Abstract Background The clinical course of inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC) after liver transplantation (LT) varies significantly across studies. This study aims to provide a comprehensive estimation of incidence rates (IR) for colorectal cancer (CRC) or high-grade dysplasia, bowel surgery, IBD exacerbation, and newly diagnosed IBD in PSC-IBD patients post-LT. Methods Online databases were searched from inception till January 2024 for studies reporting on patients who underwent LT for PSC with IBD diagnosed either before or after LT. The pooled IR were calculated with the "meta" package (R Studio [V.4.2.764] ) using a random effects model. Results Of 5,324 studies initially identified, 97 underwent full-text review, and 34 retrospective cohort studies were included in the meta-analysis. These cohorts encompassed 3,672 patients with LT for PSC, of whom 63% had concomitant IBD. The mean follow-up period across studies ranged widely from 2.46 years to 17.3 years. A pooled analysis of 21 studies reporting on colorectal neoplasia revealed an overall IR of CRC or high-grade dysplasia post-liver transplantation of 6.7 cases per 1,000 person-years (95% CI 4.3-9.0) (Figure 1A). Across 18 studies, 17.8% (n=195/1094) patients with concomitant IBD at the time of LT experienced clinical exacerbation, defined as worsening of IBD symptoms, increased inflammatory activity at endoscopy, or required optimization of IBD treatment post-transplantation. The pooled IR of clinical exacerbation was 34.1 cases per 1,000 person-years (95% CI 22.7-45.5), though heterogeneity was high (I² = 76%). Notably, meta-regression revealed a decline in IR of clinical exacerbation over time exclusively within European countries, with no observed change elsewhere. Additionally, 16 studies reported on newly diagnosed IBD in PSC patients without pre-existing IBD at LT, with pooled IR of 12.6 cases per 1,000 person-years (95% CI 9.7-15.5) (Figure 1B). The overall bowel surgery rate post-LT was 20.2 cases (95% CI 16.9-23.4) per 1,000 person-years within 23 studies. More specifically, pooled colectomy rates for neoplasia and therapy refractory IBD were 10.5 cases (95% CI 6.7-14.2) in 16 studies, and 13.8 cases (95% CI 9.4-18.3) per 1,000 person-years in 10 studies, respectively. Conclusion This meta-analysis provides a thorough assessment of IBD outcomes in PSC-IBD patients following liver transplantation, highlighting the considerable incidence rates of colorectal neoplasia and newly diagnosed IBD. Close clinical follow-up and regular endoscopic surveillance remain essential in PSC patients post-LT.
Objective
To discuss the effect of ulinastatin in the level of plasma inflammatory cytokines, C-reactive protein (CRP), IL-8, IL-10 and tumor necrosis factor (TNF-α), of patients with severe asthma.
Methods
The paper included 90 patients with severe asthma were randomly divided into the experimental group and the control group, who visited hospital to seek medical treatment from March 2016 to March 2017.Two groups of patients were given routine treatment, such as oxygen, anti-inflammatory, inhalation, hormone therapy, experimental group treated with 10 days.of ulinastatin in the treatment.collected peripheral blood samples, detected the level of CRP, IL-10, TNF-α and other inflammatory cytokines in plasma by adopting enzyme linked immunosorbent assay (ELISA) and scatter turbidimetry.Analysis of changes of inflammatory cytokines in plasma after treatment with ulinastatin in patients with severe asthma treatment.
Results
Two groups of patients after treatment, the level of CRP, IL-8, TNF-α were decreased significantly compare with before treatment (P<0.05), and the level of IL-10 increased significantly compared with those before treatment (P<0.05). After treatment, the level of CRP, IL-8, TNF-α with experimental group were lower than the control group (P<0.05), and the level of IL-10 were higher than the control group (P<0.05).
Conclusions
Effect of ulinastatin on the treatment of patients with severe asthma effectively, can significantly reduce the inflammatory cytokines level of CRP, IL-8, TNF-α, and elevated the inflammatory cytokines level of IL-10, can be used as an adjunctive therapy in drug treatment in patients with severe asthma.
