Circadian clock-related genome-wide mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity.

BACKGROUND: Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can contribute to inflammatory diseases such as Ulcerative colitis (UC). This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences. METHODS: Summary statistics of protein, DNA methylation and gene expression quantitative trait loci in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively) were used. Genetic variants located within or near 152 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables. Causal relationships with UC and its comorbidities were then estimated through employed Summary data-based Mendelian Randomization (SMR) and Inverse-Variance-Weighted MR (IVW-MR). RESULTS: Through preliminary SMR analysis, we identified a potential causal relationship between circadian clock-related genes and UC along with its comorbidities, which was further confirmed by IVW-MR analysis. Our study identified strong evidence of positive correlation involving seven overlapping genes (CSNK1E, OPRL1, PIWIL2, RORC, MAX, PPP5C, and AANAT) through MWAS and TWAS in UC, four overlapping genes (OPRL1, CHRNB2, FBXL17, and SIRT1) in UC with PSC, and three overlapping genes (ARNTL, USP7, and KRAS) in UC with arthropathy. CONCLUSIONS: This SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. Furthermore, our investigation pinpointed candidate genes that could potentially serve as drug targets.

Efficacy and immune-inflammatory mechanism of acupuncture-related therapy in animal models of knee osteoarthritis: a preclinical systematic review and network meta-analysis.

BACKGROUND: Many KOA patients have not reached indications for surgery, thus we need to find effective non-surgical treatments. Acupuncture is thought to have the potential to modulate inflammation and cytokines in KOA through the immune system. However, the mechanisms have not been elucidated, and there is no network Meta-analysis of acupuncture on KOA animals. So we evaluate the effect and mechanism of acupuncture-related therapy in KOA animals. METHODS: A comprehensive search was conducted in multiple databases including PubMed, Web of Science, Embase, CBM, CNKI, WanFang, and VIP Database to identify relevant animal studies focusing on acupuncture therapy for KOA. The included studies were assessed for risk of bias using SYRCLE's Risk of Bias tool. Subsequently, pair-wise meta-analysis and network meta-analysis were performed using Stata 15.0 software, evaluating outcomes such as Lequesne index scale, Mankin score, IL-1ß, TNF-α, MMP3, and MMP13. RESULTS: 56 RCTs with 2394 animals were included. Meta-analysis showed that among the 6 outcomes, there were significant differences between acupuncture and model group; the overall results of network meta-analysis showed that the normal group or sham operation group performed the best, followed by the acupotomy, acupuncture, and medicine group, and the model group had the worst effect, and there were significant differences between 6 interventions. CONCLUSIONS: Acupuncture-related therapy can be a possible treatment for KOA. The mechanism involves many immune-inflammatory pathways, which may be mediated by DAMPs/TLR/NF-κB/MAPK,PI3K/Akt/NF-κB pathway, or IFN-γ/JAK-STAT pathway. It needs to be further confirmed by more high-quality animal experiments or meta-analysis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO identifier: CRD42023377228.

Mendelian randomization and Bayesian model averaging of autoimmune diseases and Long COVID.

Background: Following COVID-19, reports suggest Long COVID and autoimmune diseases (AIDs) in infected individuals. However, bidirectional causal effects between Long COVID and AIDs, which may help to prevent diseases, have not been fully investigated. Methods: Summary-level data from genome-wide association studies (GWAS) of Long COVID (N = 52615) and AIDs including inflammatory bowel disease (IBD) (N = 377277), Crohn's disease (CD) (N = 361508), ulcerative colitis (UC) (N = 376564), etc. were employed. Bidirectional causal effects were gauged between AIDs and Long COVID by exploiting Mendelian randomization (MR) and Bayesian model averaging (BMA). Results: The evidence of causal effects of IBD (OR = 1.06, 95% CI = 1.00-1.11, p = 3.13E-02), CD (OR = 1.10, 95% CI = 1.01-1.19, p = 2.21E-02) and UC (OR = 1.08, 95% CI = 1.03-1.13, p = 2.35E-03) on Long COVID was found. In MR-BMA, UC was estimated as the highest-ranked causal factor (MIP = 0.488, MACE = 0.035), followed by IBD and CD. Conclusion: This MR study found that IBD, CD and UC had causal effects on Long COVID, which suggests a necessity to screen high-risk populations.

