Sodium sulfite-driven Helicobacter pylori eradication: Unraveling oxygen dynamics through multi-omics investigation.

Due to the emergence and spread of multidrug resistance in Helicobacter pylori (H. pylori), its eradication has become difficult. Sodium sulfite (SS), a widely used food additive for ensuring food safety and storage, has been recognized as an effective nonbactericidal agent for H. pylori eradication. However, the mechanism by which H. pylori adapts and eventually succumbs under low- or no-oxygen conditions remains unknown. In this study, we aimed to evaluate the anti-H. pylori effect of SS and investigated the multiomics mechanism by which SS kills H. pylori. The results demonstrated that SS effectively eradicated H. pylori both in vitro and in vivo. H. pylori responds to the oxygen changes regulated by SS, downregulates the HcpE gene, which is responsible for redox homeostasis in bacteria, decreases the activities of enzymes related to oxidative stress, and disrupts the outer membrane structure, increasing susceptibility to oxidative stress. Furthermore, SS downregulates the content of cytochrome C in the microaerobic respiratory chain, leading to a sharp decrease in ATP synthesis. Consequently, the accumulation of triglycerides (TGs) in bacteria due to oxidative stress supports anaerobic respiration, meeting their energy requirements. The multifaceted death of H. pylori caused by SS does not result in drug resistance. Thus, screening of the redox homeostasis of HcpE as a new target for H. pylori infection treatment could lead to the development of a novel approach for H. pylori eradication therapy.

Patient-tailored dose reduction of tumor necrosis factor inhibitors in axial spondyloarthritis.

Tumor necrosis factor inhibitors have been widely used in the field of axial spondyloarthritis, with current guidelines now recommending dose reduction instead of withdrawal of biologics. Systemic review and meta-analyses in literature have summarized present tapering strategies and principles in published heterogeneous studies. In this study, we reviewed and provided an update on present evidence based on prospective and retrospective studies from 2008 to 2022 by performing a literature review of related publications on remission or relapse from PubMed. We further stated the core issues concerning dose reduction, including the timing, optimization, intensity, maintenance, monitoring, factors associated with tapering and solutions to de-escalation failure. Remission/relapse should be the principal consideration in dose reduction implementation for individuals without comorbidities. As a treat-to-target scope of this multifaceted systemic disease, extra-articular manifestations such as uveitis, psoriasis, inflammatory bowel disease, cardiovascular complication, hip involvement and progressed structural damage influence patient-tailored dose reduction plans. Safety concerns and costs should be integrated into the decision-making schedule to optimize the individualized dose reduction paradigm.

MRI lesions in SpA: a comparison with noninflammatory back pain using propensity score adjustment method.

Background: Magnetic resonance imaging (MRI) is important in the management of axial spondyloarthritis (SpA). However, many MRI lesions are not exclusive to axial SpA. Further characterization of these lesions may lead to better clinical decisions. Objective: The objective of this study was to compare the frequency of individual spinal MRI lesions between axial SpA and noninflammatory back pain. The factors associated with individual lesions in participants with axial SpA were also determined. Design: This was a cross-sectional observational study. Methods: MRI lesions in 447 participants with axial SpA and 122 participants with noninflammatory back pain were compared using the propensity score adjustment method. Individual lesions included discovertebral lesions (DVL), Modic type 1 lesions, DVL without Modic type 1 lesions, facet joint lesions, costovertebral joint lesions, corner inflammatory lesions (CIL), and fatty corner lesions (FCL). The factors associated with the lesions were determined using regression analyses. Results: Among participants with axial SpA, 81.9% were HLA-B27-positive, 55.0% had radiographic axial SpA, and 60.5% had radiographic features of spinal damage (mSASSS >2). Almost half (48.6% in axial SpA versus 31.1% in noninflammatory back pain) had inflammatory lesions on spinal MRI. In propensity score matching with noninflammatory back pain, axial SpA had an increased occurrence of DVL without Modic type 1 lesion (OR = 3.43, p = 0.01), costovertebral lesion (OR = 11.89, p = 0.02), number of CIL (B = 1.19, p < 0.001), and number of FCL (B = 3.33, p < 0.001). Similar associations were found in the regression models in the radiographic axial SpA subgroup: DVL without Modic type 1 lesion (OR = 2.46, p = 0.001), costovertebral lesion (OR = 3.86, p < 0.001), number of CIL (B = 1.13, p < 0.001), and FCL (B = 2.29, p < 0.01). Conclusion: MRI lesions including DVL without Modic type 1, costovertebral joint lesions, CIL, and FCL were more specific in axial SpA.

