[Identification of Osteoarthritis Inflamm-Aging Biomarkers by Integrating Bioinformatic Analysis and Machine Learning Strategies and the Clinical Validation]. / ç”Ÿç‰©ä¿¡æ¯å­¦å’Œæœºå™¨å­¦ä¹ ç­–ç•¥è¯†åˆ«éª¨å ³èŠ‚ç‚Žç‚Žæ€§è¡°è€ç”Ÿç‰©æ ‡å¿—ç‰©ä¸Žä¸´åºŠéªŒè¯.

Objective: To identify inflamm-aging related biomarkers in osteoarthritis (OA). Methods: Microarray gene profiles of young and aging OA patients were obtained from the Gene Expression Omnibus (GEO) database and aging-related genes (ARGs) were obtained from the Human Aging Genome Resource (HAGR) database. The differentially expressed genes of young OA and older OA patients were screened and then intersected with ARGs to obtain the aging-related genes of OA. Enrichment analysis was performed to reveal the potential mechanisms of aging-related markers in OA. Three machine learning methods were used to identify core senescence markers of OA and the receiver operating characteristic (ROC) curve was used to assess their diagnostic performance. Peripheral blood mononuclear cells were collected from clinical OA patients to verify the expression of senescence-associated secretory phenotype (SASP) factors and senescence markers. Results: A total of 45 senescence-related markers were obtained, which were mainly involved in the regulation of cellular senescence, the cell cycle, inflammatory response, etc. Through the screening with the three machine learning methods, 5 core senescence biomarkers, including FOXO3, MCL1, SIRT3, STAG1, and S100A13, were obtained. A total of 20 cases of normal controls and 40 cases of OA patients, including 20 cases in the young patient group and 20 in the elderly patient group, were enrolled. Compared with those of the young patient group, C-reactive protein (CRP), interleukin (IL)-6, and IL-1ß levels increased and IL-4 levels decreased in the elderly OA patient group (P<0.01); FOXO3, MCL1, and SIRT3 mRNA expression decreased and STAG1 and S100A13 mRNA expression increased (P<0.01). Pearson correlation analysis demonstrated that the selected markers were associated with some indicators, including erythrocyte sedimentation rate (ESR), IL-1ß, IL-4, CRP, and IL-6. The area under the ROC curve of the 5 core aging genes was always greater than 0.8 and the C-index of the calibration curve in the nomogram prediction model was 0.755, which suggested the good calibration ability of the model. Conclusion: FOXO3, MCL1, SIRT3, STAG1, and S100A13 may serve as novel diagnostic biomolecular markers and potential therapeutic targets for OA inflamm-aging.

Integrating clinical data mining, network analysis and experimental validation reveal the anti-inflammatory mechanism of Huangqin Qingre Chubi Capsule in rheumatoid arthritis treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqin Qingre Chubi Capsule (HQC) is a Chinese medicinal compound used for the treatment of damp-heat pattern rheumatism, guided by the traditional Chinese medicine syndrome differentiation practice. HQC has been used in the clinical treatment of rheumatic diseases for more than 20 years with remarkable efficacy. HQC has been experimentally shown to exert anti-arthritic effects via the Wnt signaling pathway. AIM OF THE STUDY: This study used clinical data mining, network analysis, and in vitro and in vivo tests to investigate the anti-arthritic and possible anti-inflammatory mechanism of HQC. Specifically, emphasis was placed on the function of the hsa_circ_0091,685/EIF4A3/IL-17 axis in the anti-inflammatory process. MATERIALS AND METHODS: A random walk model was used to evaluate the effects of HQC on clinical immune inflammatory marker function in patients with RA. Network analysis was used to predict the potential target genes and pathways of HQC. Hematoxylin & eosin, safranin O-fast green and toluidine blue staining, immunohistochemistry, and transmission electron microscopy were performed to evaluate the anti-arthritic effects of HQC in rat models. Cell Counting Kit-8 assay, quantitative real-time polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, and RNA pull-down were used to study the anti-proliferation and anti-inflammatory mechanisms of HQC. RESULTS: Patients with RA who underwent HQC treatment showed a significant reduction in inflammatory response levels, according to retrospective clinical study. Network analysis revealed that HQC potentially targeted genes and pathways related to inflammation, especially IL-6, IL-17, TNF-α, IL-23, and IL-17 signaling pathway. Animal experiments showed that HQC inhibits inflammation through the IL-17 signaling pathway in rat models. Cellular experiments showed that HQC-containing serum inhibited the inflammatory response in patients with RA-FLS or RA by blocking hsa_circ_0091,685 and EIF4A3 expression. CONCLUSION: In RA patients, HQC reduces the inflammatory response. The antiproliferative and anti-inflammatory qualities of HQC are responsible for its therapeutic impact. The suppression of the hsa_circ_0091,685/EIF4A3/IL-17 axis was linked to these favorable outcomes.

