance of cows. Research has shown the protective effect of taurine against hepatotoxicity both and . This study aimed to investigate the effect of taurine on the metabolomics of mammary epithelial cells of dairy cows under high-temperature conditions. Mammary epithelial cells were exposed to 0 mmol/L (HS, control), 8 mmol/L (HT-8), and 32 mmol/L (HT-32) of taurine, then incubated at 42°C for 6 h. Metabolomics analysis was conducted using Liquid Chromatograph Mass Spectrometer (LC-MS). Compared with the HS group, 2,873 and 3,243 metabolites were detected in the HT-8 group in positive and negative ion modes. Among these, 108 and 97 metabolites were significantly upregulated in positive and negative ion modes, while 60 and 166 metabolites were downregulated. Notably, 15 different metabolites such as palmitic acid, adenine and hypoxanthine were screened out in the HT-8 group. Compared with the HS group, 2,873 and 3,243 metabolites were, respectively, detected in the HT-32 group in the positive and negative ion modes. Among those metabolites, 206 metabolites were significantly up-regulated, while 206 metabolites were significantly downregulated in the positive mode. On the other hand, 497 metabolites were significantly upregulated in the negative mode, while 517 metabolites were reported to be downregulated. Noteworthy, 30 distinct metabolites, such as palmitic acid, phytosphingosine, hypoxanthine, nonanoic acid, and octanoic acid, were screened out in the HT-32 group. KEGG enrichment analysis showed that these metabolites were mainly involved in lipid metabolism, purine metabolism and other biological processes. Overall, our study indicates that taurine supplementation alters the metabolites primarily associated with purine metabolism, lipid metabolism and other pathways to alleviate heat stress in bovine mammary epithelial cells.
PubMed: 38915889
DOI: 10.3389/fvets.2024.1393276 -
Drug Design, Development and Therapy 2024SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan, has been extensively studied in drug delivery systems. However, its impact on neural...
PURPOSE
SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan, has been extensively studied in drug delivery systems. However, its impact on neural metabolism remains unclear. This study aims to investigate the toxic effects of SN-38 on mouse brain metabolism.
METHODS
Male mice were divided into an SN-38 group and a control group. The SN-38 group received SN-38 (20 mg/kg/day) via intraperitoneal injection, while the control group was given an equal volume of a blank solvent mixture (DMSO and saline, ratio 1:9). Gas chromatography-mass spectrometry (GC-MS) was employed to analyze differential metabolites in the cortical and hippocampal regions of the SN-38-treated mice.
RESULTS
SN-38 induced metabolic disturbances in the central nervous system. Eighteen differential metabolites were identified in the hippocampus and twenty-four in the cortex, with six common to both regions. KEGG pathway enrichment analysis revealed statistically significant alterations in six metabolic pathways in the hippocampus and ten in the cortex (P<0.05).
CONCLUSION
This study is the first to demonstrate the neurotoxicity of SN-38 in male mice through metabolomics. Differential metabolites in the hippocampal and cortical regions were closely linked to purine metabolism, pyrimidine metabolism, amino acid metabolism, and glyceride metabolism, indicating disruptions in the blood-brain barrier, energy metabolism, and central signaling pathways.
Topics: Animals; Male; Irinotecan; Mice; Metabolomics; Brain; Gas Chromatography-Mass Spectrometry; Injections, Intraperitoneal
PubMed: 38915864
DOI: 10.2147/DDDT.S457698 -
Lipids in Health and Disease Jun 2024Uric acid (UA), a liver-derived metabolite, is intimately tied to metabolic disorders. Although ample research underscores its connection with hypertriglyceridemia...
BACKGROUND
Uric acid (UA), a liver-derived metabolite, is intimately tied to metabolic disorders. Although ample research underscores its connection with hypertriglyceridemia (HTG), studies focusing on adolescents remain limited. To fill the gaps in epidemiology,this study focused on analyzing the relationship between the levels of uric acid and HTG in a demographic sample comprising adolescents from the United States.
METHODS
In this study, a total of 4,435 participants through the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2020. The exposure variable was serum uric acid (SUA), the effect variable was HTG, and the covariates included demographic, questionnaire, physical examination and laboratory indicators. We utilized weighted logistic regression and meticulous subgroup evaluations to discern the intrinsic link between SUA and HTG. Stratified analyses augmented the validation of this association, while smooth curve fitting probed for potential nonlinear correlations.