Benefits of tumor necrosis factor inhibitors for cardiovascular disease in ankylosing spondylitis.

Ankylosing spondylitis (AS) has been associated with an increased cardiovascular disease (CVD) risk, with current guidelines recommending multiple CVD-related risk assessment strategies. CVD risk prediction using a scoring model with lipids might be another promising alternative, for which ultrasound screening for subclinical atherosclerosis may be considered together with surrogate markers. Theoretically, tumor necrosis factor inhibitors (TNFi), which are known to inhibit endothelial activation and inflammation caused by the disease and underlying metabolic dysfunction, might prevent microvascular events. In this narrative review, we summarized the evidence of TNFi effects on CVD in AS. Although early case reports revealed that CVD occurred during TNFi treatment, more recent evidence shows that it could be successfully treated. Studies of TNFi on lipid changes and subclinical atherosclerosis have shown controversial results, possibly due to genetic predisposition, differences in affinity for membrane-bound TNF leading to insufficient inhibition of inflammation or primary failure response to TNFi, and not enough follow-up time to identify potential significance. Overall, patients vulnerable to CVD could benefit from long-term administration of TNFi when inflammation is under control. Besides healthy lifestyle modification, traditional CVD risk factors and metabolic syndrome-related diseases should be further assessed and treated if necessary.

Clinical, radiological, and magnetic resonance imaging characteristics of axial spondyloarthritis with late onset.

We aimed to investigate the clinical, diagnostic, and imaging features of patients with late onset axial spondyloarthritis (SpA) with initial symptom manifestation aged over 45 years. Participants with axial SpA were consecutively recruited. Clinical, demographic, blood, and imaging parameters were compared between the groups with early (≤45 years) and late onset (>45 years) at a cross-sectional level. Logistic regressions were used to determine the independent associations with axial SpA with late onset. A total of 455 participants were recruited. Among them, 70 (15.4%) had late onset disease. Multivariate analyses showed that axial SpA with late onset was associated with higher C-reactive protein based ankylosing spondylitis disease activity index (ASDAS-CRP) (B = 0.10; P = .04), higher intensity of spinal inflammation as measured by maximum apparent diffusion coefficient (spinal ADC max) (B = 0.27; P = .03) and mean ADC (spinal ADC mean) (B = 0.30; P = .004), lower modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) (B = -0.12; P = .02), more tender joint count (B = 0.12; P = .02), and fewer inflammatory back pain (IBP) (OR = 0.26; P < .001). Axial SpA with late onset had higher clinical disease activity, higher intensity of spinal MRI inflammation, less radiographic damage, and more tender joint count. There was also less inflammatory back pain, which could make the diagnosis more difficult.

The role and mechanism of 1,25-dihydroxyvitamin D3 in regulating the Rho-kinase signaling pathway in asthmatic rats.

BACKGROUND: Bronchial asthma (referred to as asthma in the present study) is the most common chronic airway inflammatory disease in childhood. The present study aimed to investigate the effect of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] on VDR expression, which is closely associated with asthmatic airway smooth muscle cells (ASMCs), and explored its role and mechanism in the Rho-kinase signaling pathway. METHODS: The acute asthma model was induced by ovalbumin (OVA) and pertussis bacillus, and ASMCs obtained from asthmatic rats were cultured in vitro. These cells were randomly divided into five groups: control (N) group, TNF-α (TNF) group, 1,25-(OH)2D3 (VD) group, dexamethasone (DXM) group, and 1,25-(OH)2D3 + DXM (L) group. The protein expression levels of VDR, ROCK, MLC20 and P-MLC20 were detected by western blot, and the mRNA expression levels of VDR, ROCK, MLC20 and P-MLC20 were detected by real-time quantitative PCR. RESULTS: The expression of ROCK, MLC20 and P-MLC20 in each treatment group were significantly lower, when compared to the TNF group (P<0.05), but this remained stronger than (P<0.05) or similar to (P>0.05) that in the N group. CONCLUSIONS: The regulation mechanism of 1,25-(OH)2D3 in alleviating asthma should be correlated to its regulation of the expression of related signaling molecules in the Rho-kinase signaling pathway, and this effect may be achieved by regulating the mRNA and protein expression of the VDR gene.