Association between traditional Chinese Medicine and osteoarthritis outcome: A 5-year matched cohort study.

Objective: The aim of this study was to investigate the relationship between Traditional Chinese medicine (TCM) and pain reduction, hospital readmission, and joint replacement in patients with osteoarthritis (OA). Chinese herbal medicine (CHM) prescription patterns were further analyzed to confirm the association with prognosis and quality of life in OA patients. Methods: We retrospectively followed 3,850 hospitalized patients with osteoarthritis between January 2018 and December 2022 using the hospital's HIS system. Propensity score matching (PSM) was used for data matching. Cox's proportional risk model was used to assess the impact of various factors on the outcomes of patients with OA, including pain worsening, readmission, and joint replacement. The Kaplan-Meier survival curve was applied to determine the impact of TCM intervention time on patient outcomes. Data mining methods including association rules, cluster analysis, and random walks have been used to assess the efficacy of TCM. Results: The utilization rate of TCM in OA patients was 67.01% (2,511/3,747). After PSM matching, 1,228 TCM non-user patients and 1,228 TCM user patients were eventually included. The outcomes of pain worsening, re-admission rate, and joint replacement rate of the TCM non-user group were observably higher than those of the TCM user group with OA (p < 0.05). Based on the Cox proportional risk model, TCM is an independent protective factor. Compared with non-TCM users, TCM users had 58.4% lower rates of pain, 51.1% lower rates of re-admission, and 42% lower rates of joint replacement. In addition, patients in the high-exposure subgroup (TCM＞24 months) had a markedly lower risk of outcome events than those in the low-exposure subgroup (TCM ≤24 months). Data mining methods have shown that TCM therapy can significantly improve immune-inflammatory indices, VAS scores, and SF-36 scale scores in OA patients. Conclusion: s TCM acts as a protective factor to improve the prognosis of patients with OA, and the benefits of long-term use of herbal medicines are even greater.

Traditional Chinese Medicine is Associated with the Reduction in Endpoint Events in Patients with Gouty Arthritis: Cohort Study and Association Rule Analysis.

Objective: This study aimed to evaluate the effect of traditional Chinese medicine (TCM) on endpoint events in patients with gouty arthritis (GA). Methods and Materials: A total of 2091 hospitalized GA patients were followed up by telephone, and propensity score matching (PSM) was used to reduce potential bias in the study design. Cox proportional risk model and Kaplan-Meier survival curve were utilized to analyze the impact and time effect of factors on the readmission of GA patients. The differences of laboratory indexes before and after treatment between the low and high exposure groups were compared, and the types and frequencies of medicines in all patients were counted. Association rule analysis was performed to investigate the association between TCM and test indexes or endpoint events. Results: After 1:1 PSM, 187 patients were enrolled in the TCM group and 187 patients in the non-TCM group. The incidence of readmission, new tophus, and all-cause death was lower in the TCM group than that in the non-TCM group (P < 0.05). Cox proportional risk regression analysis showed that TCM, NSAIDs and uric acid lowering drug were independent protective factors for GA readmission. The protective effect was enhanced by the prolongation of TCM treatment and the drug combinations. Kaplan-Meier survival curves indicated a significantly lower readmission rate in the high exposure group than in the low exposure group (P < 0.01). Compared with before treatment, NLR, hs-CRP, UA, TC and other laboratory indexes of the low and high exposure groups were improved after treatment (P < 0.01); The improvement of TG and TC in the high exposure group was more significant than the low exposure group (P < 0.01). The analysis of medicines used by all patients identified the top 20 Chinese herbal medicines and the top 2 Chinese patent medicines. The core drugs identified through association rule analysis that can improve test index and reduce the incidence of endpoint events include Yiyiren, Danshen, and HQC, among others. The network diagram of association rule analysis intuitively shows the relationship between core drugs and "improvement of indicators" and "the absence of endpoint events". Conclusion: TCM is associated with a reduced incidence of endpoint events in patients with GA.