RESULTS
The study included 4,435 participants. Male adolescents exhibit elevated SUA levels. After adjusting for all variables, the weighted multiple logistic regression model revealed that SUA was positively correlated with HTG risk (OR = 1.006, 95% CI: 1.005-1.007). This relationship was consistent across the three tertiles group of SUA (T1: OR = 1.006 [95% CI: 1.005-1.007]; T2: OR = 1.006 [95% CI: 1.005-1.007]; T3: OR = 1.004 [95% CI: 1.003-1.006]; P for trend < 0.001). Stratified analyses confirmed that the positive correlation between SUA and HTG risk was significant, irrespective of sex, age or race.
CONCLUSIONS
In American children and adolescents aged 12 to 18 years, there was a pronounced association between SUA and HTG. SUA could serve as a risk indicator for HTG. It is recommended that children diagnosed with HTG should be regularly tested for SUA levels. In addition, it is recommended that SUA be included in the comprehensive care of children diagnosed with HTG.
Topics: Humans; Uric Acid; Adolescent; Hypertriglyceridemia; Male; Female; Child; Cross-Sectional Studies; Nutrition Surveys; Logistic Models; Risk Factors; United States; Triglycerides
PubMed: 38915087
DOI: 10.1186/s12944-024-02182-1 -
Journal of Nanobiotechnology Jun 2024Photothermal therapy (PTT) is a promising cancer treatment method due to its ability to induce tumor-specific T cell responses and enhance therapeutic outcomes. However,...
Photothermal therapy (PTT) is a promising cancer treatment method due to its ability to induce tumor-specific T cell responses and enhance therapeutic outcomes. However, incomplete PTT can leave residual tumors that often lead to new metastases and decreased patient survival in clinical scenarios. This is primarily due to the release of ATP, a damage-associated molecular pattern that quickly transforms into the immunosuppressive metabolite adenosine by CD39, prevalent in the tumor microenvironment, thus promoting tumor immune evasion. This study presents a photothermal nanomedicine fabricated by electrostatic adsorption among the Fe-doped polydiaminopyridine (Fe-PDAP), indocyanine green (ICG), and CD39 inhibitor sodium polyoxotungstate (POM-1). The constructed Fe-PDAP@ICG@POM-1 (FIP) can induce tumor PTT and immunogenic cell death when exposed to a near-infrared laser. Significantly, it can inhibit the ATP-adenosine pathway by dual-directional immunometabolic regulation, resulting in increased ATP levels and decreased adenosine synthesis, which ultimately reverses the immunosuppressive microenvironment and increases the susceptibility of immune checkpoint blockade (aPD-1) therapy. With the aid of aPD-1, the dual-directional immunometabolic regulation strategy mediated by FIP can effectively suppress/eradicate primary and distant tumors and evoke long-term solid immunological memory. This study presents an immunometabolic control strategy to offer a salvage option for treating residual tumors following incomplete PTT.
Topics: Animals; Photothermal Therapy; Immunotherapy; Mice; Nanomedicine; Tumor Microenvironment; Cell Line, Tumor; Humans; Indocyanine Green; Neoplasms; Adenosine Triphosphate; Adenosine; Mice, Inbred C57BL; Apyrase; Female; Phototherapy
PubMed: 38915007
DOI: 10.1186/s12951-024-02643-w -
PloS One 2024Non-alcoholic fatty liver disease (NAFLD) is independently associated with atrial fibrillation (AF) risk. The uric acid (UA) to high-density lipoprotein cholesterol...
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) is independently associated with atrial fibrillation (AF) risk. The uric acid (UA) to high-density lipoprotein cholesterol (HDL-C) ratio (UHR) has been shown to be closely associated with cardiovascular disease (CVD) and NAFLD. The aim of this study is to clarify whether elevated UHR is associated with the occurrence of AF in patients with NAFLD and to determine whether UHR predicted AF.
METHODS
Patients diagnosed with NAFLD in the Department of Cardiovascular Medicine of the Second Hospital of Shanxi Medical University from January 1, 2020, to December 31, 2021, were retrospectively enrolled in this study. The study subjects were categorized into AF group and non-AF group based on the presence or absence of combined AF. Logistic regression was performed to evaluate the correlation between UHR and AF. Sensitivity analysis and subgroup interaction analysis were performed to verify the robustness of the study results. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff value for UHR to predict the development of AF in patients with NAFLD.