Prior transfusion of umbilical cord mesenchymal stem cells can effectively alleviate symptoms of motion sickness in mice through interleukin 10 secretion.

BACKGROUND: Motion sickness (MS) is a disease that occurs during unbalanced movement, characterized by gastrointestinal symptoms and autonomic nervous system activation. Current clinical treatments for MS are limited. Recent evidence indicates that the levels of pro-inflammatory cytokines increase during MS and are associated with an inner ear immune imbalance. In the present study, mesenchymal stem cells (MSCs) have been shown to exert strong immuno-suppressive effects. AIM: To explore whether umbilical cord-derived mesenchymal stem cells (UC-MSCs) can prevent the occurrence of MS, and the underlying mechanism regulated by MSCs in a mouse model of MS. METHODS: A total of 144 (equal numbers of males and females) 5wkold BALB/c mice were randomly divided into five groups: Normal group (n = 16), MS group (n = 32), MSCs group (n = 32), MS + MSCs group (n = 32), and MS + AS101/MSCs group (n = 32). The MSCs group (n = 32), MS + MSCs group (n = 32), and MS + AS101/MSCs group (n = 32) were preventively transplanted with UC-MSCs or AS101-treated UC-MSCs (1 × 106 cells/mouse). Mice in the MS (n = 32), MS + MSCs, and MS + AS101/MSCs groups were subjected to rotation on a centrifuge for 10 min at 8 × g/min for MS model establishment on days 3, 5, 8, and 10 after UC-MSCs injection. The Morris water maze (MWM) test was used to observe the symptom of dizziness. Enzyme-linked immunosorbent assay (ELISA) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to detect the levels of inflammatory cytokines in mice peripheral blood and the petrous part of the temporal bone samples. Western blot analysis was performed to analyze the JAK2/STAT3 signaling pathway in the cochlear tissues. Histological examination was performed by hematoxylin and eosin (HE) staining for conventional morphological evaluation in the petrous part of temporal bone samples. RESULTS: The MWM test demonstrated that UC-MSCs improved the symptoms of MS. The MS + MSCs group was faster than the MS group on days 3 and 5 (P = 0.036 and P = 0.002, respectively). ELISA and RT-qPCR showed that the serum and mRNA levels of interleukin-10 (IL-10) in the cochlear tissues were increased after transplantation with UC-MSCs (MS + MSCs group vs MS group at 3 and 5 d, P = 0.002 and c P < 0.001, respectively). RT-qPCR results confirmed a significant increase in IL-10 levels at four time points (MS + MSCs group vs MS group, P = 0.009, P = 0.009, P = 0.048, and P = 0.049, respectively). This suggested that UC-MSCs reduced the sensitivity of the vestibular microenvironment by secreting IL-10. Moreover, Western blot analysis showed that the MSCs activated the JAK2/STAT3 signaling pathway in the cochlear tissues. The levels of IL-10, IL-10RA, JAK2, STAT3, and phosphorylated JAK2 and STAT3 in the MS + MSCs group were increased compared to those of the MS group (P < 0.05). The morphological changes in the four groups showed no significant differences. The role of IL-10 secretion on the ability of UC-MSCs to successfully improve the symptoms of MS was confirmed by the diminished therapeutic effects associated with treatment with the IL-10 inhibitor ammonium trichloro (dioxoethylene-o,o') tellurate (AS101). CONCLUSION: Prophylactic transplantation of UC-MSCs can alleviate the clinical symptoms of MS in mice, particularly at 3-5 d after preventive transplantation. The mechanism for UC-MSCs to reduce the sensitivity of vestibular cortex imbalance may be the secretion of IL-10. The next step is to demonstrate the possibility of curing MS in the vestibular environment by intermittent transplantation of MSCs. Above all, MSCs are expected to become a new method for the clinical prevention and treatment of MS.

Head-to-Head Comparison of Etanercept vs. Adalimumab in the Treatment of Ankylosing Spondylitis: An Open-Label Randomized Controlled Crossover Clinical Trial.

