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Genetic associations in ankylosing spondylitis: circulating proteins as drug targets and biomarkers.Frontiers in Immunology 2024Ankylosing spondylitis (AS) is a complex condition with a significant genetic component. This study explored circulating proteins as potential genetic drug targets or...
BACKGROUND
Ankylosing spondylitis (AS) is a complex condition with a significant genetic component. This study explored circulating proteins as potential genetic drug targets or biomarkers to prevent AS, addressing the need for innovative and safe treatments.
METHODS
We analyzed extensive data from protein quantitative trait loci (pQTLs) with up to 1,949 instrumental variables (IVs) and selected the top single-nucleotide polymorphism (SNP) associated with AS risk. Utilizing a two-sample Mendelian randomization (MR) approach, we assessed the causal relationships between identified proteins and AS risk. Colocalization analysis, functional enrichment, and construction of protein-protein interaction networks further supported these findings. We utilized phenome-wide MR (phenMR) analysis for broader validation and repurposing of drugs targeting these proteins. The Drug-Gene Interaction database (DGIdb) was employed to corroborate drug associations with potential therapeutic targets. Additionally, molecular docking (MD) techniques were applied to evaluate the interaction between target protein and four potential AS drugs identified from the DGIdb.
RESULTS
Our analysis identified 1,654 plasma proteins linked to AS, with 868 up-regulated and 786 down-regulated. 18 proteins (AGER, AIF1, ATF6B, C4A, CFB, CLIC1, COL11A2, ERAP1, HLA-DQA2, HSPA1L, IL23R, LILRB3, MAPK14, MICA, MICB, MPIG6B, TNXB, and VARS1) that show promise as therapeutic targets for AS or biomarkers, especially MAPK14, supported by evidence of colocalization. PhenMR analysis linked these proteins to AS and other diseases, while DGIdb analysis identified potential drugs related to MAPK14. MD analysis indicated strong binding affinities between MAPK14 and four potential AS drugs, suggesting effective target-drug interactions.
CONCLUSION
This study underscores the utility of MR analysis in AS research for identifying biomarkers and therapeutic drug targets. The involvement of Th17 cell differentiation-related proteins in AS pathogenesis is particularly notable. Clinical validation and further investigation are essential for future applications.
Topics: Spondylitis, Ankylosing; Humans; Biomarkers; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Protein Interaction Maps; Genetic Predisposition to Disease; Blood Proteins; Mendelian Randomization Analysis; Molecular Docking Simulation; Genome-Wide Association Study
PubMed: 38835753
DOI: 10.3389/fimmu.2024.1394438 -
Intelligent bell facial paralysis assessment: a facial recognition model using improved SSD network.Scientific Reports Jun 2024With the continuous progress of technology, the subject of life science plays an increasingly important role, among which the application of artificial intelligence in...
With the continuous progress of technology, the subject of life science plays an increasingly important role, among which the application of artificial intelligence in the medical field has attracted more and more attention. Bell facial palsy, a neurological ailment characterized by facial muscle weakness or paralysis, exerts a profound impact on patients' facial expressions and masticatory abilities, thereby inflicting considerable distress upon their overall quality of life and mental well-being. In this study, we designed a facial attribute recognition model specifically for individuals with Bell's facial palsy. The model utilizes an enhanced SSD network and scientific computing to perform a graded assessment of the patients' condition. By replacing the VGG network with a more efficient backbone, we improved the model's accuracy and significantly reduced its computational burden. The results show that the improved SSD network has an average precision of 87.9% in the classification of light, middle and severe facial palsy, and effectively performs the classification of patients with facial palsy, where scientific calculations also increase the precision of the classification. This is also one of the most significant contributions of this article, which provides intelligent means and objective data for future research on intelligent diagnosis and treatment as well as progressive rehabilitation.
Topics: Humans; Bell Palsy; Neural Networks, Computer; Female; Male; Facial Expression; Adult; Artificial Intelligence; Middle Aged; Facial Paralysis; Facial Recognition; Automated Facial Recognition
PubMed: 38834661
DOI: 10.1038/s41598-024-63478-x -
Cancer Immunology, Immunotherapy : CII Jun 2024Patients treated with immune checkpoint inhibitors (ICIs) are at risk of considerable adverse events, and the ongoing struggle is to accurately identify the subset of...
Two nomograms constructed for predicting the efficacy and prognosis of advanced non‑small cell lung cancer patients treated with anti‑PD‑1 inhibitors based on the absolute counts of lymphocyte subsets.
BACKGROUND
Patients treated with immune checkpoint inhibitors (ICIs) are at risk of considerable adverse events, and the ongoing struggle is to accurately identify the subset of patients who will benefit. Lymphocyte subsets play a pivotal role in the antitumor response, this study attempted to combine the absolute counts of lymphocyte subsets (ACLS) with the clinicopathological parameters to construct nomograms to accurately predict the prognosis of advanced non-small cell lung cancer (aNSCLC) patients treated with anti-PD-1 inhibitors.