Systemic inflammation response index as an emerging biomarker in osteoarthritis patients: a bibliometric and large sample retrospective investigation.

OBJECTIVES: To determine the value of the whole-blood inflammatory response index as an emerging biomarker for the assessment of disease activity in osteoarthritis (OA). METHODS: Extensive analysis of the literature on OA and whole-blood inflammatory indicators were provided through a bibliometric approach. Clinical characteristics and indicators of OA patients and healthy controls (HC) were retrospectively analysed. Four whole-blood inflammatory response indices - neutrophil/lymphocyte count (NLR), platelet/lymphocyte count (PLR), monocyte/lymphocyte count (MLR), and systemic inflammation response index (SIRI), as well as clinical traits like the OA patient's self-perception and immune-inflammatory indicators were analysed for correlations. Cut-off values were determined using receiver operating characteristic (ROC) curves, and they were subsequently employed in logistic regression models to work out whole-blood inflammatory indices and disease activity. RESULTS: The pathophysiology of osteoarthritis has received most of the spotlight in literature studies of OA and whole-blood inflammation indicators. The "inflammation", "osteoarthritis" and "disease activity" were the top 3 key word clusters. Retrospective analysis showed that MLR, NLR, PLR, and SIRI were markedly higher in OA subjects compared to HC subjects. ROC curve consequences manifested that SIRI and NLR could separate OA from healthy controls. NLR, PLR, MLR, and SIRI proved to be related to immune-inflammatory markers, visual analogue scale (VAS) scores, and short-form (SF)-36 scores with regard to correlation analysis and association criteria. Logistic regression manifested that SIRI, NLR, and C-reactive protein (CRP) forecasted disease activity, however, the model that combined SIRI and CRP was superior to CRP alone. CONCLUSIONS: SIRI may serve as a non-invasive, appropriate biomarker to correlate with disease activity.

[Correlation of traditional Chinese medicine to reduced re-admission risk in ankylosing spondylitis patients with dampness-heat syndrome: a retrospective cohort study].

This study aimed to analyze the impact of traditional Chinese medicine(TCM) on the risk of re-admission for ankylosing spondylitis(AS) patients with dampness-heat syndrome. In this study, a telephone follow-up was conducted on 1 295 AS inpatients, and after screening and exclusions, 1 044 successfully followed-up patients were included. A retrospective cohort study was conducted using propensity score matching(PSM), and a Cox proportional risk model was employed to assess the effect of various factors on the risk of re-admission for AS patients with dampness-heat syndrome. Kaplan-Meier survival curves were used to analyze the effect of TCM intervention time on re-admission. The incidence rate of dampness-heat syndrome in AS patients was found to be 51.3% in this study. After 1∶1 PSM, 385 AS patients with dampness-heat syndrome and 385 AS patients without dampness-heat syndrome were included for analysis. The results indicated that the re-admission rate was higher for patients with dampness-heat syndrome compared with those without dampness-heat syndrome(P<0.05). AS patients with dampness-heat syndrome in the TCM group had a lower admission rate than those in the non-TCM group(P=0.01). The cox proportional risk model demonstrated that TCM was an independent protective factor, as it reduced the risk of re-admission by 35%(HR=0.35, 95%CI[0.26, 0.95], P<0.05). Moreover, the subgroup with high exposure(time to use Chinese medicine >12 months) had a significantly lower risk of re-admission than that with low TCM exposure(time to use Chinese medicine ≤12 months). The re-admission rate for AS patients with dampness-heat syndrome was higher than that without dampness-heat syndrome, and TCM was identified as a protective factor in reducing the risk of re-admission. Furthermore, a longer duration of TCM intervention was associated with a lower risk of re-admission.