RESULTS
A total of 421 patients with NAFLD were included, including 171 in the AF group and 250 in the non-AF group. In the univariate regression analysis, NAFLD patients with higher UHR were more likely to experience AF, and the risk of AF persisted after confounding factors were adjusted for (OR: 1.010, 95%CI: 1.007-1.013, P<0.001). AF risk increased with increasing UHR quartile (P for trend < 0.001). Despite normal serum UA and HDL-C, UHR was still connected with AF in patients with NAFLD. All subgroup variables did not interact significantly with UHR in the subgroup analysis. The ROC curve analysis showed that the areas under the curve for UA, HDL-C, and UHR were 0.702, 0.606, and 0.720, respectively, suggesting that UHR has a higher predictive value for AF occurrence in NAFLD patients compared to HDL-C or UA alone.
CONCLUSION
Increased UHR level was independently correlated with a high risk of AF in NAFLD patients.
Topics: Humans; Uric Acid; Atrial Fibrillation; Non-alcoholic Fatty Liver Disease; Male; Female; Cholesterol, HDL; Middle Aged; Retrospective Studies; ROC Curve; Risk Factors; Aged; Adult
PubMed: 38913677
DOI: 10.1371/journal.pone.0305952 -
ELife Jun 2024Allosteric cooperativity between ATP and substrates is a prominent characteristic of the cAMP-dependent catalytic subunit of protein kinase A (PKA-C). This long-range...
Allosteric cooperativity between ATP and substrates is a prominent characteristic of the cAMP-dependent catalytic subunit of protein kinase A (PKA-C). This long-range synergistic action is involved in substrate recognition and fidelity, and it may also regulate PKA's association with regulatory subunits and other binding partners. To date, a complete understanding of this intramolecular mechanism is still lacking. Here, we integrated NMR(Nuclear Magnetic Resonance)-restrained molecular dynamics simulations and a Markov State Model to characterize the free energy landscape and conformational transitions of PKA-C. We found that the apoenzyme populates a broad free energy basin featuring a conformational ensemble of the active state of PKA-C (ground state) and other basins with lower populations (excited states). The first excited state corresponds to a previously characterized inactive state of PKA-C with the αC helix swinging outward. The second excited state displays a disrupted hydrophobic packing around the regulatory (R) spine, with a flipped configuration of the F100 and F102 residues at the αC-β4 loop. We validated the second excited state by analyzing the F100A mutant of PKA-C, assessing its structural response to ATP and substrate binding. While PKA-C preserves its catalytic efficiency with Kemptide, this mutation rearranges the αC-β4 loop conformation, interrupting the coupling of the two lobes and abolishing the allosteric binding cooperativity. The highly conserved αC-β4 loop emerges as a pivotal element to control the synergistic binding of nucleotide and substrate, explaining how mutations or insertions near or within this motif affect the function and drug sensitivity in homologous kinases.
Topics: Molecular Dynamics Simulation; Allosteric Regulation; Adenosine Triphosphate; Catalytic Domain; Cyclic AMP-Dependent Protein Kinases; Protein Conformation; Protein Binding; Nucleotides; Substrate Specificity; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
PubMed: 38913408
DOI: 10.7554/eLife.91506 -
Scientific Reports Jun 2024Microglia, brain-resident macrophages, can acquire distinct functional phenotypes, which are supported by differential reprogramming of cell metabolism. These...
Microglia, brain-resident macrophages, can acquire distinct functional phenotypes, which are supported by differential reprogramming of cell metabolism. These adaptations include remodeling in glycolytic and mitochondrial metabolic fluxes, potentially altering energy substrate availability at the tissue level. This phenomenon may be highly relevant in the brain, where metabolism must be precisely regulated to maintain appropriate neuronal excitability and synaptic transmission. Direct evidence that microglia can impact on neuronal energy metabolism has been widely lacking, however. Combining molecular profiling, electrophysiology, oxygen microsensor recordings and mathematical modeling, we investigated microglia-mediated disturbances in brain energetics during neuroinflammation. Our results suggest that proinflammatory microglia showing enhanced nitric oxide release and decreased CX3CR1 expression transiently increase the tissue lactate/glucose ratio that depends on transcriptional reprogramming in microglia, not in neurons. In this condition, neuronal network activity such as gamma oscillations (30-70 Hz) can be fueled by increased ATP production in mitochondria, which is reflected by elevated oxygen consumption. During dysregulated inflammation, high energy demand and low glucose availability can be boundary conditions for neuronal metabolic fitness as revealed by kinetic modeling of single neuron energetics. Collectively, these findings indicate that metabolic flexibility protects neuronal network function against alterations in local substrate availability during moderate neuroinflammation.