Background: Anti-tumor necrosis factor biological agents had been proved to have a dramatic effect in ankylosing spondylitis (AS). We aimed to determine the efficacy and safety of crossover effects of adalimumab vs. etanercept in AS patients. Methods: A randomized, open-label crossover study was done in patients with active AS. Patients were randomized into two sequence groups, etanercept first (treatment arm) vs. adalimumab first (control arm) 8 weeks and then switched over for another 8 weeks. The primary endpoints were the difference of the Bath AS activity index and AS disease activity score (ASDAS)crp at week 16. Secondary endpoints were ASDASesr, ASAS20, and ASAS40 response rates and the proportion of patients achieving ASDAS inactive disease and low disease activity at weeks 8 and 16. Patient global assessment and preference was grading on a numerical scale. Results: A total of 21 patients were screened, and 19 of them were randomly allocated into the treatment arm (n = 9) and control arm (n = 9). At baseline, age, sex, Bath AS activity index, and ASDAS of both arms were comparable (p > 0.05). Both arms showed dramatic improvement, whereas no significance was observed between the changes of ASDAScrp (0.90 ± 1.39 vs. 1.24 ± 1.40 at week 8, p = 0.612; 1.02 ± 1.22 vs. 1.26 ± 1.44 at week 16, p = 0.707, respectively). ASAS20 and ASAS40 response rates were also comparable at week 8 (33 vs. 44%, p = 1.000; 22 vs. 22%, p = 1.000) and week 16 (22 vs. 22%, p = 1.000; 22 vs. 22%, p = 1.000), respectively. Both arms were well-tolerated without a serious adverse event. Adalimumab was relatively more favorable by patients in both arms, with a total mean grading score of 0.4 (-5-5, p = 0.218). Conclusion: Etanercept and adalimumab can both dramatically improve disease activity in 16 weeks. Crossover administration of etanercept and adalimumab revealed comparable efficacy and safety. Trial Registration: The protocol was approved by the Institutional Review Board with the register CS08019 from Chung Shan Medical University Hospital (CSMUH), Taichung, Taiwan and registered at ClinicalTrials.gov Protocol Registration and Results System: NCT02489760.

Ixekizumab for the treatment of ankylosing spondylitis.

INTRODUCTION: Ixekizumab (IXE) is a high affinity IgG4 approved for the treatment of ankylosing spondylitis (AS). Recently, two phase III randomized clinical trials (COAST-V, COAST-W) showed significant and sustained improvements in signs and symptoms of AS as evaluated by ASAS40 response. Areas covered: The authors performed a comprehensive literature search on this topic, by a review of published articles to date. The authors introduced the structure and the mechanism of action of IXE, and critically reviewed data from clinical trials, concerning its efficacy and safety in AS.Expert opinion: IXE proved dramatic efficacy and tolerable safety in patients with AS, in particular, patients with intolerance or insufficient response to TNFi, which provides an alternative and breakthrough for the treatment options of AS. IXE might not work in AS with IBD and uveitis involvement. Patients treated with IXE should be aware of candida infection in long term application.

Intensity of spinal inflammation is associated with radiological structural damage in patients with active axial spondyloarthritis.

OBJECTIVE: The aim was to investigate the relationship between the intensity of spinal inflammation using the apparent diffusion coefficient (ADC) and radiographic progression in axial SpA. METHODS: This is a cross-sectional study of participants with axial SpA and back pain. Clinical, biochemical and radiological parameters were collected. The ankylosing spondylitis disease activity score (ASDAS)-CRP was determined. Radiographic progression was represented by the modified Stoke ankylosing spondylitis spine score (mSASSS). MRI with short tau inversion recovery (STIR) and diffusion-weighted imaging sequences were performed simultaneously. Inflammatory lesions on STIR were used for the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI indexes and as references in outlining regions of interest in ADC maps to produce mean (ADCmean) and maximal (ADCmax) ADC values. Univariate and multivariate linear regression analyses were used to determine independent associations between ADC and radiographic progression. RESULTS: The 84 participants with identifiable lesions on spinal ADC maps recruited were characterized by a mean (s.d.) age of 45.01 (13.68) years, long disease duration [13.40 (11.01) years] and moderate clinical disease activity [ASDAS-CRP 2.07 (0.83)]. Multivariate regression analysis using ADCmean as the independent variable showed that age (regression coefficient [B] = 0.34; P = 0.01), male sex (B = 0.25; P = 0.04) and ADCmean (B = 0.30; P = 0.01) were positively associated with mSASSS. Multivariate regression analysis using ADCmax as the independent variable showed a tendency for ADCmax to be associated with mSASSS (B = 0.21; P = 0.07). CONCLUSION: The intensity of spinal inflammation as determined by ADC is associated with radiographic progression in participants with active axial SpA.