Gasdermin E suppresses tumour growth by activating anti-tumour immunity.

Cleavage of the gasdermin proteins to produce pore-forming amino-terminal fragments causes inflammatory cell death (pyroptosis)1. Gasdermin E (GSDME, also known as DFNA5)-mutated in familial ageing-related hearing loss2-can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells3-5. GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer2,6, suggesting that GSDME might be a tumour suppressor. Here we show that 20 of 22 tested cancer-associated GSDME mutations reduce GSDME function. In mice, knocking out Gsdme in GSDME-expressing tumours enhances, whereas ectopic expression in Gsdme-repressed tumours inhibits, tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes: it is abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages, as well as the number and functions of tumour-infiltrating natural-killer and CD8+ T lymphocytes. Killer-cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase 3. Uncleavable or pore-defective GSDME proteins are not tumour suppressive. Thus, tumour GSDME acts as a tumour suppressor by activating pyroptosis, enhancing anti-tumour immunity.

Real-Time Monitoring of Tyrosine Hydroxylase Activity with a Ratiometric Fluorescent Probe.

Parkinson's disease (PD) represents the second most widespread neurodegenerative disease, and early monitoring and diagnosis are urgent at present. Tyrosine hydroxylase (TH) is a key enzyme for producing dopamine, the levels of which can serve as an indicator for assessing the severity and progression of PD. This renders the specific detection and visualization of TH a strategically vital way to meet the above demands. However, a fluorescent probe for TH monitoring is still missing. Herein, three rationally designed wash-free ratiometric fluorescent probes were proposed. Among them, TH-1 exhibited ideal photophysical properties and specific dual-channel bioimaging of TH activity in SH-SY5Y nerve cells. Moreover, the probe allowed for in vivo imaging of TH activity in zebrafish brain and living striatal slices of mice. Overall, the ratiometric fluorescent probe TH-1 could serve as a potential tool for real-time monitoring of PD in complex biosystems.

Icariside II in NSCLC and COVID-19: Network pharmacology and molecular docking study.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) are susceptible to coronavirus disease-2019 (COVID-19), but current treatments are limited. Icariside II (IS), a flavonoid compound derived from the plant epimedin, showed anti-cancer,anti-inflammation and immunoregulation effects. The present study aimed to evaluate the possible effect and underlying mechanisms of IS on NSCLC patients with COVID-19 (NSCLC/COVID-19). METHODS: NSCLC/COVID-19 targets were defined as the common targets of NSCLC (collected from The Cancer Genome Atlas database) and COVID-19 targets (collected from disease database of Genecards, OMIM, and NCBI). The correlations of NSCLC/COVID-19 targets and survival rates in patients with NSCLC were analyzed using the survival R package. Prognostic analyses were performed using univariate and multivariate Cox proportional hazards regression models. Furthermore, the targets in IS treatment of NSCLC/COVID-19 were defined as the overlapping targets of IS (predicted from drug database of TMSCP, HERBs, SwissTarget Prediction) and NSCLC/COVID-19 targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of these treatment targets were performed aiming to understand the biological process, cellular component, molecular function and signaling pathway. The hub targets were analyzed by a protein-protein interaction network and the binding capacity with IS was characterized by molecular docking. RESULTS: The hub targets for IS in the treatment of NSCLC/COVID-19 includes F2, SELE, MMP1, MMP2, AGTR1 and AGTR2, and the molecular docking results showed that the above target proteins had a good binding degree to IS. Network pharmacology showed that IS might affect the leucocytes migration, inflammation response and active oxygen species metabolic process, as well as regulate the interleukin-17, tumor necrosus factor and hypoxia-inducible factor-1 signaling pathway in NSCLC/COVID-19. CONCLUSIONS: IS may enhance the therapeutic efficacy of current clinical anti-inflammatory and anti-cancer therapy to benefit patients with NSCLC combined with COVID-19.

Low-dose or high-dose amoxicillin in vonoprazan-based dual therapy for Helicobacter pylori eradication? A systematic review and meta-analysis.

