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Frontiers in Endocrinology 2024The relationship between adiposity and sepsis has received increasing attention. This study aims to explore the causal relationship between life course adiposity and the... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
The relationship between adiposity and sepsis has received increasing attention. This study aims to explore the causal relationship between life course adiposity and the sepsis incidence.
METHODS
Mendelian randomization (MR) method was employed in this study. Instrumental variants were obtained from genome-wide association studies for life course adiposity, including birth weight, childhood body mass index (BMI), childhood obesity, adult BMI, waist circumference, visceral adiposity, and body fat percentage. A meta-analysis of genome-wide association studies for sepsis including 10,154 cases and 454,764 controls was used in this study. MR analyses were performed using inverse variance weighted, MR Egger regression, weighted median, weighted mode, and simple mode. Instrumental variables were identified as significant single nucleotide polymorphisms at the genome-wide significance level ( < 5×10). The sensitivity analysis was conducted to assess the reliability of the MR estimates.
RESULTS
Analysis using the MR analysis of inverse variance weighted method revealed that genetic predisposition to increased childhood BMI ( = 1.29, = 0.003), childhood obesity ( = 1.07, = 0.034), adult BMI ( = 1.38, < 0.001), adult waist circumference ( = 1.01, = 0.028), and adult visceral adiposity ( = 1.53, < 0.001) predicted a higher risk of sepsis. Sensitivity analysis did not identify any bias in the MR results.
CONCLUSION
The results demonstrated that adiposity in childhood and adults had causal effects on sepsis incidence. However, more well-designed studies are still needed to validate their association.
Topics: Humans; Mendelian Randomization Analysis; Adiposity; Sepsis; Genome-Wide Association Study; Body Mass Index; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Pediatric Obesity; Adult; Waist Circumference; Child; Male; Female
PubMed: 38948521
DOI: 10.3389/fendo.2024.1413690 -
F1000Research 2023Tyrosine-protein kinase SYK, encoded by the gene, is a non-receptor type protein kinase which mediates immune signal transduction through immunoreceptors....
Tyrosine-protein kinase SYK, encoded by the gene, is a non-receptor type protein kinase which mediates immune signal transduction through immunoreceptors. Tyrosine-protein kinase SYK expression has been associated with the development of various inflammatory diseases, cancer and neurodegenerative conditions. The reproducibility of tyrosine-protein kinase SYK research would help elucidate the mechanism in which it causes neuroinflammation as well as its potential as a novel target to treat Alzheimer's disease. This would be facilitated with the availability of high-quality tyrosine-protein kinase SYK. In this study, we characterized thirteen tyrosine-protein kinase SYK commercial antibodies for Western Blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.
Topics: Syk Kinase; Humans; Immunoprecipitation; Fluorescent Antibody Technique; Blotting, Western; Antibodies; Animals; Cell Line
PubMed: 38948505
DOI: 10.12688/f1000research.140456.2 -
F1000Research 2023Nintedanib (NTB) is a multiple tyrosine kinase inhibitor, been investigated for many disease conditions like idiopathic pulmonary fibrosis (IPF), systemic sclerosis...
A stability indicating method development and validation of a rapid and sensitive RP-HPLC method for Nintedanib and its application in quantification of nanostructured lipid carriers.
BACKGROUND
Nintedanib (NTB) is a multiple tyrosine kinase inhibitor, been investigated for many disease conditions like idiopathic pulmonary fibrosis (IPF), systemic sclerosis interstitial lung disease (SSc-ILD) and non-small cell lung cancer (NSCLC). NTB is available as oral capsule formulation, but its ability to detect degradants formed through oxidative, photolytic and hydrolytic processes makes it difficult to quantify. In the current work, a novel reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated.