METHODS
This retrospective study included a training cohort (n = 200) and validation cohort (n = 100) with aNSCLC patients treated with anti-PD-1 inhibitors. Logistic and Cox regression were conducted to identify factors associated with efficacy and progression-free survival (PFS) respectively. Nomograms were built based on independent influencing factors, and assessed by the concordance index (C-index), calibration curve and receiver operating characteristic (ROC) curve.
RESULT
In training cohort, lower baseline absolute counts of CD3 (P < 0.001) and CD4 (P < 0.001) were associated with for poorer efficacy. Hepatic metastases (P = 0.019) and lower baseline absolute counts of CD3 (P < 0.001), CD4 (P < 0.001), CD8 (P < 0.001), and B cells (P = 0.042) were associated with shorter PFS. Two nomograms to predict efficacy at 6-week after treatment and PFS at 4-, 8- and 12-months were constructed, and validated in validation cohort. The area under the ROC curve (AUC-ROC) of nomogram to predict response was 0.908 in training cohort and 0.984 in validation cohort. The C-index of nomogram to predict PFS was 0.825 in training cohort and 0.832 in validation cohort. AUC-ROC illustrated the nomograms had excellent discriminative ability. Calibration curves showed a superior consistence between the nomogram predicted probability and actual observation.
CONCLUSION
We constructed two nomogram based on ACLS to help clinicians screen of patients with possible benefit and make individualized treatment decisions by accurately predicting efficacy and PFS for advanced NSCLC patient treated with anti-PD-1 inhibitors.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Nomograms; Female; Male; Lung Neoplasms; Prognosis; Immune Checkpoint Inhibitors; Retrospective Studies; Middle Aged; Aged; Lymphocyte Subsets; Adult; Lymphocyte Count
PubMed: 38833153
DOI: 10.1007/s00262-024-03738-x -
Journal of Inflammation Research 2024Acute gouty arthritis (AGA) is characterized by the accumulation of monosodium urate crystals within the joints, leading to inflammation and severe pain. Western...
BACKGROUND
Acute gouty arthritis (AGA) is characterized by the accumulation of monosodium urate crystals within the joints, leading to inflammation and severe pain. Western medicine treatments have limitations in addressing this condition. Previous studies have shown the efficacy of Qinpi Tongfeng formula (QPTFF) in treating AGA, but further investigation is needed to understand its mechanism of action.
METHODS
We used ultra-high-performance liquid chromatography tandem Q-Exactive Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-MS) to identify compounds in QPTFF. Target proteins regulated by these compounds were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Chemistry Database, and Swiss Target Prediction Database. AGA-related targets were searched and screened from various databases, including Genecards, PharmGKB, Drugbank, etc. Intersection targets of QPTFF and AGA were analyzed for protein-protein interaction networks, GO function enrichment, and KEGG pathway enrichment. We then verified QPTFF's mechanism of action using an AGA rat model, assessing pathological changes via H&E staining and target expression via ELISA, RT-qPCR, and Western blot.
RESULTS
UHPLC-Q-Orbitrap-MS identified 207 compounds in QPTFF, with 55 selected through network pharmacology. Of 589 compound-regulated targets and 1204 AGA-related targets, 183 potential targets were implicated in QPTFF's treatment of AGA. Main target proteins included IL-1β, NFKBIA, IL-6, TNF, CXCL8, and MMP9, with the IL-17 signaling pathway primarily regulated by QPTFF. Experimental results showed that medium and high doses of QPTFF significantly reduced serum inflammatory factors and MMP-9 expression, and inhibited IL-17A, IL-6, IKK-β, and NF-κB p65 mRNA and protein expression in AGA rats compared to the model group.
CONCLUSION
Key targets of QPTFF include IL-1β, NFKBIA, IL-6, TNF-α, CXCL8, and MMP9. QPTFF effectively alleviates joint inflammation in AGA rats, with high doses demonstrating no liver or kidney toxicity. Its anti-inflammatory mechanism in treating AGA involves the IL-17A/NF-κB p65 signaling pathway.
PubMed: 38828049
DOI: 10.2147/JIR.S454098 -
Frontiers in Pediatrics 2024This study aimed to analyse the research hotspots and frontiers in the field of paediatric fever between 2013 and 2023.
OBJECTIVE
This study aimed to analyse the research hotspots and frontiers in the field of paediatric fever between 2013 and 2023.
METHODS
The included articles were visually analysed using CiteSpace 6.1.R6 software.