Key words:
Severe asthma; Ulinastatin; C-reactive protein; Interleukin-10; Tumor necrosis factor-α
Inorganic nitrate is an indispensable nutrient that has been used in experimental studies for the prevention and treatment of several diseases. However, the short half-life of nitrate limits its clinical application. To increase the usability of nitrate and overcome the challenges of traditional combination drug discovery through large-scale high-throughput biological experiments, we developed a swarm learning-based combination drug prediction system that identified vitamin C as the drug of choice to be combined with nitrate. Employing microencapsulation technology, we used vitamin C, sodium nitrate, and chitosan 3000 as the core materials to prepare a nitrate nanoparticle, which we named Nanonitrator. The long-circulating delivery ability of nitrate by Nanonitrator significantly increased the efficacy and effect duration of nitrate in irradiation-induced salivary gland injury, without compromising safety. Nanonitrator at the same dose could better maintain intracellular homeostasis than nitrate (with or without vitamin C), emphasizing its potential for clinical use. More importantly, our work provides a method for incorporating inorganic compounds into sustained-release nanoparticles.
The aim of the study was to investigate the associations between physical activity (PA)-related miRNAs and metabolic syndrome (MetS). A case-control study was conducted in 209 subjects with MetS and 234 controls. The MetS was defined by the International Diabetes Foundation (IDF) criteria of 2005. Serum PA-related miRNAs were detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays. Association analysis was performed by logistic regression models. The expression levels of miR-126 and miR-130a were lower in the highest metabolic equivalent hours per week (MET-h/week) quartile than in the lowest quartile [miR-126: Q5 vs. Q1, median (5-95%), 1.67 (0.54, 2.45) vs. 1.35 (0.45, 2.45), p=0.012; miR-130a: Q5 vs. Q1, median (5-95%), 0.90 (0.44, 1.35) vs. 0.53 (0.26, 1.01), p<0.001]. However, miR-197 exhibited a trend with increased MET-h/week [Q5 vs. Q1, median (5-95%), 1.35 (0.45, 2.63) vs. 2.18 (0.87, 4.77), p=0.009]. MiR-126 increased MetS risk significantly while the effect of miR-197 was opposite (miR-126: OR=1.37, 95% CI 1.07-1.75; p=0.012; miR-197: OR=0.68, 95% CI 0.51-0.92; p=0.010). Individuals in the highest MET-h/week quartile had lower prevalence and odds rate of MetS compared with those in the lowest quartile (Q4 vs. Q1: OR=0.58, 95% CI 0.33-1.05; p for trend=0.026). However, further adjustment of both PA associated miRNAs abolished that association. All these results suggested that the association between PA and MetS risk might partly depend on miR-126 and miR-197.
The metabolism of exogenous substances is affected by the gut microbiota, and the relationship between them has become a hot topic. However, the mechanisms by which the microbiota regulates drug metabolism have not been clearly defined. This study characterizes the expression profiles of host drug-processing genes (DPGs) in antibiotics-treated rats by using an unbias quantitative RNA-sequencing method and investigates the effects of antibiotics-induced depletion of rat microbiota on the pharmacokinetic behaviors of cytochrome P450s (CYPs) probe drugs, and bile acids metabolism by ultra-performance liquid chromatography-tandem mass spectrometry. Our results show that antibiotics treatments altered the mRNA expressions of 112 DPGs in the liver and jejunum of rats. The mRNA levels of CYP2A1, CYP2C11, CYP2C13, CYP2D, CYP2E1, and CYP3A of CYP family members were significantly downregulated in antibiotics-treated rats. Furthermore, antibiotics treatments also resulted in a significant decrease in the protein expressions and enzyme activities of CYP3A1 and CYP2E1 in rat liver. Pharmacokinetic results showed that, except for tolbutamide, antibiotics treatments significantly altered the pharmacokinetic behaviors of phenacetin, omeprazole, metoprolol, chlorzoxazone, and midazolam. In conclusion, the presence of stable, complex, and diverse gut microbiota plays a significant role in regulating the expression of host DPGs, which could contribute to some individual differences in pharmacokinetics.
SIGNIFICANCE STATEMENT
This study investigated how the depletion of rat microbiota by antibiotics treatments influences the expression profiles of host DPGs and the pharmacokinetic behaviors of CYPs probe drugs. Combined with previous studies in germ-free mice, this study will improve the understanding of the role of gut microbiota in drug metabolism and contribute to the understanding of individual differences in the pharmacokinetics of some drugs.