METHODS
The developed method is simple, precise, reproducible, stable and accurate. The inherent stability of NTB was evaluated using the proposed analytical method approach and force degradation studies were carried out. NTB was separated chromatographically on the Shimadzu C column as stationary phase (250 ×4.6 mm, 5 µm) using an isocratic elution method with 0.1% v/v triethyl amine (TEA) in HPLC grade water and acetonitrile (ACN) in the ratio 35:65% v/v. The mobile phase was pumped at a constant flow rate of 1.0 ml/min, and the eluent was detected at 390 nm wavelength.
RESULTS
NTB was eluted at 6.77±0.00 min of retention time (t ) with a correlation coefficient of 0.999, the developed method was linear in the concentration range of 0.5 µg/ml to 4.5 µg/ml. The recovery rate was found to be in the range of 99.391±0.468% for 1.5 µg/ml concentration. Six replicate standards were determined to have an % RSD of 0.04.
CONCLUSION
The formulation excipients didn't interfere with the determination of NTB, demonstrating the specificity of the developed method. The proposed approach of the analytical method developed can be used to quantify the amount of NTB present in bulk drugs and pharmaceutical formulations.
Topics: Chromatography, High Pressure Liquid; Indoles; Chromatography, Reverse-Phase; Lipids; Drug Stability; Drug Carriers; Nanostructures; Reproducibility of Results
PubMed: 38948504
DOI: 10.12688/f1000research.138786.2 -
Frontiers in Pharmacology 2024The escalation of global population aging has accentuated the prominence of senile diabetes mellitus (SDM) as a consequential public health concern. Oxidative stress and...
Network analysis combined with experimental assessment to explore the therapeutic mechanisms of New Shenqi Pills formula targeting mitochondria on senile diabetes mellitus.
BACKGROUND
The escalation of global population aging has accentuated the prominence of senile diabetes mellitus (SDM) as a consequential public health concern. Oxidative stress and chronic inflammatory cascades prevalent in individuals with senile diabetes significantly amplify disease progression and complication rates. Traditional Chinese Medicine (TCM) emerges as a pivotal player in enhancing blood sugar homeostasis and retarding complication onset in the clinical management of senile diabetes. Nonetheless, an evident research gap persists regarding the integration of TCM's renal tonification pharmacological mechanisms with experimental validation within the realm of senile diabetes therapeutics.
AIMS
The objective of this study was to investigate the mechanisms of action of New Shenqi Pills (SQP) in the treatment of SDM and make an experimental assessment.
METHODS
Network analysis is used to evaluate target pathways related to SQP and SDM. Mitochondrial-related genes were obtained from the MitoCarta3.0 database and intersected with the common target genes of the disease and drugs, then constructing a protein-protein interaction (PPI) network making use of the GeneMANIA database. Representative compounds in the SQP were quantitatively measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to ensure quality control and quantitative analysis of the compounds. A type 2 diabetes mice (C57BL/6) model was used to investigate the pharmacodynamics of SQP. The glucose lowering efficacy of SQP was assessed through various metrics including body weight and fasting blood glucose (FBG). To elucidate the modulatory effects of SQP on pancreatic beta cell function, we measured oral glucose tolerance test (OGTT), insulin histochemical staining and tunel apoptosis detection, then assessed the insulin-mediated phosphoinositide 3-kinase (PI3K)/protein kinase A (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway in diabetic mice via Western blotting. Additionally, we observe the structural changes of the nucleus, cytoplasmic granules and mitochondria of pancreatic islet β cells.
RESULTS
In this investigation, we identified a total of 1876 genes associated with senile diabetes, 278 targets of SQP, and 166 overlapping target genes, primarily enriched in pathways pertinent to oxidative stress response, peptide response, and oxygen level modulation. Moreover, an intersection analysis involving 1,136 human mitochondrial genes and comorbidity targets yielded 15 mitochondria-related therapeutic targets. Quality control assessments and quantitative analyses of SQP revealed the predominant presence of five compounds with elevated concentrations: Catalpol, Cinnamon Aldehyde, Rehmanthin D, Trigonelline, and Paeonol Phenol. Vivo experiments demonstrated notable findings. Relative to the control group, mice in the model group exhibited significant increases in body weight and fasting blood glucose levels, alongside decreased insulin secretion and heightened islet cell apoptosis. Moreover, β-cells nuclear condensation and mitochondrial cristae disappearance were observed, accompanied by reduced expression levels of p-GSK-3β protein in islet cells ( < 0.05 or < 0.01). Conversely, treatment groups administered SQP and Rg displayed augmented expressions of the aforementioned protein markers ( < 0.05 or < 0.01), alongside preserved mitochondrial cristae structure in islet β cells.