Huangqin Qingre Chubi Capsule is Associated with Reduced Risk of Readmission in Patients with Rheumatoid Arthritis: A Real-World Retrospective Cohort Study.

Purpose: The therapeutic effects of Huangqin Qingre Chubi (HQC) in rheumatoid arthritis (RA) have been documented. However, there is a lack of real-world clinical evidence supporting its efficacy. Methods: Patients diagnosed with RA were recruited from the First Affiliated Hospital of the Anhui University of Chinese Medicine. Patient information was obtained from the hospital's database. Propensity score matching (PSM), Kaplan-Meier curve, and Cox proportional hazards model were used to control confounding factors and analyze the factors influencing readmission. Association rule analysis and random walk evaluation models were used to evaluate the correlations among HQC treatment, inflammation indicators, and self-perception of patients (SPP) scale. Results: After PSM, 3423 patients were enrolled, with 1142 in the HQC group and 2281 in the non-HQC group. The readmission risk of the HQC group was significantly lower than that of the non-HQC group. Combined univariate and multivariate analysis results revealed that risk factors for readmission were age >60 years, female sex, hypertension, chronic gastritis, and elevated levels of laboratory indices, including anticyclic citrullinated peptide and complement component 3 (C3) and C4. HQC, disease-modifying antirheumatic drugs, nonsteroidal anti-inflammatory drugs, and glucocorticoid therapy were protective factors for readmission. HQC treatment was closely associated with improvements in many factors, including erythrocyte sedimentation rate, C-reactive protein, C3, rheumatoid factor levels, visual analog scale, depression self-assessment scale, and patient-reported activity index scores with RA. Conclusion: HQC treatment can reduce the risk of readmission and significantly improve immune inflammatory indicators and SPP in patients with RA, with no risk of hepatorenal toxicity.

[Identification of Characteristic lncRNA Molecular Markers in Osteoarthritis by Integrating GEO Database and Machine Learning Strategies and Experimental Validation].

Objective: To screen for long non-coding RNA (lncRNA) molecular markers characteristic of osteoarthritis (OA) by utilizing the Gene Expression Omnibus (GEO) database combined with machine learning. Methods: The samples of 185 OA patients and 76 healthy individuals as normal controls were included in the study. GEO datasets were screened for differentially expressed lncRNAs. Three algorithms, the least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF), were used to screen for candidate lncRNA models and receiver operating characteristic (ROC) curves were plotted to evaluate the models. We collected the peripheral blood samples of 30 clinical OA patients and 15 health controls and measured the immunoinflammatory indicators. RT-PCR was performed for quantitative analysis of the expression of lncRNA molecular markers in peripheral blood mononuclear cells (PBMC). Pearson analysis was performed to examine the correlation between lncRNA and indicators for inflammation of the immune system. Results: A total of 14 key markers were identified with LASSO, 6 genes were identified with SVM-RFE, and 24 genes were identified with RF. Venn diagram was used to screen for overlapping genes identified with the three algorithms, showing HOTAIR, H19, MIR155 HG, and NKILA to be the overlapping genes. The ROC curves showed that these four lncRNAs all had an area under the curve ( AUC) greater than 0.7. The RT-PCR findings revealed relatively elevated expression of HOTAIR, H19, and MIR155HG and decreased expression of NKILA in the PBMC of OA patients compared with those of the normal group ( P<0.01). The results were consistent with the bioinformatics predictions. Pearson analysis showed that the candidate lncRNAs were correlated with clinical indicators for inflammation. Conclusion: HOTAIR, H19, MIR155 HG, and NKILA can be used as molecular markers for the clinical diagnosis of OA and are correlate with clinical indicators of inflammation of the immune system.