To investigate the susceptibility to carbon tetrachloride and benzene in offspring of expanded simple tandem repeats (ESTR) mutation mice exposed to formaldehyde (FA).F5 and F10 offspring (200 mg/m3 x 2 hours) served as H group and ICR mice were used as control group (group C). The F5 and F10 offspring were exposed to 10 ml/kg carbon tetrachloride at the doses of 0.05%, 0.50% or 5.00% for 24 hours, respectively or 500 or 1000 mg/kg benzene for 24 hours, respectively by intraperitoneal injection. Serum alanine transaminase (ALT), aspartate transaminase (AST) and the hepatic superoxide dismutase (SOD) or malondialdehyde (MDA) were detected; also the hepatic pathological changes were observed under light microscope; the micronucleus in sternum bone marrow cells as the biomarker of benzene blood toxicity were measured.ALT and AST activities in group C of F5 mice exposed to 0.50% and 5.00% CCl4, ALT in groups C and H of F10 mice exposed to 0.05%, 0.50%, 5.00% CCl4, AST in groups C and H of F10 mice exposed to 0.50% and 5.00% CCl4 were significantly higher than those in controls, respectively (P<0.05); as compared to the control, hepatic SOD activities in group C of F5 and F10 mice exposed to 0.50% and 5.00% CCl4, in group H of F5 mice exposed to 0.50% and 5.00% CCl4 and F10 mice exposed to 5.00% CCl4 were significantly reduced, respectively (P<0.05); however, MDA contents in group C of F10 mice exposed to 0.50% and 5.00% CCl4, in group H of F5 mice exposed to 0.05% and 0.50%, 5.00% CCl4 and F10 mice exposed to 0.50% and 5.00% CCl4 were significantly increased than those in control group, respectively (P<0.05). The susceptibility to CCl4 in ESTR mutation F5 mice exposed to FA was significantly higher than that in control F5 mice, but the susceptibility to CCl4 in ESTR mutation F10 mice exposed to FA was significantly lower than that in control F10 mice. The histopathological examination showed that the injury of hepatocytes in C and H groups significantly increased CCl4 doses, and the injury of hepatocytes in H group was higher than that in C group. The micronuclear rates in C and H group mice exposed to benzene(500 mg/kg C group, F5 and F10 mice; 1000 mg/kg C group, F5 and F10 mice; 500 mg/kg H group, F5 and F10 mice; 1000 mg/kg C group, F5 and F10 mice) were 5.88 per thousand +/- 4.55 per thousand, 8.25 per thousand +/- 2.06 per thousand, 7.50 per thousand +/- 6.99 per thousand, 10.67 per thousand +/- 1.16 per thousand, 7.88 per thousand +/- 3.09 per thousand, 9.20 per thousand +/- 1.30 per thousand, 9.63 per thousand +/- 4.34 per thousand and 13.33 per thousand +/- 2.08 per thousand, respectively, which were significantly higher than those (1.13 per thousand +/- 0.35 per thousand, 1.20 per thousand +/- 0.82 per thousand, 1.25 per thousand +/- 0.46 per thousand, 1.33 per thousand +/- 1.03 per thousand) in the solvent control group (P<0.05 or P<0.01).FA could result in the change of susceptibility to CCl4 and benzene in offspring of ESTR mutation mice. ESTR mutation may be a biomarker of the susceptibility to chemicals, but the molecular mechanisms should be investigated in the future.
Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy with a high prevalence in China. This study aimed to characterize the ICC tissues' bacterial metagenomics signature and explore its antitumor potential for cancer. In this study, 16S rRNA sequencing was carried out on 99 tissues to characterize the features of intratumoral microbiota, followed by single-cell RNA sequencing (scRNA-seq) and multilevel validation. The presence of microbial DNA in tissues was determined using staining, fluorescence in situ hybridization (FISH), and transmission electron microscopy (TEM). A Gram-positive aerobic bacterium, identified as Staphylococcus capitis, was cultured from fresh tissues. Meanwhile, scRNA-seq showed that intratumoral bacteria could be present in multiple cell types. Using 16S rRNA sequencing, we identified a total of 2,320,287 high-quality reads corresponding to 4,594 OTU (operational taxonomic units) sequences. The most abundant bacterial orders include Burkholderiales, Pseudomonadales, Xanthomonadales, Bacillales and Clostridiales. Alpha and Beta diversity analysis revealed specific features in different tissues. In addition, the content of Paraburkholderia fungorum was significantly higher in the paracancerous tissues and negatively correlated with CA199 (Carbohydrate antigen199) levels. The results of in vitro and in vivo experiments suggest that P. fungorum possesses an antitumor activity against tumors. Metabolomics and transcriptomics showed that P. fungorum could inhibit tumor growth through alanine, aspartate and glutamate metabolism. We determined the characteristic profile of the intratumoral microbiota and the antitumor effect of P. fungorum in ICC.
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