Topics: Animals; Neurons; Energy Metabolism; Microglia; Mice; Neuroinflammatory Diseases; Glucose; Mitochondria; Nitric Oxide; Lactic Acid; Nerve Net; Brain; Oxygen Consumption; Adenosine Triphosphate; Inflammation; Male; Mice, Inbred C57BL
PubMed: 38909138
DOI: 10.1038/s41598-024-64872-1 -
Journal of Dairy Science Jun 2024Interventions targeting the gut microbiota, such as fecal microbiota transplantation, prove effective in repairing the intestinal barrier and facilitating the recovery...
Changes in Rumen Epithelial Morphology and Transcriptome, Rumen Metabolome, and Blood Biochemical Parameters in Lactating Dairy Cows with Subacute Rumen Acidosis Following Rumen Content Transplantation.
Interventions targeting the gut microbiota, such as fecal microbiota transplantation, prove effective in repairing the intestinal barrier and facilitating the recovery of its function and metabolism. However, the regulatory mechanisms governing the remodeling of rumen epithelial morphology and function, rumen metabolism, and host metabolism in cows of subacute ruminal acidosis (SARA) remain poorly understood. Here, we explored the changes in rumen epithelial morphology and transcriptome, rumen metabolome, and blood biochemical parameters in SARA cows following rumen content transplantation (RCT). The entire experiment consisted of 2 periods: the SARA induction period and the RCT period. During the SARA induction period, 12 ruminally cannulated lactating Holstein cows were randomly allocated into 2 groups, fed either a conventional diet [CON; n = 4; 40% concentrate, dry matter (DM) basis] or a high-grain diet (HG; n = 8; 60% concentrate, DM basis). Following the SARA induction period, the RCT period started. The HG cows were randomly assigned to 2 groups: the donor-recipient (DR) group and the self-recipient (SR) group. Rumen contents were entirely removed from both groups before RCT. For the DR group, cows were administered 70% rumen content from the CON cows, paired based on comparable body weight; for the SR group, each cow received 70% self-derived rumen content. The results revealed no significant differences in the thicknesses of the stratum corneum, granulosum, and spinosum/basale layers, as well as the total depth of the epithelium between the SR and DR groups. All these measurements exhibited a decreasing trend and fluctuations over time after the transfer. Notably, these fluctuations tended to stabilize at 13 or 16 d after RCT in the SR group, whereas they tended to stabilize after 8 or 13 d of transfer for the DR group. Transcriptome sequencing revealed that a total of 277 differentially expressed genes (DEGs) were identified between the 2 groups. Enrichment analysis showed that the DEGs were significantly enriched in 11 Gene Ontology biological processes and 14 KEGG pathways. The DEGs corresponding to almost any of these 11 biological process terms and 14 pathways showed mixed up- or downregulation following RCT. Metabolomics analysis indicated that a total of 33 differential metabolites were detected between the SR and DR groups, mainly enriched in 5 key metabolic pathways, including plant polysaccharides and starch degradation, lipid metabolism, amino sugar and nucleotide metabolism, purine metabolism, and Krebs cycle. Among them, the levels of differential metabolites associated with the degradation of plant polysaccharides and starches, metabolism of amino sugars and nucleotides, and purine metabolism pathways were significantly elevated in the DR cows. The results of blood biochemical parameters showed that the triglyceride concentration of the DR cows was increased than that of the SR cows, comparable to the level observed in the CON cows during the SARA induction period. Generally, our findings indicated that RCT facilitated the recovery of rumen epithelial morphological structure but did not promote its function recovery. Moreover, RCT enhanced rumen plant polysaccharide and starch degradation, amino sugar and nucleotide sugar metabolism, as well as purine metabolism. Additionally, it further promoted the recovery of plasma metabolites related to lipid metabolism.
PubMed: 38908691
DOI: 10.3168/jds.2024-24694