The Independent Value of Neutrophil to Lymphocyte Ratio in Gouty Arthritis: A Narrative Review.

Since the incidence of gouty arthritis (GA) exhibits yearly increases, accurate assessment and early treatment have significant values for improving disease conditions and monitoring prognosis. Neutrophil to lymphocyte ratio (NLR) is a common indicator in blood routine, which has the characteristics of easy access and low cost. In recent years, NLR has been proven to be an effective indicator for guiding the diagnosis, treatment, and prognosis of various diseases. Moreover, NLR has varying degrees of relationship with various inflammatory biomarkers, which can affect and reflect the inflammatory response in the body. This paper reviews the independent value of NLR for GA and its underlying molecular pathological mechanisms, intending to contribute to the further application of NLR.

The Diagnostic Features of Peripheral Blood Biomarkers in Identifying Osteoarthritis Individuals: Machine Learning Strategies and Clinical Evidence.

BACKGROUND: People with osteoarthritis place a huge burden on society. Early diagnosis is essential to prevent disease progression and to select the best treatment strategy more effectively. In this study, the aim was to examine the diagnostic features and clinical value of peripheral blood biomarkers for osteoarthritis. OBJECTIVE: The goal of this project was to investigate the diagnostic features of peripheral blood and immune cell infiltration in osteoarthritis (OA). METHODS: Two eligible datasets (GSE63359 and GSE48556) were obtained from the GEO database to discern differentially expressed genes (DEGs). The machine learning strategy was employed to filtrate diagnostic biomarkers for OA. Additional verification was implemented by collecting clinical samples of OA. The CIBERSORT website estimated relative subsets of RNA transcripts to evaluate the immune-inflammatory states of OA. The link between specific DEGs and clinical immune-inflammatory markers was found by correlation analysis. RESULTS: Overall, 67 robust DEGs were identified. The nuclear receptor subfamily 2 group C member 2 (NR2C2), transcription factor 4 (TCF4), stromal antigen 1 (STAG1), and interleukin 18 receptor accessory protein (IL18RAP) were identified as effective diagnostic markers of OA in peripheral blood. All four diagnostic markers showed significant increases in expression in OA. Analysis of immune cell infiltration revealed that macrophages are involved in the occurrence of OA. Candidate diagnostic markers were correlated with clinical immune-inflammatory indicators of OA patients. CONCLUSION: We highlight that DEGs associated with immune inflammation (NR2C2, TCF4, STAG1, and IL18RAP) may be potential biomarkers for peripheral blood in OA, which are also associated with clinical immune-inflammatory indicators.

Regulation of autophagy by circular RNAs in rheumatoid arthritis: Potential targets of action.

Previous studies have shown that autophagic pathogenesis of rheumatoid arthritis (RA) is regulated by circular RNAs (circRNAs), which accelerate bone damage by participating in the immune inflammatory response. Therefore, exploring the mechanisms underlying circRNA regulation of autophagy is essential for maintaining homeostasis of the skeletal microenvironment in RA and may improve our understanding of the specific pathways involved in the development of therapeutics. In this review, we discuss autophagic imbalance in RA and the regulatory mechanisms of circRNAs. We also explore possible targets for circRNA regulation of autophagy in RA, which may provide us with improved knowledge regarding the pathogenesis of RA.

Targeting non-coding RNA H19: A potential therapeutic approach in pulmonary diseases.