The causal role of gut microbiota in susceptibility of Long COVID: a Mendelian randomization study.

Background: Long COVID is a major challenge facing the public. Gut microbiota is closely related to Long COVID. However, the causal effects between gut microbiota and Long COVID remains unclear. Methods: Using summary statistics from Genome-Wide Association Studies (GWAS), Mendelian randomization (MR) analyses were performed to investigate the relationship between gut microbiota and Long COVID. The primary statistical method employed was Inverse Variance Weighted (IVW). Sensitivity analyses were then conducted to evaluate the reliability of the findings and account for potential confounding variables. Finally, a reverse MR analysis was conducted to examine potential associations between Long COVID and genetically predicted gut microbiota compositions. Results: There were 2 positive and 1 negative causal effect between gut microbiota and Long COVID. Meta-analysis results show that genus Parasutterella (OR = 1.145, 95%CI = 1.035 ∼ 1.266, P = 0.008) and genus Oscillospira (OR = 1.425, 95%CI = 1.235 ∼ 1.645, P < 0.001) significantly increased the risk of Long COVID. And genus Eisenbergiella (OR = 0.861, 95%CI = 0.785 ∼ 0.943, P = 0.001) significantly decreased the risk of Long COVID. Neither the pleiotropy nor the heterogeneity was observed. Reverse causal effect does not hold. Conclusion: Our research has provided genetic evidence that establishes multiple causal relationships between the gut microbiota and Long COVID, supporting the role of the gut microbiota in Long COVID. It is possible that different taxa play a role in the development of Long COVID. The causal relationships identified in this study require further investigation.

Downregulation of PRKCI inhibits osteosarcoma cell growth by inactivating the Akt/mTOR signaling pathway.

PRKCI is abnormally expressed in various cancers, but its role in osteosarcoma is unknown. This study aimed to explore the biological function of PRKCI in osteosarcoma and its potential molecular mechanism. PRKCI expression was evaluated in osteosarcoma cell lines using Western blot analysis and reverse transcription PCR. The CCK-8 assay, colony formation assay, flow cytometry, Transwell assay, and wound-healing assay were used to detect the proliferation, colony-forming capacity, cell cycle, migration, and invasion of osteosarcoma cells when PRKCI was overexpressed or knocked down. The interaction between PRKCI and SQSTM1 was explored using immunoprecipitation. Finally, the protein molecule expression of the Akt/mTOR signaling pathway in osteosarcoma was detected when PRKCI was knocked down. Our study found that PRKCI was overexpressed in osteosarcoma cell lines. The overexpression of PRKCI promoted the proliferation and colony-forming capacity of osteosarcoma cells, while silencing PRKCI inhibited the proliferation, colony-forming capacity, migration, and invasion of osteosarcoma cells and arrested the cell cycle at the G2/M phase. Both PRKCI and SQSTM1 were overexpressed in osteosarcoma. The expression of PRKCI was only related to histological type, while that of SQSTM1 was not related to clinical characteristics. The expression of PRKCI and SQSTM1 in osteosarcoma was higher than that in chondrosarcoma. Knockdown of PRKCI inhibited the proliferation of osteosarcoma cells by inactivating the Akt/mTOR signaling pathway, suggesting that PRKCI was a potential target for osteosarcoma therapy.

Long-term effects of soluble and insoluble ferric irons on anaerobic oxidation of methane in paddy soil.