BACKGROUND: The amoxicillin dose used in dual therapy to eradicate Helicobacter pylori varies across studies and the optimal amoxicillin dose for vonoprazan-based dual therapies remains unclear. We aimed to investigate the efficacy and safety of low- and high-dose amoxicillin in vonoprazan-amoxicillin dual therapy. MATERIALS AND METHODS: A comprehensive systematic review was conducted by searching databases from inception to October 2023. All trials that evaluated the effectiveness and safety of vonoprazan-amoxicillin dual therapy for eradicating H. pylori were included. Pooled eradication rate, incidence of adverse events, relative risks, and 95% confidence intervals are presented. RESULTS: Eighteen studies with 12 low-dose amoxicillin (VLA) and 13 high-dose amoxicillin (VHA) arms were included. The pooled eradication rates were 82.4% and 86.8% for VLA therapy, and 86.0% and 90.9% for VHA therapy by the intention-to-treat and per-protocol analyses, respectively. In the subgroup analysis stratified by duration, the eradication rates achieved in 7 days, 10 days, and 14 days treatments with VLA and VHA dual therapies were 80.8%, 84.2%, 83.1%, and 67.3%, 88.8%, 87.5%, respectively. In the four randomized controlled trials that directly compared VLA and VHA dual therapies, the efficacy was not statistically different in the intention-to-treat (76.9% vs 81.4%, p = 0.337) and per-protocol (81.6% vs 84.0%, p = 0.166) analyses. Additionally, the incidence of adverse events (p = 0.965) and compliance (p = 0.994) were similar in both groups. CONCLUSION: VLA therapy demonstrated comparable efficacy and safety to VHA therapy, along with regional differences. An appropriately extended treatment duration may be critical for therapeutic optimization of vonoprazan-amoxicillin treatment.

Efficacy and Safety of Cold Snare Polypectomy versus Cold Endoscopic Mucosal Resection for Resecting 3-10 mm Colorectal Polyps: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: The safety and efficacy of cold snare polypectomy (CSP) compared to those of cold endoscopic mucosal resection (CEMR) have been reported. This meta-analysis compared the efficacy and safety of CEMR and CSP. METHODS: PubMed, Embase, Web of Science, and Cochrane Library databases were systematically searched to identify randomized controlled trials comparing the efficacy and safety of CEMR and CSP in removing 3-10 mm polyps. The outcomes assessed included complete resection rate, intraoperative bleeding rate, delayed bleeding rate, perforation, and polyp removal time. The results are reported as risk ratios (RR) and 95% confidence intervals (CIs) derived from a Mantel-Haenszel random-effects model. RESULTS: Seven studies comprising 1,911 polyps were included in the analysis. The complete resection rate of CEMR was comparable to that of CSP (RR: 1.01, 95% CI: 0.99-1.04, p = 0.32). Comparable results were also demonstrated for intraoperative bleeding rate (polyp-based analysis: RR: 1.22, 95% CI: 0.33-4.43, p = 0.77), delayed bleeding rate (polyp-based analysis: RR: 1.34, 95% CI: 0.44-4.15, p = 0.61), and polyp removal time (mean difference: 28.31 s, 95% CI: -21.40-78.02, p = 0.26). No studies reported cases of perforation. CONCLUSION: CEMR has comparable efficacy and safety to CSP in removing 3-10 mm polyps. Further randomized controlled trials with long-term follow-up are warranted to compare and validate efficacy.

Bismuth-Containing Quadruple Therapy for Helicobacter pylori Eradication: A Randomized Clinical Trial of 10 and 14 Days.