RESULTS
A total of 2,662 Chinese-language articles and 1,456 English-language articles were included in the study. Based on the Chinese literature, research groups were identified represented by Xinmin Li, Jinling Hong and Hongshuang Luo. Based on the English literature, research groups were formed represented by Henriette Moll, Santiago Mintegi and Elizabeth Alpern. Tianjin University of Traditional Chinese Medicine was the institution with the largest number of publications in the Chinese literature, and the Centers For Disease Control And Prevention was the institution with the largest number of publications in the English literature. The research on paediatric fever mainly focused on mechanism exploration, green treatment and clinical management.
CONCLUSION
Several relatively stable research groups have been formed. Future studies on the differential diagnosis, rational drug use, standardised management and clinical practice guidelines for paediatric fever are needed.
PubMed: 38827220
DOI: 10.3389/fped.2024.1383342 -
ACS Omega May 2024Curcumin, a compound derived from turmeric, is traditionally utilized in East Asian medicine for treating various health conditions, including epilepsy. Despite its...
Curcumin, a compound derived from turmeric, is traditionally utilized in East Asian medicine for treating various health conditions, including epilepsy. Despite its involvement in numerous cellular signaling pathways, the specific mechanisms and targets of curcumin in epilepsy treatment have remained unclear. Our study focused on identifying the primary targets and functional pathways of curcumin in the brains of epileptic mice. Using drug affinity responsive target stabilization (DARTS) and affinity chromatography, we identified key targets in the mouse brain, revealing 232 and 70 potential curcumin targets, respectively. Bioinformatics analysis revealed a strong association of these proteins with focal adhesions and cytoskeletal components. Further experiments using DARTS, along with immunofluorescence staining and cell migration assays, confirmed curcumin's ability to regulate the dynamics of focal adhesions and influence cell migration. This study not only advances our understanding of curcumin's role in epilepsy treatment but also serves as a model for identifying therapeutic targets in neurological disorders.
PubMed: 38826549
DOI: 10.1021/acsomega.4c00825 -
Discover Oncology Jun 2024Alterations in telomeres constitute some of the earliest occurrences in the tumourigenesis of prostate adenocarcinoma (PRAD) and persist throughout the progression of...
Alterations in telomeres constitute some of the earliest occurrences in the tumourigenesis of prostate adenocarcinoma (PRAD) and persist throughout the progression of the tumour. While the activity of telomerase and the length of telomeres have been demonstrated to correlate with the prognosis of PRAD, the prognostic potential of telomere-related genes (TRGs) in this disease remains unexplored. Utilising mRNA expression data from the Cancer Genome Atlas (TCGA), we devised a risk model and a nomogram to predict the survival outcomes of patients with PRAD. Subsequently, our investigations extended to the relationship between the risk model and immune cell infiltration, sensitivity to chemotherapeutic drugs, and specific signalling pathways. The risk model we developed is predicated on seven key TRGs, and immunohistochemistry results revealed significant differential expression of three TRGs in tumours and paracancerous tissues. Based on the risk scores, PRAD patients were stratified into high-risk and low-risk cohorts. The Receiver operating characteristics (ROC) and Kaplan-Meier survival analyses corroborated the exceptional predictive performance of our novel risk model. Multivariate Cox regression analysis indicated that the risk score was an independent risk factor associated with Overall Survival (OS) and was significantly associated with T and N stages of PRAD patients. Notably, the high-risk group exhibited a greater response to chemotherapy and immunosuppression compared to the low-risk group, offering potential guidance for treatment strategies for high-risk patients. In conclusion, our new risk model, based on TRGs, serves as a reliable prognostic indicator for PRAD. The model holds significant value in guiding the selection of immunotherapy and chemotherapy in the clinical management of PRAD patients.
PubMed: 38825615
DOI: 10.1007/s12672-024-00986-2 -
Frontiers in Immunology 2024Several previous studies have reported an association between rheumatoid arthritis (RA) and epilepsy, but the causal relationship is unclear. The aim of this study was...
BACKGROUND
Several previous studies have reported an association between rheumatoid arthritis (RA) and epilepsy, but the causal relationship is unclear. The aim of this study was to assess the connection between RA and epilepsy in a European population using Mendelian randomization (MR).
METHODS
Genome-wide association study summary data on RA and epilepsy from European populations were included. Univariate MR (UVMR) and multivariate MR were used to investigate the causal relationship between the two conditions. Three analysis methods were applied: inverse variance weight (IVW), MR-Egger, and weighted median, with IVW being the primary method. Cochran Q statistics, MR-PRESSO, MR-Egger intercept, leave-one-out test, and MR-Steiger test were combined for the sensitivity analysis.
RESULTS
UVMR showed a positive association between RA and epilepsy risk (OR=1.038, 95% CI=1.007-1.038, p=0.017) that was supported by sensitivity analysis. Further MVMR after harmonizing the three covariates of hypertension, alcohol consumption, and smoking, confirmed the causal relationship between RA and epilepsy (OR=1.049, 95% CI=1.011-1.087, p=0.010).