Iron-dependent anaerobic oxidation of methane (Fe-AOM) is an important process to reduce methane emissions into the atmosphere. It is well known that iron bioavailability largely influences microbial iron reduction, but the long-term effects of different ferric irons on soil Fe-AOM remain unknown. In this work, paddy soil in the ferruginous zone was collected and inoculated with insoluble ferrihydrite and soluble EDTA-Fe(III) for 420 days. Stable isotope experiments, activity inhibition tests, and molecular biological techniques were performed to reveal the activity, microbial community, and possible mechanism of paddy soil Fe-AOM. The results showed that ferrihydrite was a better electron acceptor for long-term Fe-AOM cultivation. Although EDTA-Fe(III) is highly bioavailable and could stimulate Fe-AOM activity for a short time, it restricted the activity increase in the long term. The abundances of archaea, iron-reducing bacteria (IRB), and gene mcrA largely increased after cultivation, indicating the important roles of mcrA-carrying archaea and IRB. Remarkably, archaeal communities were similar, but bacteria were totally different with different ferric irons. The results of the microbial community and activity inhibition suggested that Fe-AOM was performed likely by the cooperation between archaea (Methanomassiliicoccaceae or pGrfC26) and IRB in the cultures.

Enhanced anaerobic oxidation of methane with the coexistence of iron oxides and sulfate fertilizer in paddy soil.

Iron oxides and sulfate are usually abundant in paddy soil, but their role in reducing methane emissions is little known. In this work, paddy soil was anaerobically cultivated with ferrihydrite and sulfate for 380 days. An activity assay, inhibition experiment, and microbial analysis were conducted to evaluate the microbial activity, possible pathways, and community structure, respectively. The results showed that anaerobic oxidation of methane (AOM) was active in the paddy soil. The AOM activity was much higher with ferrihydrite than sulfate, and an extra 10% of AOM activity was stimulated when ferrihydrite and sulfate coexisted. The microbial community was highly similar to the duplicates but totally different with different electron acceptors. The microbial abundance and diversity decreased due to the oligotrophic condition, but mcrA-carrying archaea increased 2-3 times after 380 days. Both the microbial community and the inhibition experiment implied that there was an intersection between iron and sulfur cycles. A "cryptic sulfur cycle" might link the two cycles, in which sulfate was quickly regenerated by iron oxides, and it might contribute 33% of AOM in the tested paddy soil. Complex links between methane, iron, and sulfur geochemical cycles occur in paddy soil, which may be significant in reducing methane emissions from rice fields.

miR-1251-5p Overexpression Inhibits Proliferation, Migration, and Immune Escape in Clear Cell Renal Cell Carcinoma by Targeting NPTX2.

Background: miR-1251-5p was identified as a tumor suppressor in a variety of malignancies; however, its biological function in clear cell renal cell carcinoma (ccRCC) is unknown. Methods: The Cancer Genome Atlas (TCGA) database was used to download expression information, including miR-1251-5p, in 521 ccRCC tissues and 71 ordinary tissues, and bioinformatics was used to explore possible target mRNAs. The relationship between miR-1251-5p, target mRNA activity, and clinical factors was examined. To estimate the biological activity of miR-1251-5p and target mRNA in ccRCC cells, we used MTT, colony formation, enzyme-linked immunosorbent, and Transwell assays. We employed a dual-luciferase reporter assay and a western blot to examine the molecular mechanisms of miR-1251-5p in ccRCC cells. In addition, the expressions of miR-1251-5p and target mRNA were further verified in the GEO database. Results: Our findings revealed that miR-1251-5p binds with NPTX2's 3'-UTR. In TCGA and GEO datasets, miR-1251-5p activity is found to be lower in ccRCC tissues than that in nearby conventional tissues, although NPTX2 activity is higher. In ccRCC sufferers, miR-1251-5p and NPTX2 act as biomarkers that indicate a bad prognosis. Meanwhile, in miR-1251-5p tissues, NPTX2 expression and multiple clinical variables (survival status, grade, T staging, N staging, M staging, and clinical stage) had significant differences (p < 0.05). Structurally, miR-1251-5p inhibited proliferation, migration, and immune escape of ccRCC cells by targeting NPTX2. Conclusion: Our findings indicate that miR-1251-5p constrained ccRCC cell advancement, migration, and immune evasion via targeting NPTX2, providing novel insights into ccRCC target treatment.

Synergistic effect of glycated chitosan and photofrin photodynamic therapy on different breast tumor model.