BACKGROUND: Bismuth-containing quadruple therapy is the first-line treatment for eradicating Helicobacter pylori (H. pylori). The optimal duration for H. pylori eradication using bismuth-containing quadruple therapy remains controversial. Therefore, we aimed to compare the clinical effects of the 10- and 14-day bismuth-containing quadruple treatment regimen to eradicate H. pylori. METHODS: Treatment-naïve patients with H. pylori infection (n = 1300) were enrolled in this multicenter randomized controlled study across five hospitals in China. They were randomized into 10- or 14-day treatment groups to receive bismuth-containing quadruple therapy as follows: vonoprazan 20 mg twice daily; bismuth 220 mg twice daily; amoxicillin 1000 mg twice daily; and either clarithromycin 500 mg twice daily or tetracycline 500 mg four times daily. At least 6 weeks after treatment, we performed a 13C-urea breath test to evaluate H. pylori eradication. RESULTS: The per-protocol eradication rates were 93.22% (564/605) and 93.74% (569/607) (p < 0.001) and the intention-to-treat eradication rates were 88.62% (576/650) and 89.38% (581/650) (p = 0.007) for the 10- and 14-day regimens, respectively. Incidence of adverse effects was lower in patients who received 10- vs. 14 days of treatment (22.59% vs. 28.50%, p = 0.016). We observed no significant differences in the compliance to treatment or the discontinuation of therapy because of severe adverse effects between the groups. CONCLUSION: Compared with the 14-day bismuth-containing quadruple regimens, the 10-day regimen demonstrated a non-inferior efficacy and lower incidence of adverse effects. Therefore, the 10-day regimen is safe and tolerated and could be recommended for H. pylori eradication (NCT05049902).

A feasibility study to predict 3D dose delivery accuracy for IMRT using DenseNet with log files.

OBJECTIVE: This study aims to explore the feasibility of DenseNet in the establishment of a three-dimensional (3D) gamma prediction model of IMRT based on the actual parameters recorded in the log files during delivery. METHODS: A total of 55 IMRT plans (including 367 fields) were randomly selected. The gamma analysis was performed using gamma criteria of 3% /3 mm (Dose Difference/Distance to Agreement), 3% /2 mm, 2% /3 mm, and 2% /2 mm with a 10% dose threshold. In addition, the log files that recorded the gantry angle, monitor units (MU), multi-leaf collimator (MLC), and jaws position during delivery were collected. These log files were then converted to MU-weighted fluence maps as the input of DenseNet, gamma passing rates (GPRs) under four different gamma criteria as the output, and mean square errors (MSEs) as the loss function of this model. RESULTS: Under different gamma criteria, the accuracy of a 3D GPR prediction model decreased with the implementation of stricter gamma criteria. In the test set, the mean absolute error (MAE) of the prediction model under the gamma criteria of 3% /3 mm, 2% /3 mm, 3% /2 mm, and 2% /2 mm was 1.41, 1.44, 3.29, and 3.54, respectively; the root mean square error (RMSE) was 1.91, 1.85, 4.27, and 4.40, respectively; the Sr was 0.487, 0.554, 0.573, and 0.506, respectively. There was a correlation between predicted and measured GPRs (P <  0.01). Additionally, there was no significant difference in the accuracy between the validation set and the test set. The accuracy in the high GPR group was high, and the MAE in the high GPR group was smaller than that in the low GPR group under four different gamma criteria. CONCLUSIONS: In this study, a 3D GPR prediction model of patient-specific QA using DenseNet was established based on log files. As an auxiliary tool for 3D dose verification in IMRT, this model is expected to improve the accuracy and efficiency of dose validation.

Dosimetry and treatment efficiency of SBRT using TaiChiB radiotherapy system for two-lung lesions with one overlapping organs at risk.