CONCLUSION
This study demonstrated that RA is associated with an increased risk of epilepsy. It has emphasized that the monitoring of epilepsy risk in patients diagnosed with RA should be strengthened in clinical practice, and further studies are needed in the future to explore the potential mechanism of action connecting the two conditions.
Topics: Humans; Arthritis, Rheumatoid; Mendelian Randomization Analysis; Epilepsy; Genome-Wide Association Study; Europe; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Risk Factors; Male; Female
PubMed: 38817604
DOI: 10.3389/fimmu.2024.1389549 -
World Journal of Clinical Cases May 2024Lumbar radiculopathy spondylosis is a relatively common orthopedic disease with a high incidence rate. It most commonly occurs in the lumbar 4-5 and lumbar 5-sacral 1...
BACKGROUND
Lumbar radiculopathy spondylosis is a relatively common orthopedic disease with a high incidence rate. It most commonly occurs in the lumbar 4-5 and lumbar 5-sacral 1 vertebrae, which account for approximately 95% of cases. It mostly occurs in people aged 30-50 years old and greatly affects their quality of life.
AIM
To determine the effect of triple-voltage acupuncture combined with helium-neon laser irradiation on the quality of care and improvement of symptoms in patients with lumbar radiculopathy spondylolisthesis.
METHODS
In this study, we selected 120 patients with lumbar radiculopathy spondylosis who were treated at our hospital between June 2019 to June 2020. The patients were divided into control and observation groups according to the random number table method, with 60 patients in each group. Patients in the observation group were treated with three-volt moxibustion combined with helium-neon laser irradiation, and those in the control group were treated with lumbar traction. After 1 month of treatment, the lumbar pain scores, lumbar spine motor functions, clinical treatment effects, and nursing satisfaction of the two groups were compared.
RESULTS
The results showed that acupuncture combined with laser irradiation significantly improved the patients' clinical symptoms, , reduced their low back pain, significantly lower numerical rating scale pain scores in the observation group than in the control group, and better lumbar spine motility than in the control group, compared to lumbar traction. In addition, they were cared for. The treatment effectiveness rate of the observation group was 95.5%, which was significantly higher than that of the control group (81.67%). Satisfaction with care was higher than 90 points in both groups, but the difference was not statistically significant.
CONCLUSION
Our study provides a clinical rationale for the future treatment of patients with lumbar spine disease. However, further extensive research is needed for validation.
PubMed: 38817227
DOI: 10.12998/wjcc.v12.i15.2522 -
Phytomedicine : International Journal... Jul 2024Heart failure is a life-threatening cardiovascular disease and characterized by cardiac hypertrophy, inflammation and fibrosis. The traditional Chinese medicine formula...
Heart failure is a life-threatening cardiovascular disease and characterized by cardiac hypertrophy, inflammation and fibrosis. The traditional Chinese medicine formula Qiangxinyin (QXY) is effective for the treatment of heart failure while the underlying mechanism is not clear. This study aims to identify the active ingredients of QXY and explore its mechanisms protecting against cardiac hypertrophy. We found that QXY significantly protected against isoproterenol (ISO)-induced cardiac hypertrophy and dysfunction in zebrafish. Eight compounds, including benzoylmesaconine (BMA), atractylenolide I (ATL I), icariin (ICA), quercitrin (QUE), psoralen (PRN), kaempferol (KMP), ferulic acid (FA) and protocatechuic acid (PCA) were identified from QXY. PRN, KMP and icaritin (ICT), an active pharmaceutical ingredient of ICA, prevented ISO-induced cardiac hypertrophy and dysfunction in zebrafish. In H9c2 cardiomyocyte treated with ISO, QXY significantly blocked the calcium influx, reduced intracellular lipid peroxidative product MDA, stimulated ATP production and increased mitochondrial membrane potential. QXY also inhibited ISO-induced cardiomyocyte hypertrophy and cytoskeleton reorganization. Mechanistically, QXY enhanced the phosphorylation of Smad family member 2 (SMAD2) and myosin phosphatase target subunit-1 (MYPT1), and suppressed the phosphorylation of myosin light chain (MLC). In conclusion, PRN, KMP and ICA are the main active ingredients of QXY that protect against ISO-induced cardiac hypertrophy and dysfunction largely via the blockage of calcium influx and inhibition of mitochondrial dysfunction as well as cytoskeleton reorganization.
Topics: Animals; Zebrafish; Cardiomegaly; Isoproterenol; Drugs, Chinese Herbal; Myocytes, Cardiac; Membrane Potential, Mitochondrial; Calcium; Rats; Cardiotonic Agents; Cell Line
PubMed: 38810550
DOI: 10.1016/j.phymed.2024.155717