Non-coding RNA is still one of the most popular fields in biology research. In recent years, people paid more attention to the roles of H19 in lung diseases, which expressed abnormally in various pathological process. Therefore, this review focus on the regulatory role of H19 in asthma, pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), lung injury, pneumonia, lung cancer, etc. And the potential therapeutic agents and molecular treatments of H19 are collected. The aim is to demonstrate its underlying mechanism in pulmonary diseases and to guide the basic research targeting H19 into clinical drug translation.

The Link between Circadian Clock Genes and Autophagy in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD), a progressive respiratory disease, is characterized by the alveolar epithelium injury and persistent airway inflammation. It is documented that oscillation and dysregulated expression of circadian clock genes, like Bmal1, Per1, and Per2, involved in COPD pathogenies, including chronic inflammation and imbalanced autophagy level, and targeting the associations of circadian rhythm and autophagy is promising strategies in the management and treatment of COPD. Herein, we reviewed the mechanisms of the circadian clock and the unbalance of the autophagic level in COPD, as well as the link between the two, so as to provide further theoretical bases for the study on the pathogenesis of COPD.

[Effect of human telomerase reverse transcriptase gene antisense oligonucleotide on sensitivity of gemcitabine in pancreatic cancer cell].

OBJECTIVE: To evaluate whether antisense oligonucleotides (ASODN) targeting hTERT mRNA could sensitize human pancreatic cancer cell to gemcitabine in vitro. METHODS: hTERT mRNA expression was measured by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) assay. Telomerase activity was examined by TRAP, polyacrylamide gel electrophoresis and silver staining. The proliferation capacity and the apoptosis of cancer cells were evaluated by MTT assay and double staining with both Annexin V-FITC and PI. RESULTS: Transient transfection in human pancreatic cancer cell with hTERT ASODN diminished the abundance of hTERT mRNA in a concentration-dependent fashion. And 0.2 micromol/L ASODN decreased the telomerase activity by 0.47-fold in cancer cell. The IC(50) value of gemcitabine in ASODN-transfected cell was (0.8 +/- 0.2) micromol/L while that in oligofectamine-transfected control cell (7.3 +/- 0.9) micromol/L with a statistically significant difference. hTERT ASODN significantlly increased the gemcitabine-induced apoptosis rate in pancreatic cancer cell. The gemcitabine-induced apoptosis rate in ASODN-transfected cell was 60.28% while that in oligofectamine-transfected control cell 17.34%. CONCLUSION: hTERT antisense oligodeoxynucleotide can increase the sensitivity of pancreatic cancer cell to gemcitabine. The mechanism may be due to the down-regulated expression of hTERT mRNA and telomerase activity.

Antitumor efficacy of human telomerase reverse transcriptase gene antisense oligonucleotide in pancreatic cancer cells.

Human telomerase reverse transcriptase (hTERT) is the key component of telomerase catalytic activity, and is associated with tumorigenesis. Recent evidence suggests that the down-regulation of hTERT could rapidly induce an antiproliferative effect in tumor cells, independent of the telomere-elongating function of the enzyme. To test the immediate antitumor efficacy of this down-regulation, antisense oligodeoxynucleotides (AS-ODN) targeting hTERT mRNA were transfected into two human pancreatic cancer cell lines in vitro. In both cell lines, single transfection with AS-ODN decreased the level of hTERT mRNA expression in a dose-dependent manner (from 0.05 to 0.2 µM), while transfection with 0.2 µM hTERT AS-ODN for 24 h achieved the maximum down-regulation of hTERT mRNA. Additionally, 0.2 µM AS-ODN significantly reduced telomerase activity in the cell lines. However, after the first transfection with 0.2 µM AS-ODN, almost no inhibition of cell proliferation was observed in either of the lines, while multiple consecutive transfections with the same concentration of AS-ODN resulted in a continuous reduction in cell viability, the significant inhibition of colony formation ability and increased cell apoptotic rates. Cell cycle analysis indicated that hTERT AS-ODN mainly arrested the cell cycle at the G0/G1 phase in the cells. The data validate an antisense oligonucleotide approach to hTERT inhibition therapy in pancreatic cancer cells.