Purpose: This study aims to assess the dosimetry and treatment efficiency of TaiChiB-based Stereotactic Body Radiotherapy (SBRT) plans applying to treat two-lung lesions with one overlapping organs at risk. Methods: For four retrospective patients diagnosed with two-lung lesions each patient, four treatment plans were designed including Plan Edge, TaiChiB linac-based, RGS-based, and a linac-RGS hybrid (Plan TCLinac, Plan TCRGS, and Plan TCHybrid). Dosimetric metrics and beam-on time were employed to evaluate and compare the TaiChiB-based plans against Plan Edge. Results: For Conformity Index (CI), Plan TCRGS outperformed all other plans with an average CI of 1.06, as opposed to Plan Edge's 1.33. Similarly, for R50 %, Plan TCRGS was superior with an average R50 % of 3.79, better than Plan Edge's 4.28. In terms of D2 cm, Plan TCRGS also led with an average of 48.48%, compared to Plan Edge's 56.25%. For organ at risk (OAR) sparing, Plan TCRGS often displayed the lowest dosimetric values, notably for the spinal cord (Dmax 5.92 Gy) and lungs (D1500cc 1.00 Gy, D1000cc 2.61 Gy, V10 Gy 15.14%). However, its high Dmax values for the heart and great vessels sometimes exceeded safety thresholds. Plan TCHybrid presented a balanced approach, showing doses comparable to or better than Plan Edge without crossing safety limits. In terms of beam-on time, Plan TCLinac emerged as the most efficient treatment option in three out of four cases, followed closely by Plan Edge in one case. Plan TCRGS, despite its dosimetric advantages, was the least efficient, recording notably longer beam-on times, with a peak at 33.28 minutes in Case 2. Conclusion: For patients with two-lung lesions treated by SBRT whose one lesion overlaps with OARs, the Plan TCHybrid delivered by TaiChiB digital radiotherapy system can be recommended as a clinical option.

Predicting the error magnitude in patient-specific QA during radiotherapy based on ResNet.

BACKGROUND: The error magnitude is closely related to patient-specific dosimetry and plays an important role in evaluating the delivery of the radiotherapy plan in QA. No previous study has investigated the feasibility of deep learning to predict error magnitude. OBJECTIVE: The purpose of this study was to predict the error magnitude of different delivery error types in radiotherapy based on ResNet. METHODS: A total of 34 chest cancer plans (172 fields) of intensity-modulated radiation therapy (IMRT) from Eclipse were selected, of which 30 plans (151 fields) were used for model training and validation, and 4 plans including 21 fields were used for external testing. The collimator misalignment (COLL), monitor unit variation (MU), random multi-leaf collimator shift (MLCR), and systematic MLC shift (MLCS) were introduced. These dose distributions of portal dose predictions for the original plans were defined as the reference dose distribution (RDD), while those for the error-introduced plans were defined as the error-introduced dose distribution (EDD). Different inputs were used in the ResNet for predicting the error magnitude. RESULTS: In the test set, the accuracy of error type prediction based on the dose difference, gamma distribution, and RDD + EDD was 98.36%, 98.91%, and 100%, respectively; the root mean squared error (RMSE) was 1.45-1.54, 0.58-0.90, 0.32-0.36, and 0.15-0.24; the mean absolute error (MAE) was 1.06-1.18, 0.32-0.78, 0.25-0.27, and 0.11-0.18, respectively, for COLL, MU, MLCR and MLCS. CONCLUSIONS: In this study, error magnitude prediction models with dose difference, gamma distribution, and RDD + EDD are established based on ResNet. The accurate prediction of the error magnitude under different error types can provide reference for error analysis in patient-specific QA.

Interface Metal Oxides Regulating Electronic State around Nickel Species for Efficient Alkaline Hydrogen Electrocatalysis.

Heterogeneous electrocatalysis typically depends on the surface electronic states of active sites. Modulating the surface charge state of an electrocatalysts can be employed to improve performance. Among all the investigated materials, nickel (Ni)-based catalysts are the only non-noble-metal-based alternatives for both hydrogen oxidation and evolution reactions (HOR and HER) in alkaline electrolyte, while their activities should be further improved because of the unfavorable hydrogen adsorption behavior. Hereto, Ni with exceptional HOR electrocatalytic performance by changing the d-band center by metal oxides interface coupling formed in situ is endowed. The resultant MoO2 coupled Ni heterostructures exhibit an apparent HOR activity, even approaching to that of commercial 20% Pt/C benchmark, but with better long-term stability in alkaline electrolyte. An exceptional HER performance is also achieved by the Ni-MoO2 heterostructures. The experiment results are rationalized by the theoretical calculations, which indicate that coupling MoO2 with Ni results in the downshift of d-band center of Ni, and thus weakens hydrogen adsorption and benefits for hydroxyl adsorption. This concept is further proved by other metal oxides (e.g., CeO2 , V2 O3 , WO3 , Cr2 O3 )-formed Ni-based heterostructures to engineer efficient hydrogen electrocatalysts.