CONCLUSION
Our findings suggest that SQP can ameliorate diabetes by reducing islet cell apoptosis and resist oxidative stress. These insulin-mediated PI3K/AKT/GSK-3β pathway plays an important regulatory role in this process.
PubMed: 38948458
DOI: 10.3389/fphar.2024.1339758 -
World Journal of Hepatology Jun 2024Hepatocellular carcinoma (HCC) is a primary contributor to cancer-related mortality on a global scale. However, the underlying molecular mechanisms are still poorly...
BACKGROUND
Hepatocellular carcinoma (HCC) is a primary contributor to cancer-related mortality on a global scale. However, the underlying molecular mechanisms are still poorly understood. Long noncoding RNAs are emerging markers for HCC diagnosis, prognosis, and therapeutic target. No study of LINC01767 in HCC was published.
AIM
To conduct a multi-omics analysis to explore the roles of LINC01767 in HCC for the first time.
METHODS
DESeq2 Package was used to analyze different gene expressions. Receiver operating characteristic curves assessed the diagnostic performance. Kaplan-Meier univariate and Cox multivariate analyses were used to perform survival analysis. The least absolute shrinkage and selection operator (LASSO)-Cox was used to identify the prediction model. Subsequent to the validation of LINC01767 expression in HCC fresh frozen tissues through quantitative real time polymerase chain reaction, next generation sequencing was performed following LINC01767 over expression (GSE243371), and Gene Ontology/Kyoto Encyclopedia of Genes and Genomes/Gene Set Enrichment Analysis/ingenuity pathway analysis was carried out. experiment in Huh7 cell was carried out.
RESULTS
LINC01767 was down-regulated in HCC with a log fold change = 1.575 and was positively correlated with the cancer stemness. LINC01767 was a good diagnostic marker with area under the curve (AUC) [0.801, 95% confidence interval (CI): 0.751-0.852, = 0.0106] and an independent predictor for overall survival (OS) with hazard ratio = 1.899 (95%CI: 1.01-3.58, = 0.048). LINC01767 nomogram model showed a satisfied performance. The top-ranked regulatory network analysis of LINC01767 showed the regulation of genes participating various pathways. LASSO regression identified the 9-genes model showing a more satisfied performance than 5-genes model to predict the OS with AUC > 0.75. LINC01767 was down-expressed obviously in tumor than para-tumor tissues in our cohort as well as in cancer cell line; the over expression of LINC01767 inhibit cell proliferation and clone formation of Huh7 .
CONCLUSION
LINC01767 was an important tumor suppressor gene in HCC with good diagnostic and prognostic performance.
PubMed: 38948436
DOI: 10.4254/wjh.v16.i6.932 -
World Journal of Experimental Medicine Jun 2024Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen... (Review)
Review
Mitochondrial dysfunction is a key driver of cardiovascular disease (CVD) in metabolic syndrome and diabetes. This dysfunction promotes the production of reactive oxygen species (ROS), which cause oxidative stress and inflammation. Angiotensin II, the main mediator of the renin-angiotensin-aldosterone system, also contributes to CVD by promoting ROS production. Reduced activity of sirtuins (SIRTs), a family of proteins that regulate cellular metabolism, also worsens oxidative stress. Reduction of energy production by mitochondria is a common feature of all metabolic disorders. High SIRT levels and 5' adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta, which promotes ketosis. Ketosis, in turn, increases autophagy and mitophagy, processes that clear cells of debris and protect against damage. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of drugs used to treat type 2 diabetes, have a beneficial effect on these mechanisms. Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events. SGLT2i also increase mitochondrial efficiency, reduce oxidative stress and inflammation, and strengthen tissues. These findings suggest that SGLT2i hold great potential for the treatment of CVD. Furthermore, they are proposed as anti-aging drugs; however, rigorous research is needed to validate these preliminary findings.