Metastases and recurrence of cancer are the main causes of failure and death. Induction of a long-term tumor specific immunity seems to be a great strategy to deal with this challenge. Laser immunotherapy (LIT), using immunomodulatory techniques in combination with photodynamic therapy (PDT), so as to enhance an already robust immune response, has been proposed and investigated by numerous researchers. In our study, mice bearing EMT6 breast tumors and 4T1 metastatic breast tumors were addressed in various permutations of the different components in LIT. The survival rates and the tumor growth curve of EMT6 breast tumors bearing mice were analyzed. We compared the level of inflammatory reaction, cell apoptosis and activated immune cells infiltration of local tumors. We validated the systemic effect of LIT through the 4T1 metastatic breast tumors bearing mice. The results not only proved that concomitant with Glycated chitosan (GC) can improve the effect of inhibiting the tumor growth, improving survival, enhancing local inflammatory reaction and attracting acted immune cells to tumor by photodynamic therapy with Photofrin, but also intuitively proved the systemic effect and long-term effect of LIT.

Optimization of methane-dependent oxygenic denitrification in sequencing batch reactors by insights into the microbial interactions.

Methane-dependent oxygenic denitrification (O2DN) is a promising technology used for reducing greenhouse gas emissions of nitrous oxide (N2O) during wastewater treatment. Heterotrophic bacteria are associated with methane-dependent O2DN bacteria, and it has been proposed that metabolic cross-feeding occurs between the two populations above. In this study, a mathematical model was developed to describe the microbial processes and interactions between methane-dependent O2DN bacteria and associated heterotrophic bacteria in a sequencing batch reactor (SBR). A growth factor-dependent decoupling of metabolism and growth of methane-dependent O2DN bacteria was introduced into the model. Effects of influent substrates, operating parameters, and initial biomass on microbial community and reactor performance were then investigated, and the above parameters were optimized using the model. Results surprisingly show that organic matter in the influent greatly stimulated the growth of methane-dependent O2DN bacteria but slightly limited the increase of heterotrophic bacteria. This effect could be explained by the increased excretion of growth factors by heterotrophic bacteria and the intensified competition for nitrite when methane-dependent O2DN bacteria increased. These results will assist in providing a new understanding of microbial interactions in methane-dependent O2DN systems and offer a new and efficient strategy for operating methane-dependent O2DN reactors.

Retrospective analysis of therapeutic effect and prognostic factors on early glottic carcinoma.

OBJECTIVE: To investigate the therapeutic effect of surgery, radiotherapy and photodynamic therapy on early glottic carcinoma and prognostic factors. METHODS: Retrospective analysis of 202 cases with early glottic carcinoma (Tis-T2N0M0) underwent surgery (n=152), radiotherapy (n=20) and PDT (n=30) from 2000 to 2013 The KPS score, the disease-free survival (DFS), overall survival (OS), local control (LC), larynx preservation rate, laryngeal function were evaluated. The methods of χ (2)test or Fisher's exact probability method, Kaplan Meier method, log-rank test of Kaplan-Meier method, Cox proportional hazards model were used to analyze the data. RESULTS: There was no statistical significance in OS, DFS and LC among the three groups. The laryngeal function preservation rate of RT group, PDT group and Surgery group were 90%, 86.7% and 65.1% respectively, with the former two groups significantly superior to Surgery group. While there is no statistical significance between RT group and PDT group. Single factor analysis showed that KPS score before treatment, vocal fold mobility limitation and differentiation degree could have an effect on prognosis. Multivariate regression analyses indicated that anterior commissure invasion, T stage and KPS score before treatment were independent adverse prognostic factors for OS. T stage and differentiation degree were adverse prognostic factors for DFS. T stage was also an adverse factor of LC. Thirty-three cases experienced local recurrence or cervical lymph node metastasis. Three groups showed no statistical difference in local recurrence or lymph node metastasis, with twenty-two cases in Surgery group, four in RT group and seven in PDT group. CONCLUSIONS: The therapeutic effect was approximate in surgery group, radiotherapy group and photodynamic group, and all three treatment regimens achieved good clinical effect. Radiotherapy and photodynamic therapy may be the first or very important treatment on early stage glottic squamous cell cancer (Tis∼T2N0M0). However only 6 patients underwent PDT for T2 disease, making definitive treatment conclusions for this subgroup unclear.