Rational Synthesis of Core-Shell-Structured Nickel Sulfide-Based Nanostructures for Efficient Seawater Electrolysis.

Versatile electrocatalysis at higher current densities for natural seawater splitting to produce hydrogen demands active and robust catalysts to overcome the severe chloride corrosion, competing chlorine evolution, and catalyst poisoning. Hereto, the core-shell-structured heterostructures composed of amorphous NiFe hydroxide layer capped Ni3 S2 nanopyramids which are directly grown on nickel foam skeleton (NiS@LDH/NF) are rationally prepared to regulate cooperatively electronic structure and mass transport for boosting oxygen evolution reaction (OER) performance at larger current densities. The prepared NiS@LDH/NF delivers the anodic current density of 1000 mA cm-2 at the overpotential of 341 mV in 1.0 m KOH seawater. The feasible surface reconstruction of Ni3 S2 -FeNi LDH interfaces improves the chemical stability and corrosion resistance, ensuring the robust electrocatalytic activity in seawater electrolytes for continuous and stable oxygen evolution without any hypochlorite production. Meanwhile, the designed Ni3 S2 nanopyramids coated with FeNi2 P layer (NiS@FeNiP/NF) still exhibit the improved hydrogen evolution reaction (HER) activity in 1.0 m KOH seawater. Furthermore, the NiS@FeNiP/NF||NiS@LDH/NF pair requires cell voltage of 1.636 V to attain 100 mA cm-2 with a 100% Faradaic efficiency, exhibiting tremendous potential for hydrogen production from seawater.

Alterations of the gut microbiome and metabolic profile in CVB3-induced mice acute viral myocarditis.

BACKGROUND: Acute viral myocarditis (AVMC) is an inflammatory disease of the myocardium. Evidence indicates that dysbiosis of gut microbiome and related metabolites intimately associated with cardiovascular diseases through the gut-heart axis. METHODS: We built mouse models of AVMC, then applied 16 S rDNA gene sequencing and UPLC-MS/MS metabolomics to explore variations of gut microbiome and disturbances of cardiac metabolic profiles. RESULTS: Compared with Control group, analysis of gut microbiota showed lower diversity in AVMC, decreased relative abundance of genera mainly belonging to the phyla Bacteroidetes, and increased of phyla Proteobacteria. Metabolomics analysis showed disturbances of cardiac metabolomics, including 62 increased and 84 decreased metabolites, and mainly assigned to lipid, amino acid, carbohydrate and nucleotide metabolism. The steroid hormone biosynthesis, cortisol synthesis and secretion pathway were particularly enriched in AVMC. Among them, such as estrone 3-sulfate, desoxycortone positively correlated with disturbed gut microbiome. CONCLUSION: In summary, both the structure of the gut microbiome community and the cardiac metabolome were significantly changed in AVMC. Our findings suggest that gut microbiome may participate in the development of AVMC, the mechanism may be related to its role in dysregulated metabolites such as steroid hormone biosynthesis.

Improving CBCT image quality to the CT level using RegGAN in esophageal cancer adaptive radiotherapy.