PubMed: 38948421
DOI: 10.5493/wjem.v14.i2.91519 -
Infectious Medicine Jun 2024Swift and accurate detection of , which is a prominent causative pathogen associated with seafood contamination, is required to effectively combat foodborne disease and...
BACKGROUND
Swift and accurate detection of , which is a prominent causative pathogen associated with seafood contamination, is required to effectively combat foodborne disease and wound infections. The gene is relatively conserved within and is primarily involved in the expression and regulation of virulence genes with a notable degree of specificity. The aim of this study was to develop a rapid, simple, and constant temperature detection method for in clinical and nonspecialized laboratory settings.
METHODS
In this study, specific primers and CRISPR RNA were used to target the gene to construct a reaction system that combines recombinase polymerase amplification (RPA) with CRISPR‒Cas13a. The whole-genome DNA of the sample was extracted by self-prepared sodium dodecyl sulphate (SDS) nucleic acid rapid extraction reagent, and visual interpretation of the detection results was performed by lateral flow dipsticks (LFDs).
RESULTS
The specificity of the RPA-CRISPR/Cas13a-LFD method was validated using strain ATCC-17802 and six other non-parahaemolytic species. The results demonstrated a specificity of 100%. Additionally, the genomic DNA of was serially diluted and analysed, with a minimum detectable limit of 1 copy/µL for this method, which was greater than that of the TaqMan-qPCR method (10 copies/µL). The established methods were successfully applied to detect wild-type , yielding results consistent with those of TaqMan-qPCR and MALDI-TOF MS mass spectrometry identification. Finally, the established RPA-CRISPR/Cas13a-LFD method was applied to whole blood specimens from mice infected with , and the detection rate of by this method was consistent with that of the conventional PCR method.
CONCLUSIONS
In this study, we describe an RPA-CRISPR/Cas13a detection method that specifically targets the gene and offers advantages such as simplicity, rapidity, high specificity, and visual interpretation. This method serves as a valuable tool for the prompt detection of in nonspecialized laboratory settings.
PubMed: 38948389
DOI: 10.1016/j.imj.2024.100111 -
Frontiers in Bioengineering and... 2024The simulation-to-reality (sim2real) problem is a common issue when deploying simulation-trained models to real-world scenarios, especially given the extremely high...
The simulation-to-reality (sim2real) problem is a common issue when deploying simulation-trained models to real-world scenarios, especially given the extremely high imbalance between simulation and real-world data (scarce real-world data). Although the cycle-consistent generative adversarial network (CycleGAN) has demonstrated promise in addressing some sim2real issues, it encounters limitations in situations of data imbalance due to the lower capacity of the discriminator and the indeterminacy of learned sim2real mapping. To overcome such problems, we proposed the imbalanced Sim2Real scheme (ImbalSim2Real). Differing from CycleGAN, the ImbalSim2Real scheme segments the dataset into paired and unpaired data for two-fold training. The unpaired data incorporated discriminator-enhanced samples to further squash the solution space of the discriminator, for enhancing the discriminator's ability. For paired data, a term targeted regression loss was integrated to ensure specific and quantitative mapping and further minimize the solution space of the generator. The ImbalSim2Real scheme was validated through numerical experiments, demonstrating its superiority over conventional sim2real methods. In addition, as an application of the proposed ImbalSim2Real scheme, we designed a finger joint stiffness self-sensing framework, where the validation loss for estimating real-world finger joint stiffness was reduced by roughly 41% compared to the supervised learning method that was trained with scarce real-world data and by 56% relative to the CycleGAN trained with the imbalanced dataset. Our proposed scheme and framework have potential applicability to bio-signal estimation when facing an imbalanced sim2real problem.