OBJECTIVE: This study aimed to improve the image quality and CT Hounsfield unit accuracy of daily cone-beam computed tomography (CBCT) using registration generative adversarial networks (RegGAN) and apply synthetic CT (sCT) images to dose calculations in radiotherapy. METHODS: The CBCT/planning CT images of 150 esophageal cancer patients undergoing radiotherapy were used for training (120 patients) and testing (30 patients). An unsupervised deep-learning method, the 2.5D RegGAN model with an adaptively trained registration network, was proposed, through which sCT images were generated. The quality of deep-learning-generated sCT images was quantitatively compared to the reference deformed CT (dCT) image using mean absolute error (MAE), root mean square error (RMSE) of Hounsfield units (HU), and peak signal-to-noise ratio (PSNR). The dose calculation accuracy was further evaluated for esophageal cancer radiotherapy plans, and the same plans were calculated on dCT, CBCT, and sCT images. RESULTS: The quality of sCT images produced by RegGAN was significantly improved compared to the original CBCT images. ReGAN achieved image quality in the testing patients with MAE sCT vs. CBCT: 43.7 ± 4.8 vs. 80.1 ± 9.1; RMSE sCT vs. CBCT: 67.2 ± 12.4 vs. 124.2 ± 21.8; and PSNR sCT vs. CBCT: 27.9 ± 5.6 vs. 21.3 ± 4.2. The sCT images generated by the RegGAN model showed superior accuracy on dose calculation, with higher gamma passing rates (93.3 ± 4.4, 90.4 ± 5.2, and 84.3 ± 6.6) compared to original CBCT images (89.6 ± 5.7, 85.7 ± 6.9, and 72.5 ± 12.5) under the criteria of 3 mm/3%, 2 mm/2%, and 1 mm/1%, respectively. CONCLUSION: The proposed deep-learning RegGAN model seems promising for generation of high-quality sCT images from stand-alone thoracic CBCT images in an efficient way and thus has the potential to support CBCT-based esophageal cancer adaptive radiotherapy.

Advances in Neuroimaging and Multiple Post-Processing Techniques for Epileptogenic Zone Detection of Drug-Resistant Epilepsy.

Among the approximately 20 million patients with drug-resistant epilepsy (DRE) worldwide, the vast majority can benefit from surgery to minimize seizure reduction and neurological impairment. Precise preoperative localization of epileptogenic zone (EZ) and complete resection of the lesions can influence the postoperative prognosis. However, precise localization of EZ is difficult, and the structural and functional alterations in the brain caused by DRE vary by etiology. Neuroimaging has emerged as an approach to identify the seizure-inducing structural and functional changes in the brain, and magnetic resonance imaging (MRI) and positron emission tomography (PET) have become routine noninvasive imaging tools for preoperative evaluation of DRE in many epilepsy treatment centers. Multimodal neuroimaging offers unique advantages in detecting EZ, especially in improving the detection rate of patients with negative MRI or PET findings. This approach can characterize the brain imaging characteristics of patients with DRE caused by different etiologies, serving as a bridge between clinical and pathological findings and providing a basis for individualized clinical treatment plans. In addition to the integration of multimodal imaging modalities and the development of special scanning sequences and image post-processing techniques for early and precise localization of EZ, the application of deep machine learning for extracting image features and deep learning-based artificial intelligence have gradually improved diagnostic efficiency and accuracy. These improvements can provide clinical assistance for precisely outlining the scope of EZ and indicating the relationship between EZ and functional brain areas, thereby enabling standardized and precise surgery and ensuring good prognosis. However, most existing studies have limitations imposed by factors such as their small sample sizes or hypothesis-based study designs. Therefore, we believe that the application of neuroimaging and post-processing techniques in DRE requires further development and that more efficient and accurate imaging techniques are urgently needed in clinical practice. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.

Fucoxanthin from marine microalgae: A promising bioactive compound for industrial production and food application.

Fucoxanthin attracts increasing attentions due to its potential health benefits, which has been exploited in several food commodities. However, fucoxanthin available for industrial application is mainly derived from macroalgae, and is not yet sufficiently cost-effective compared with microalgae. This review focuses on the strategies to improve fucoxanthin productivity and approaches to reduce downstream costs in microalgal production. Here we comprehensively and critically discuss ways and methods to increase the cell growth rate and fucoxanthin content of marine microalgae, including strain screening, condition optimization, design of culture mode, metabolic and genetic engineering, and scale-up production of fucoxanthin. The approaches in downstream processes provide promising alternatives for fucoxanthin production from marine microalgae. Besides, this review summarizes fucoxanthin improvements in solubility and bioavailability by delivery system of emulsion, nanoparticle, and hydrogel, and discusses fucoxanthin metabolism with gut microbes. Fucoxanthin production from marine microalgae possesses numerous advantages in environmental sustainability and final profits to meet incremental global market demands of fucoxanthin. Strategies of adaptive evolution, multi-stage cultivation, and bioreactor improvements have tremendous potentials to improve economic viability of the production. Moreover, fucoxanthin is promising as the microbiota-targeted ingredient, and nanoparticles can protect fucoxanthin from external environmental factors for improving the solubility and bioavailability.

Up-regulation of PPAR-γ involved in the therapeutic effect of icariin on cigarette smoke-induced inflammation.

Icariin (ICA) might be a potential anti-inflammatory medication in a variety of diseases including COPD, and previous studies showed that ICA could attenuate cigarette smoke (CS)-induced inflammation by inhibiting nuclear factor (NF)-κB. Peroxisome proliferator-activated receptor (PPAR) γ, a nuclear hormone receptor, has been reported to play a critical role in the inflammatory process in COPD. Whether PPAR-γ is involved in the anti-inflammatory effect of icariin on COPD has scarcely been explored. This study aimed at investigating the role of ICA in PPAR-γ expression in the CS-induced model, and then elucidating the therapeutic effects of ICA on COPD based on the PPARγ-NF-κB signaling pathway. The Beas-2B cells and H292 cells were induced with cigarette smoke extract (CSE) for 8 h after treatment with ICA for 16 h. The PPARγ expression and NF-κB pathway-related indicators were detected by western blotting, cellular immunofluorescence, and Real-time PCR. The PPARγ knock down or T0070907-treated Beas-2B cells were constructed to further investigate the relationship between the inhibition of NF-κB by ICA and PPARγ. A COPD model was established by CS exposure for 6 months, and ICA (40 mg/kg) was administrated by gastric perfusion. Then, the pulmonary function, lung histology, inflammatory cytokine levels, and protein expressions were detected. We found ICA up-regulated PPARγ protein expression in both Beas-2B cells and H292 cells, and it improved CSE-induced PPARγ down regulation and NF-κB activation. Furthermore, the inhibition of NF-κB pathway by ICA was partially dependent on PPARγ in the PPARγ knock down or T0070907-treated Beas-2B cells, suggesting that ICA attenuated CSE-induced inflammatory responses were associated with modulating the PPARγ-NF-κB pathway. Moreover, ICA showed similar effects on PPARγ and NF-κB expressions in the COPD model, and it effectively ameliorated the pulmonary function and lung inflammatory infiltration in the COPD rat model. Conclusively, the therapeutic effect of ICA on COPD was indirectly achieved by reducing airway inflammation, which was partially associated with modulating the PPARγ-NF-κB signaling pathway.

Efficacy and safety of a 14-day modified concomitant therapy for refractory Helicobacter pylori infection: a pilot study.

BACKGROUND AND AIM: After three treatment failures, Helicobacter pylori infection is deemed refractory as antibiotic treatment options become significantly limited. This study evaluated the efficacy and safety of a 14-day modified concomitant therapy for managing refractory H. pylori infection. METHODS: Patients who had failed to respond to three or more rounds of H. pylori therapies were recruited for this study. They received a 14-day modified concomitant therapy, including esomeprazole 40 mg, amoxicillin 1000 mg, and furazolidone 100 mg twice daily and tetracycline 500 mg four times daily. Demographic data, adverse events, and patient compliance were recorded. The presence of H. pylori was reevaluated 6 weeks following treatment. Eradication rate was assessed as the primary outcome. RESULTS: Overall, 59 participants received the 14-day modified concomitant therapy. In the intention-to-treat and per-protocol analyses, the eradication rate was 84.7% (50/59) and 89.3% (50/56), respectively. H. pylori was successfully isolated from 75.0% (12/16) of patients. The resistance rate of H. pylori to metronidazole, levofloxacin, and clarithromycin was 91.7% (11/12), 58.3% (7/12), and 50.0% (6/12), respectively. Resistance to amoxicillin, furazolidone, or tetracycline was not observed. The frequency of adverse events was 35.6% (21/59), with no serious adverse events reported. CONCLUSION: The 14-day modified concomitant therapy appears to be appropriate for refractory H. pylori infection and is particularly promising for the Chinese population. A randomized controlled trial is warranted to verify its efficacy, especially in the current environment of increasing antibiotic resistance.

Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation.

T helper 17 (TH17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor ß (TGFß) is instrumental in TH17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFß enables TH17 cell differentiation remains elusive. Here we reveal that TGFß enables TH17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGFß signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGFß neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFß stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFß-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable TH17 cell differentiation. This study reveals a critical mechanism by which TGFß controls TH17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating TH17-related diseases.

Aberrant modular segregation of brain networks in female patients with bulimia nervosa.

OBJECTIVE: Bulimia nervosa (BN) is an eating disorder associated with the dysfunction of intrinsic brain networks. However, whether the network disruptions in BN patients manifest as dysconnectivity or imbalances of network modular segregation remains unclear. METHOD: We collected data from 41 women with BN and 41 matched healthy control (HC) women. We performed graph theory analysis based on resting-state functional magnetic resonance imaging (RS-fMRI) data; then, we computed the participation coefficient (PC) among brain modules to characterize the modular segregation for the BN and HC groups. The number of intra- and inter-modular connections was calculated to explain the PC changes. Additionally, we examined the potential associations of the measures mentioned above with clinical variables within the BN group. RESULTS: Compared with the HC group, the BN group showed significantly decreased PC in the fronto-parietal network (FPN), cingulo-opercular network (CON), and cerebellum (Cere). Additionally, the number of intra-modular connections of the default mode network (DMN) and the number of the inter-modular connections between the DMN and CON, FPN and Cere, and CON and Cere in the BN group were lower than those in the HC group. The nodal level analysis showed that the BN group had a decreased PC of the anterior prefrontal cortex (aPFC), dorsal frontal cortex (dFC), inferior parietal lobule (IPL), thalamus, and angular gyrus. Further, these metrics were significantly correlated with clinical variables in the BN group. DISCUSSION: These findings may provide novel insights to capture atypical topologies associated with pathophysiology mechanisms and clinical symptoms underlying BN.

Butyrogenic effect of galactosyl and mannosyl carbohydrates and their regulation on piglet intestinal microbiota.

Diarrhea is a global problem that causes economic losses in the pig industry. There is a growing attention on finding new alternatives to antibiotics to solve this problem. Hence, this study aimed to compare the prebiotic activity of low-molecular-weight hydrolyzed guar gum (GMPS) with commercial manno-oligosaccharide (MOS) and galacto-oligosaccharide (GOS). We further identified their combined effects along with probiotic Clostridium butyricum on regulating the intestinal microbiota of diarrheal piglet by in vitro fermentation. All the tested non-digestible carbohydrates (NDCs) showed favorable short-chain fatty acid-producing activity, and GOS and GMPS showed the highest production of lactate and butyrate, respectively. After 48 h of fermentation, the greatest enhancement in the abundance of Clostridium sensu stricto 1 was observed with the combination of GMPS and C. butyricum. Notably, all the selected NDCs significantly decreased the abundances of pathogenic bacteria genera Escherichia-Shigella and Fusobacterium and reduced the production of potentially toxic metabolites, including ammonia nitrogen, indole, and skatole. These findings demonstrated that by associating with the chemical structure, GMPS exhibited butyrogenic effects in stimulating the proliferation of C. butyricum. Thus, our results provided a theoretical foundation for further application of galactosyl and mannosyl NDCs in the livestock industry. KEY POINTS: • Galactosyl and mannosyl NDCs showed selective prebiotic effects. • GMPS, GOS, and MOS reduced pathogenic bacteria and toxic metabolites production. • GMPS specifically enhanced the Clostridium sensu stricto 1 and butyrate production.