PubMed: 38948382
DOI: 10.3389/fbioe.2024.1334643 -
Frontiers in Genetics 2024The DNA damage repair (DDR) system in human genome is pivotal in maintaining genomic integrity. Pathogenic variation (PV) in DDR genes impairs their function, leading to...
INTRODUCTION
The DNA damage repair (DDR) system in human genome is pivotal in maintaining genomic integrity. Pathogenic variation (PV) in DDR genes impairs their function, leading to genome instability and increased susceptibility to diseases, especially cancer. Understanding the evolution origin and arising time of DDR PV is crucial for comprehending disease susceptibility in modern humans.
METHODS
We used big data approach to identify the PVs in DDR genes in modern humans. We mined multiple genomic databases derived from 251,214 modern humans of African and non-Africans. We compared the DDR PVs between African and non-African. We also mined the DDR PVs in the genomic data derived from 5,031 ancient humans. We used the DDR PVs from ancient humans as the intermediate to further the DDR PVs between African and non-African.
RESULTS AND DISCUSSION
We identified 1,060 single-base DDR PVs across 77 DDR genes in modern humans of African and non-African. Direct comparison of the DDR PVs between African and non-African showed that 82.1% of the non-African PVs were not present in African. We further identified 397 single-base DDR PVs in 56 DDR genes in the 5,031 ancient humans dated between 45,045 and 100 years before present (BP) lived in Eurasian continent therefore the descendants of the latest out-of-Africa human migrants occurred 50,000-60,000 years ago. By referring to the ancient DDR PVs, we observed that 276 of the 397 (70.3%) ancient DDR PVs were exclusive in non-African, 106 (26.7%) were shared between non-African and African, and only 15 (3.8%) were exclusive in African. We further validated the distribution pattern by testing the PVs in and , two of the important genes in genome stability maintenance, in African, non-African, and Ancient humans. Our study revealed that DDR PVs in modern humans mostly emerged after the latest out-of-Africa migration. The data provides a foundation to understand the evolutionary basis of disease susceptibility, in particular cancer, in modern humans.
PubMed: 38948361
DOI: 10.3389/fgene.2024.1408952 -
Psychology Research and Behavior... 2024Money source influences risk-taking behaviors. Although studies consistently indicated that individuals demonstrate a higher propensity to make risky investments when...
INTRODUCTION
Money source influences risk-taking behaviors. Although studies consistently indicated that individuals demonstrate a higher propensity to make risky investments when utilizing non-labor income as opposed to labor income, explanations as to why non-labor income leads to continuously blowing money into risky investments are scarce.
METHODS
The current study leverages a computational modeling approach to compare the differences in the dynamic risk investment process among individuals endowed with income from different sources (ie, non-labor income vs labor income) to understand the shaping force of higher risk-taking propensity in individuals with non-labor income. A total of 103 participants were recruited and completed the Balloon Analogue Risk Task (BART) with an equal monetary endowment, either as a token for completion of survey questionnaires (representing labor income) or as a prize from a lucky draw game (representing non-labor income).
RESULTS
We found that individuals endowed with non-labor income made more risky investments in BART compared to those with labor income. With computational modeling, we further identified two key differences in the dynamic risk investment processes between individuals endowed with labor and those with non-labor income. Specifically, individuals endowed with non-labor income had a higher preset expectation for risk-taking and displayed desensitization towards losses during risk investments, in contrast to individuals with labor income.
DISCUSSION
This study contributed to a better understanding of the psychological mechanisms of why individuals make more risk-taking behaviors with non-labor income, namely higher preset expectations of risk-taking and desensitization towards losses. Future research could validate these findings across diverse samples with varying backgrounds and adopt different manipulations of labor and non-labor income to enhance the external validity of our study.
PubMed: 38948335
DOI: 10.2147/PRBM.S462466